bims-proteo Biomed News
on Proteostasis
Issue of 2026–08–16
sixty-five papers selected by
Eric Chevet, INSERM
  1. The integrated stress response kinase GCN2 prevents ZAKα-Dependent inflammatory hyperactivation in macrophages.
  2. Structures of the UBR4 complex reveal a giant arena to capture diverse substrates for ubiquitin chain elongation.
  3. Decoding the impact of lipid saturation on ER signaling networks, ERSU, UPR, and ERAD.
  4. Principles of ribosome-associated protein quality control during the synthesis of CFTR.
  5. The role of N-glycans and their processing in ER-to-lysosome-associated degradation of disease-causing mutant Neuroserpin.
  6. Dissecting PROTAB-mediated degradation of cell surface proteins.
  7. The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
  8. Studying Glycan-Dependent ERAD of Misfolded Glycoproteins in Plants.
  9. TBK1 puts the brakes on IRGQ-mediated autophagy.
  10. New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
  11. ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.
  12. Temporal gating dictates stress-induced transcript export from the nucleus.
  13. Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.
  14. Torsins organize CLCC1 assembly to safeguard ER bilayer and lipid homeostasis.
  15. An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
  16. Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.
  17. Enhanced folding capacity of green fluorescent protein facilitates vacuolar trafficking of carboxypeptidase Y.
  18. BOULE is Essential for the Dynamic Disassembly of Heat Shock Granules in Male Germ Cells.
  19. Chrysosplenetin-induced TMED3 aggregation triggers unfolded protein response in pancreatic cancer.
  20. Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
  21. Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
  22. Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
  23. Mapping interaction of assembly factor Rpn14 with the proteasome base reveals a bipartite interface and implies ordered remodeling of intersubunit contacts during proteasome biogenesis.
  24. The dystonia-associated Torsin1A sustains CLCC1 function in membrane fusion of the nuclear envelope for NPC biogenesis.
  25. The ARLA1A-NAC089 module coordinates ER phagy with the unfolded protein response to maintain cellular homeostasis in plants.
  26. Proteome-wide identification of the druggable CRBN interactome.
  27. 3'UTR-directed, kinase-proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells.
  28. SsrA-Based Targeted Protein Degradation in Escherichia coli.
  29. A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
  30. Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.
  31. A ubiquitin chain-feeding mechanism for BRCA1-A.
  32. Phosphatidylserine synthesis tunes IP3R-mediated ER Ca2+ release via phospholipid homeostasis.
  33. Dual-Organelle Secretome Conjugation and Organ-Uptake Tracking (DuO-SCOUT) Enables Deep and Sensitive Mapping of the Secreted Proteins.
  34. Retromer mediates Ypt7-dependent lipid droplet internalization.
  35. The Sec11 C-terminal short helix promotes productive engagement of internal signal sequences with the signal peptidase complex.
  36. Stress granules confer an early vulnerability in KRAS-driven pancreatic tumorigenesis.
  37. Neddylation-dependent RAB40-Cullin5 E3 ligase complex controls ubiquitin-mediated proteasomal degradation of DNAJC13.
  38. The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.
  39. Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex.
  40. Polyamines buffer labile iron to suppress ferroptosis.
  41. Deubiquitinase-targeting chimeras (DUBTACs): a game-changing approach for targeted protein stabilization in drug discovery.
  42. In-situ cryo-ET of mouse embryos reveals cytoplasmic lattices contain ubiquitin-charged E2-E3 ligase assemblies.
  43. Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
  44. USP8 controls proteostasis pathways in B cells and multiple myeloma.
  45. Senecavirus a 3C protease cleaves RETREG1 to antagonize ER-phagy and promote viral replication via endoplasmic reticulum calcium signaling.
  46. The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3.
  47. Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
  48. UbiSite Approach: Global Site-Specific Profiling of Canonical and Non-Canonical Ubiquitination in Cells and Tissues.
  49. Mapping the architecture of protein complexes in Arabidopsis using cross-linking mass spectrometry.
  50. Cardiovascular Diseases and Cancer: Convergent Proteostasis Networks at the Crossroads of Mechanisms and Therapeutic Opportunities.
  51. Codon optimization depletes stop codons in alternative reading frames of protein-coding nucleic acid therapeutics.
  52. Mechanism of Autophagic Extracellular Vesicles Revealed.
  53. Sparsomycin inhibits translation through a conserved mechanism across all domains of life.
  54. FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
  55. Protein persulfidation emerges as a conserved component of the redox response to DNA damage.
  56. Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
  57. RING-type E3 ligase RhSAREL promotes flower senescence by differentially regulating two TMBIM family members, RhTMBIM1 and RhTMBIM7, in Rosa hybrida.
  58. Stress-induced remodeling of membrane-bound organelles in budding yeast.
  59. Protocol for proteomic profiling of hypusinated protein candidates using a clickable spermidine probe.
  60. p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
  61. E3 ligase RNF145 regulates airway smooth muscle cell proliferation via the PP2A-p70S6K signaling axis.
  62. RNF5 promotes acute lung injury through HSPA5 ER-to-cytosol translocation and resultant PERK activation.
  63. Wiring autophagy: Neural circuits regulate lysosomal homeostasis in muscle.
  64. Molecular insights into NLRP1 Gly/N-degron recognition by CRL2ZER1.
  65. Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors.
  1. J Biol Chem. 2026 Aug 14. pii: S0021-9258(26)02324-0. [Epub ahead of print] 113452
    The integrated stress response kinase GCN2 prevents ZAKα-Dependent inflammatory hyperactivation in macrophages.
    R D Requião, L F Lima-Silva, P Estevão, Wlg Costa, N C Zani, I C Vasconcelos, Iep Silva, T T Xu, Hma Prado, B Steingenberger, M H Bengtson, P J Murray, P M Moraes-Vieira.
      Macrophages orchestrate inflammation through rapid and extensive proteome remodeling, yet the translational programs governing macrophage activation remain poorly defined. Here, we show that classically activated macrophages (LPS+IFNγ-treated) and alternatively activated macrophages (IL-4-treated) engage fundamentally distinct translational trajectories. Whereas alternatively activated macrophages sustain elevated protein synthesis, classically activated macrophages undergo a rapid but transient increase in translation that is subsequently restrained by the integrated stress response (ISR) kinase General Control Nonderepressible 2 (GCN2). Using puromycin incorporation, polysome profiling, and quantitative proteomics, we demonstrate that GCN2-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) limits global translation and constrains the pro-inflammatory response. Genetic loss of GCN2 results in excessive translation and hyperinflammation driven by the ribosome-associated stress sensor ZAKα (MAP3K20). Importantly, pharmacological inhibition of ZAKα in GCN2-deficient macrophages selectively normalizes tumor necrosis factor α (TNFα) secretion, establishing a functional regulatory axis in which GCN2 suppresses ZAKα-dependent inflammatory signaling. Together, these findings redefine translational control as a central checkpoint in macrophage activation, revealing how GCN2 mitigates ribosomal stress to prevent inflammatory hyperactivation, with potential therapeutic implications for TNFα-driven inflammatory diseases.
    Keywords:  GCN2 signaling; Translation control; ZAKα pathway; inflammation regulation; macrophage activation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113452
  2. FEBS J. 2026 Aug 11.
    Structures of the UBR4 complex reveal a giant arena to capture diverse substrates for ubiquitin chain elongation.
    Daniel B Grabarczyk, Tim Clausen.
      Ubiquitin ligases, members of the protein quality control machinery, target misassembled, and mislocalized proteins for degradation by tagging them with ubiquitin. The giant ubiquitin ligase UBR4 has emerged as a central regulator of protein fate by selecting a wide range of ubiquitinated protein substrates and extending degradative K48-linked chains on them-an activity which classifies it as an E4 ligase. Recent cryo-EM structures of full-length UBR4 in complex with its cofactors KCMF1 and calmodulin, combined with crystal structures of key domains, reveal how UBR4 employs a giant arena lined with substrate-binding domains to capture defective proteins, as well as the mechanism of K48-specific ubiquitin chain extension. Here, we review this structural and mechanistic data and discuss how it connects the diverse cellular functions of UBR4.
    Keywords:  E4 ligase; N‐degrons; cryo‐EM; protein quality control; ubiquitin ligase
    DOI:  https://doi.org/10.1111/febs.70690
  3. PLoS One. 2026 ;21(8): e0345910
    Decoding the impact of lipid saturation on ER signaling networks, ERSU, UPR, and ERAD.
    Xia Li, Maho Niwa.
      The faithful inheritance of a functional endoplasmic reticulum (ER) in Saccharomyces cerevisiae is safeguarded by the ER Stress Surveillance (ERSU) checkpoint, which delays cytokinesis when ER homeostasis is perturbed. Under stress, ER transmission to the daughter cell is halted, while in parallel-but through independent pathways-the Unfolded Protein Response (UPR) restores ER function and ER-associated degradation (ERAD) eliminates misfolded proteins, ultimately allowing cell cycle re-entry. ER stress also transiently stimulates sphingolipid biosynthesis, with the intermediate phytosphingosine (PHS) acting as a key activator of ERSU. Yet how broader lipid parameters-such as membrane composition and saturation-reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To begin addressing this question, a tightly controlled experimental system was employed to selectively alter lipid saturation while monitoring ER inheritance within the context of ER homeostasis maintained by the UPR and ERAD. This analysis revealed that perturbations in lipid saturation exert specific effects on ER inheritance that are distinct from their impact on UPR activation and ERAD efficiency. These findings support a central role for lipid homeostasis in ER functional regulation and suggest that membrane lipid composition contributes to the coordination of ERSU, UPR, and ERAD during ER inheritance under stress.
    DOI:  https://doi.org/10.1371/journal.pone.0345910
  4. EMBO J. 2026 Aug 12.
    Principles of ribosome-associated protein quality control during the synthesis of CFTR.
    Tom Joshua Oldfield, Raquel Gonçalves Torres, Romy Enrica Baier, Robin Renn, Débora Broch Trentini.
      Prolonged translational arrests caused by defective mRNAs activate the ribosome-associated protein quality control (RQC) pathway, which marks harmful incomplete proteins for degradation. Multipass transmembrane proteins have increased propensity to be targeted by the RQC, raising the question of whether problems in transmembrane domain insertion and assembly can also cause RQC-eliciting translational arrests. Here, we investigated RQC-mediated quality control of CFTR, a large transmembrane protein mutated in cystic fibrosis. Reporter assays showed that although a fraction of nascent CFTR expressed in HEK293 cells arrested during translation and activated the RQC, multiple interventions compromising CFTR folding and membrane insertion did not exacerbate this response. CFTR translation abortion was also largely unaffected by regulators of translation kinetics such as codon usage, the ribosome collision sensor GCN1, and the SRP ER targeting complex. We propose that the RQC can be triggered by the inherent difficulties in synthesizing transmembrane segments, resulting from their inappropriate interaction with the protein synthesis machinery. Our study uncovers and characterizes a novel physiological role for the RQC in dealing with elongation-arrested transmembrane proteins.
    DOI:  https://doi.org/10.1038/s44318-026-00883-0
  5. Autophagy Rep. 2026 ;5(1): 2712797
    The role of N-glycans and their processing in ER-to-lysosome-associated degradation of disease-causing mutant Neuroserpin.
    Carolin Hoefner, Ilaria Fregno, Maurizio Molinari.
      Most proteins synthesized in the endoplasmic reticulum (ER) are covalently modified upon addition of pre-assembled oligosaccharides to side chains of asparagine (N) residues. Processing of N-linked oligosaccharides by ER-resident glucosidases, mannosidases and glucosyltransferases determines the fate of the associated polypeptides. Terminally glucose residues are removed from N-glycans to interrupt the engagement of ER-resident glucose-binding chaperones and promote secretion of native polypeptides. Mannose residues are removed to target terminally misfolded proteins for dislocation across the ER membrane and clearance by the cytoplasmic ubiquitin proteasome system (ER-associated degradation, ERAD). Recent evidence highlights the role of persistent N-glycan glucosylation as a signal that promotes ER lectins-driven segregation of misfolded proteins in ER subdomains that are eventually delivered to endolysosomal compartments for ER-to-Lysosome-Associated Degradation (ERLAD). Here we show that the polymerization-prone Portland variant of Neuroserpin (NS_PL) associated with familial encephalopathy with NS inclusion bodies (FENIB) is a client of the ERLAD machinery. Its lysosomal clearance relies on the LC3-dependent delivery branch of ERLAD involving the lectin chaperone Calnexin (CNX), the ERphagy receptor FAM134B and the SNARE protein Syntaxin17 (STX17), which is engaged upon persistent glucosylation of the NS_PL oligosaccharide linked at the asparagine residue at position 321.
    Keywords:  Conformational disease; ERLAD; ERphagy; N-glycosylation; Neuroserpin
    DOI:  https://doi.org/10.1080/27694127.2026.2712797
  6. FEBS J. 2026 Aug 10.
    Dissecting PROTAB-mediated degradation of cell surface proteins.
    Jieyan He, Tao Sun, Mengwen Zhang, Alicia Sanoyca, Wen-Ting K Tsai, Yee-Seir Kee, Nicholas J Agard, Jing Li.
      Targeted protein degradation mediated by antibodies has emerged as a promising strategy for degrading extracellular or membrane-bound proteins. Proteolysis-Targeting Antibodies (PROTABs) are bispecific antibodies specifically designed to induce the degradation of membrane proteins by tethering them to a cell surface E3 ligase, which promotes ubiquitination and subsequent degradation. Recent studies have demonstrated the potential of PROTABs to degrade oncogenic receptors, but their underlying mechanisms remain to be fully elucidated. Here, we investigated the mechanism of action of a HER2-targeting PROTAB comprising an anti-Zinc and RING finger protein 3 (ZNRF3) arm and an anti-receptor tyrosine-protein kinase erbB-2 (HER2) arm. We show that PROTAB induces rapid ternary complex formation, followed by receptor internalization and degradation, resulting in ~ 85% target depletion within 24 h. Mechanistically, ubiquitination enhances but is not strictly required for internalization, and degradation proceeds predominantly through the lysosomal pathway. Notably, ZNRF3 is not codegraded but instead accumulates at the cell surface, while the PROTAB antibody itself is largely recycled. Importantly, target degradation does not consistently translate into growth inhibition, highlighting the role of cellular context and target dependency. Together, these findings provide a mechanistic framework for PROTAB function and inform the rational design of next-generation antibody-based degraders.
    Keywords:  E3 ubiquitin ligase; HER2; Internalization; PROTABs; Protein degradation; Ternary complex; Ubiquitination; ZNRF3
    DOI:  https://doi.org/10.1111/febs.70670
  7. Open Biol. 2026 Aug 12. pii: 260021. [Epub ahead of print]16(8):
    The p97 adaptor p47/NSFL1C is necessary for stress granule dissolution after heat stress.
    Michelle A Johnson, Richa Khanna, Sirisha Mukkavalli, Ly Nguyen, Malavika Raman.
      Stress granules form in response to diverse cellular perturbations to sequester translation components until the stress is resolved. Stress granules are composed of RNA-protein assemblies in membrane-delimited structures and must be rapidly disassembled to release components to allow translation to resume. Disassembly of stress granules formed in response to heat stress is dependent on ubiquitylation of stress granule components such as G3BP1. Ubiquitylation of stress granule proteins recruits the AAA-ATPase p97 (also known as VCP) to enable ubiquitin-dependent disassembly of these structures. Loss of p97 activity leads to the persistence of stress granules and is implicated in several age-related neurodegenerative diseases. Here, we show that p97 recruitment to stress granules is dependent on its ubiquitin-binding co-factor p47. p47 translocates to stress granules in response to a variety of cellular stressors and is required for the recruitment of p97 to stress granules. Loss of p47 leads to an inhibition in stress granule disassembly. We further show that p47 associates with G3BP1 in response to heat stress in a ubiquitin-dependent manner. Taken together, our data add to the growing list of p97 adaptors that are implicated in the recruitment of p97 for the dissolution of stress granules.
    Keywords:  VCP; degradation; phase separation; stress granule; ubiquitin
    DOI:  https://doi.org/10.1098/rsob.260021
  8. Methods Mol Biol. 2026 ;3069 157-168
    Studying Glycan-Dependent ERAD of Misfolded Glycoproteins in Plants.
    Ulrike Vavra, Christiane Veit, Richard Strasser.
      The endoplasmic reticulum (ER) is the site where proteins that are synthesized and destined for the secretory pathway fold into their native conformations. Genetic mutations, oxidative stress, reduced glycosylation, and disruption to ER folding and quality control systems are all factors that have been demonstrated to impair this process, leading to the production of misfolded proteins. It is imperative for the survival of cells that these misfolded proteins are recognized by specific signals and directed towards degradation via ER-associated degradation (ERAD), ER-phagy, or related ER-to-lysosome/vacuole transport processes. A pivotal step in this process is the recognition of specific degrons and the distinction between terminally misfolded proteins that necessitate clearance and folding intermediates that have the potential to reach their final conformation. A significant proportion of proteins that traverse the secretory pathway in eukaryotes undergo N-glycosylation. The attached N-glycans not only facilitate the folding and quality control of glycoproteins, but can also be processed to display a glycan degron signal necessary to initiate ERAD of glycoproteins. Here, we describe methods for investigating glycan-related degrons that are key determinants for the ERAD of misfolded glycoproteins in plants.
    Keywords:  Arabidopsis thaliana; ERAD; Glycoprotein; N-glycosylation; Protein degradation; Quality control
    DOI:  https://doi.org/10.1007/978-1-0716-5508-5_11
  9. Autophagy. 2026 Aug 10.
    TBK1 puts the brakes on IRGQ-mediated autophagy.
    Lina Herhaus.
      Selective autophagy requires cargo receptors that not only recognize substrates but also coordinate their engagement with the autophagy machinery. Our findings identify IRGQ as a signaling-sensitive organizer of autophagy initiation rather than a passive cargo adaptor. IRGQ contains two distinct LC3-interacting region motifs: one with unusual selectivity for GABARAPL2 and another that supports broader interaction with LC3-family proteins. Proteomics, co-immunoprecipitation and imaging place the IRGQ-GABARAPL2 complex at the interface between hATG8 proteins and core autophagy-initiation components, including ATG3, ATG7, ULK1 and ATG13. Consistently, IRGQ expression promotes hATG8 lipidation and correlates with increased LC3B puncta, supporting a model in which IRGQ nucleates a local initiation hub that couples cargo recognition to autophagosome formation. Unexpectedly, this hub is negatively regulated by TBK1. TBK1-dependent phosphorylation of GABARAPL2 at serine 10 does not broadly disrupt canonical LDS-mediated interactions, but selectively destabilizes the IRGQ-GABARAPL2 complex and weakens association with autophagy-initiation factors. This phosphorylation is induced during selective-autophagy-associated conditions, including mitophagy, xenophagy and IFNγ treatment, but not during starvation-induced bulk autophagy. Functionally, GABARAPL2 S10 phosphorylation leaves LC3 and p62 bulk-autophagy readouts largely intact while reducing GABARAPL2 flux and impairing lysosomal delivery of HLA, an IRGQ cargo. Thus, TBK1 acts as a context-dependent negative regulator of a receptor-specific autophagy axis, revealing that kinase signaling can tune selective autophagy by controlling the stability and lifetime of receptor-centered initiation hubs.
    Keywords:  Autophagy; GABARAPL2; HLA quality control; IRGQ; TBK1; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2716595
  10. Autophagy. 2026 Aug 12. 1-3
    New insights into the molecular regulation of bridge-like lipid transfer proteins revealed by the Atg2-Atg18 structure.
    Sabrina Chumpen Ramirez, Dmitry Shvarev, Fulvio Reggiori, Christian Ungermann.
      Atg9-Atg2-Atg18 complexes are essential for the biogenesis of the autophagosome as they mediate the elongation of the phagophore, the precursor structure of autophagosomes. This event occurs by the transfer of lipids through a membrane contact site (MCS) between the phagophore and the endoplasmic reticulum exit sites (ERES). The bridge-like lipid-transfer protein (BLTP) Atg2 interacts with the Atg9 and phosphatidylinositol-3-phosphate (PtdIns3P) on the phagophore and acts as a tether to establish this MCS. While not essential to form the phagophore-ERES MCS, Atg18 plays a crucial role in the phagophore elongation by stimulating Atg2 lipid transfer activity, based on in vitro experiments. To understand the molecular basis of this regulation, we recently solved the structure of the yeast Atg2-Atg18 complex using cryo-electron microscopy (cryo-EM) and identified the critical region in Atg2 required for the Atg2-Atg18 complex formation. Importantly, we applied structure-function analyses to unveil the molecular mechanism behind the Atg18-mediated stimulation of Atg2. We showed that Atg18 binding to Atg2 induces a structural repositioning of the hydrophobic cavity of Atg2 toward the membrane, which allows efficient transfer of lipids from the endoplasmic reticulum to the phagophore. Here, we summarize our recent work and extend our discussion on the molecular regulation of the lipid transfer activity, highlighting open questions concerning the function of the Atg9-Atg2-Atg18 module in the phagophore-ERES MCS.Abbreviations: ATG, autophagy related; BLTP, bridge-like lipid-transfer protein; cryo-EM, cryo-electron microscopy; ER, endoplasmic reticulum; ERES, ER exit sites; MCS, membrane contact site; PAS, phagophore assembly site; PtdIns3P, phosphatidylinositol-3-phosphate; TRAPPIII, transport protein particle III.
    Keywords:  Atg18; Atg2; Atg9; autophagy; lipid transfer; phosphatidylinositol-3-phosphate
    DOI:  https://doi.org/10.1080/15548627.2026.2716596
  11. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00910-1. [Epub ahead of print]45(8): 117832
    ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models.
    Matthew D Demmings, Erica A Kane, Elizabeth C Tennyson, Kate Hurley, Joy Zhao, Nicholas A Cruickshanks, Victoria Ciz, Jordan M Krupa, Stephen H Pasternak, Sean P Cregan.
      The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and α synucleinopathy models of PD in vitro and in vivo. We show that sustained activation of ATF4, the central ISR transcription factor, induces the coordinated transcriptional upregulation of SESN2, DDIT4, and Trib3, which cooperate to suppress both mTORC1 and mTORC2 activity. This ATF4-dependent inhibition of mTOR signaling promotes dopaminergic neuron death by facilitating activation of the pro apoptotic BCL 2 family protein PUMA. Together, these findings define a maladaptive ISR/ATF4-mTOR pathway with potential therapeutic relevance for neurodegenerative disorders characterized by chronic ISR activation.
    Keywords:  ATF4; CP: molecular biology; CP: neuroscience; ISR; PUMA; dopaminergic neurons; integrated stress response; mTOR; neurodegeneration; α-synuclein
    DOI:  https://doi.org/10.1016/j.celrep.2026.117832
  12. Genes Dev. 2026 Aug 11.
    Temporal gating dictates stress-induced transcript export from the nucleus.
    Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Prior studies have largely focused on transcriptional and translational control during stress, but how regulated nuclear mRNA export contributes to the stress response remains unresolved. We show that nuclear mRNA export is progressively inhibited during arsenite and heat stress in human cells. In contrast to previous work largely in yeast that suggests nuclear export of stress-induced transcripts is prioritized through sequence-specific mechanisms, we found that mRNA export is governed by temporal gating, in which the timing of mRNA biogenesis determines the nucleocytoplasmic distribution of mRNAs during stress. Using single-molecule mRNA imaging and transcriptome-wide analyses, we observe the majority of stress-induced mRNAs, including heat shock protein transcripts, accumulate in the nucleus during stress. However, a subset of stress-induced mRNAs, notably HMOX1, JUN, and FOS, escape nuclear retention. mRNAs transcribed early during stress, including those encoding immediate early genes, redox mediators, and protein chaperones, are exported from the nucleus prior to the global inhibition of mRNA export. In contrast, mRNAs transcribed later are retained in the nucleus until stress is resolved. Reporter RNA assays confirm that transcriptional timing determines mRNA export competence. This work reveals that the timing of mRNA production, rather than transcript-specific sequence features, is the major determinant of nuclear export efficiency of stress-induced transcripts in human cells.
    Keywords:  heat shock proteins; heat shock response; integrated stress response; nuclear export; stress-induced genes
    DOI:  https://doi.org/10.1101/gad.353896.126
  13. PLoS Genet. 2026 Aug;22(8): e1012273
    Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.
    Katherine S Yanagi, Brenda J Chen, Sheikh Omar Kunjo, Irini Topalidou, Nicolas Lehrbach.
      The ubiquitin proteasome system (UPS) is the primary mechanism for targeted protein degradation in eukaryotic cells. Dysfunction of this system is a driver of human disease and a hallmark of aging and late-onset neurodegenerative disorders. Understanding the mechanisms that ensure robust protein turnover may provide new avenues for treatment in these contexts. E3 ubiquitin ligases play critical roles in supplying ubiquitinated substrates to the proteasome, with HUWE1 being an enormous, versatile, and highly conserved member of this family. Here, we show that the C. elegans HUWE1 ortholog EEL-1 contributes to robust protein turnover, particularly during conditions that challenge the proteolytic capacity of the proteasome. We demonstrate that the ability of EEL-1/HUWE1 to safeguard protein turnover requires the HECT-type ubiquitin ligase activity, supporting a model in which EEL-1 ensures degradation via substrate ubiquitination. EEL-1 contains extensive lysine-deficient regions, found at conserved locations in its substrate-binding arena. Through unbiased mutagenesis screening and precise engineering of the EEL-1 protein, we uncover that introducing lysine residues into these regions is detrimental to UPS function and to animal physiology. Together, our findings indicate a central and evolutionarily ancient role for EEL-1/HUWE1 in maintaining optimal UPS function and support targeting this E3 for therapeutic manipulation.
    DOI:  https://doi.org/10.1371/journal.pgen.1012273
  14. Mol Cell. 2026 Aug 04. pii: S1097-2765(26)00503-4. [Epub ahead of print]
    Torsins organize CLCC1 assembly to safeguard ER bilayer and lipid homeostasis.
    Yonglun Wang, Renqian Wang, Yuanhang Yao, Rongxian Hou, Lu Yan, Yiechang Lin, Yating Hu, Youlei Li, Lingzhi Wu, Yuangang Zhu, Ning Gao, Chen Song, Xiao Wang, Zhejian Ji, Xiao-Wei Chen.
      The TMEM41B scramblase and its regulatory partner CLCC1 initiate lipid flux by equilibrating newly synthesized phospholipids across the endoplasmic reticulum (ER) bilayer, a fundamental process required for diverse events ranging from membrane biogenesis to bulk lipid supply. Loss of CLCC1/TMEM41B causes ER bilayer imbalance, which induces giant ER-enclosed lipid droplets (geLDs) and drives rapid progression into severe metabolic-dysfunction-associated steatohepatitis (MASH). Combining both human cell lines and mouse models, we herein reveal CLCC1 to be the long-missing client of the luminal torsin ATPases, which selectively engage oligomerized CLCC1 at sites of ER bilayer imbalance. Mice hepatic torsinA inactivation triggers geLD formation amid disrupted lipoprotein biogenesis and severe MASH, closely phenocopying CLCC1/TMEM41B deficiency. Mechanistically, torsins act as assembly-promoting ATPases that drive CLCC1 oligomerization for its recruitment to imbalanced bilayers. Remarkably, ectopic CLCC1 expression reverses cellular and systemic lipid disorders arising from hepatic torsinA deficiency. Hence, torsin ATPases emerge as fundamental regulators that organize CLCC1 and the downstream TMEM41B scramblase to govern lipid partitioning and membrane homeostasis.
    Keywords:  AAA+ ATPase; ER membrane homeostasis; lipid metabolism; torsins
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.017
  15. Autophagy. 2026 Aug 13. 1-11
    An expanding role for ATG8s and ATG8 E3-like ligases in maintaining membrane integrity.
    Dale P Corkery, Yao-Wen Wu.
      Endolysosomal membranes are frequently damaged by pathogenic stress associated with aging, infection, and neurodegeneration, and failure to repair such damage leads to inflammation and cell death. Recent advances identify membrane ATG8 conjugation (atg8ylation) as a key process that links damage detection to coordinated lysosomal repair, removal, and regeneration. Beyond its canonical role in macroautophagy, membrane atg8ylation also occurs on preexisting, non-autophagosomal single membranes through Conjugation of ATG8s to Single Membranes (CASM), positioning this pathway as a rapid response to membrane stress. Two E3-like ligase complexes, ATG16L1-ATG5-ATG12 and TECPR1-ATG5-ATG12, act as complementary sensors of lysosomal injury by detecting distinct physicochemical cues, including proton gradient collapse and lipid scrambling. These ligases convert damage signals into spatially restricted membrane atg8ylation, generating a membrane-associated platform that coordinates multiple downstream pathways. These include ESCRT-dependent membrane repair, ER-lysosome lipid transfer, membrane tubulation, and stress granule formation. When repair fails, membrane atg8ylation regulates lysophagy and activates lysosomal biogenesis and regeneration to restore lysosomal homeostasis. These emerging findings define membrane atg8ylation as a central organizer of membrane quality control rather than a pathway merely confined to macroautophagy. In this review, we summarize the current understanding of how membrane atg8ylation detects lysosomal damage and how this pathway coordinates other lysosomal quality control mechanisms to maintain lysosomal integrity.
    Keywords:  CASM; Lysosome; lysosomal membrane integrity; membrane atg8ylation; noncanonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2704442
  16. J Physiol. 2026 Aug 11.
    Development of a protein synthesis network at the sarco/endoplasmic reticulum in adult cardiac myocytes.
    Christoph Sandmann, Sören Brandenburg, Dennis Uhlenkamp, Bianca Meyer, Clara Sandmann, Nicole Herzog, Julia Groß, Charlotta Funaya, Hugo A Katus, Stephan E Lehnart, Christopher C Glembotski, Mirko Völkers, Shirin Doroudgar.
      The endoplasmic reticulum (ER) is the primary site for the synthesis and folding of membrane and secretory proteins, which together comprise a large fraction of the total protein output in mammalian cells. Striated muscle cells contain a specialized membrane system, the sarcoplasmic reticulum (SR), which regulates calcium homeostasis and contraction. However, the biochemical and physiological relationship between the ER and SR, as well as the extent to which both compartments contribute to protein synthesis, remain incompletely understood. Quantification of ER- and SR-associated proteins in isolated ventricular cardiac myocytes revealed that the relative abundance of ER/SR-resident protein quality control components and ribosomes decreased during postnatal maturation, whereas SR-associated Ca2 +-handling proteins increased. Immunocytochemistry revealed that the membrane compartment prominent in early postnatal stages exhibits predominantly ER characteristics and diminishes during postnatal development. In adult cardiac myocytes, the SR becomes the dominant membrane network throughout the cell, while ER markers remain enriched in the perinuclear region. Immunocytochemistry further indicated that the ER and SR perform overlapping yet distinct specialized functions, with excitation-contraction coupling localized to the SR, and initiation of secretion concentrated within the ER. In adult ventricular cardiac myocytes, ribosomes and mRNA localize adjacent to both the ER and SR, indicating their roles as direct sites of localized protein synthesis and homeostasis. These findings demonstrate that molecular differentiation and structural organization of the ER/SR during cardiac muscle development culminate in a specialized protein synthesis network within the sarco/endoplasmic reticulum of adult myocytes. KEY POINTS: Although the sarcoplasmic reticulum (SR) is the established centre for calcium regulation in striated muscle, its role in membrane and secreted protein synthesis has remained unknown. It has remained unclear whether the endoplasmic reticulum (ER) and SR coexist as distinct membrane networks in cardiac myocytes or whether they form a single system that fulfills both calcium-handling and protein synthesis functions. We found that postnatal cardiac maturation involves a major reorganization in which the centralized, ER-dominant network of neonatal myocytes is replaced by an expansive, SR-dominant network in the adult cell periphery, while ER markers become largely confined to the perinuclear region. Using stimulated emission depletion super resolution microscopy and electron microscopy, we demonstrated that active ribosomes and mRNA associate with the longitudinal SR but are spatially excluded from ryanodine receptor 2-rich junctional zones. Our results establish that the SR functions as a specialized, distributed protein synthesis network that enables adult cardiac myocytes to maintain their highly organized cellular architecture through localized translation.
    Keywords:  cardiac myocytes; endoplasmic reticulum; protein synthesis; sarcoplasmic reticulum; translation; ventricular myocyte
    DOI:  https://doi.org/10.1113/JP288658
  17. Biochem Biophys Res Commun. 2026 Aug 10. pii: S0006-291X(26)01185-X. [Epub ahead of print]833 154421
    Enhanced folding capacity of green fluorescent protein facilitates vacuolar trafficking of carboxypeptidase Y.
    Do Yeop Lee, Changhee Na, Geoni Choi, Jae-Ho Lee, Susmita Ghosh, Hee-Gyeong Yi, Dong Wook Lee.
      Efficient transport of secretory proteins through the endoplasmic reticulum (ER) is essential for their correct localization and cellular function. Misfolded proteins are retained in the ER and eliminated via ER-associated degradation (ERAD), but whether enhanced folding efficiency promotes ER exit and subsequent trafficking remains unclear. To address this question,Arabidopsis carboxypeptidase Y (CPY), a vacuolar protein that passes through the ER, Golgi apparatus, and prevacuolar compartment en route to the vacuole, was used. CPY was fused to three green fluorescent protein (GFP) variants differing in folding properties: standard GFP, superfolder GFP (sfGFP) with enhanced folding capacity, and aggregation-prone GFP[V30A]. As expected, CPY:GFP[V30A] failed to reach the vacuole and accumulated mainly as the precursor form. In contrast, CPY:sfGFP displayed markedly improved vacuolar trafficking compared with CPY:GFP, indicating that enhanced folding efficiency facilitates ER exit and downstream transport. Similar results with CPY95, a truncated CPY variant, further suggest that this effect is independent of protein length. These findings uncover a previously unrecognized role for folding efficiency in regulating secretory protein trafficking, demonstrating that protein folding status can directly influence the efficiency of ER export and vacuolar delivery.
    Keywords:  Carboxypeptidase Y; ER exit; GFP variants; Protein folding; Vacuolar trafficking
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154421
  18. Adv Sci (Weinh). 2026 Aug 13. e77155
    BOULE is Essential for the Dynamic Disassembly of Heat Shock Granules in Male Germ Cells.
    Xin Li, Nana Zhang, Zexin Bian, Baobao Geng, Liyun Cao, Peipei Liu, Zengming Li, Yan Zhao, Jun Tan.
      Heat shock triggers stress granule (SG) formation, yet their dynamics in mammalian germ cells remain unclear. Through systematic analysis, we uncovered distinct heat shock granule (HSG) composition and stage-specific assembly/disassembly in the mouse testis. Ribosome profiling revealed that germ cells selectively sustain translation of spermatogenic genes during heat shock. We identified that the germ cell-specific RNA-binding protein BOULE is essential for HSG clearance. BOULE deficiency under heat shock impairs HSG disassembly, with increased germ cell apoptosis and a disrupted ubiquitinome. Mechanistically, BOULE orchestrates HSG clearance through a two-pronged mechanism. It post-transcriptionally maintains the expression of the disassembly factors G3BP1 and FAF2. Additionally, BOULE promotes heat-shock-induced ubiquitination of G3BP1 by regulating the E3 ligase TRIM27, thereby recruiting the VCP/FAF2 complex. Our findings establish BOULE as a key regulator of proteostasis that coordinates HSG disassembly in germ cells, providing mechanistic insight into heat shock-induced germ cell damage that may contribute to male infertility.
    Keywords:  BOULE; G3BP1; germ cell; heat shock; stress granule
    DOI:  https://doi.org/10.1002/advs.77155
  19. EMBO Mol Med. 2026 Aug 13.
    Chrysosplenetin-induced TMED3 aggregation triggers unfolded protein response in pancreatic cancer.
    Zhe Zhang, Ningna Weng, Xuanhao Gu, Yi Zang, Qitai Chen, Rujia Zheng, Xishan Yang, Gubu Amu, Danyang Zhao, Zhihao Ma, Jinyan Huang, Tingbo Liang, Qi Zhang.
      Pancreatic cancer (PC) continues to demand urgent therapeutic innovation given its limited treatment options. Here, through phenotypic screening of a natural product library followed by systematic validation, we identified chrysosplenetin (CHR) as a bioactive compound with anti-PC activity. Transcriptomic profiling and functional analyses demonstrated that CHR induced endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) and subsequent apoptosis, while paradoxically triggering a protective autophagy. Genetic or pharmacological inhibition of autophagy potentiated CHR-induced antitumor efficacy. Using an integrated approach including proteomic analysis, bio-layer interferometry, cellular thermal shift assay, and molecular docking, we confirmed TMED3 as a direct target of CHR. Functional studies revealed that disruption of TMED3 expression partially restored ER homeostasis, attenuating CHR-induced UPR activation and apoptosis. Furthermore, CHR combined with standard chemotherapy or autophagy inhibitors exhibited enhanced antitumor activity in preclinical models, providing a basis for future therapeutic exploration of the TMED3-ER stress axis. Together, our findings establish TMED3 as a novel therapeutic target in PC, revealing that disrupting ER proteostasis via TMED3 perturbation represents a potential therapeutic strategy warranting further investigation.
    DOI:  https://doi.org/10.1038/s44321-026-00506-5
  20. Sci Adv. 2026 Aug 14. 12(33): eaeh0657
    Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
    Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.
      Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
    DOI:  https://doi.org/10.1126/sciadv.aeh0657
  21. Nat Neurosci. 2026 Aug 13.
    Dendritic translation and neuroproteasome-mediated degradation of endogenous tau revealed by STARFISH.
    Kalin D Konrad-Vicario, Victoria Paradise, Lara Y Demir, Chi Nguyen, Christopher D Makinson, Zhao Ming, Kapil V Ramachandran.
      In Alzheimer's disease, the protein tau is thought to redistribute from axons to the somatodendritic compartment and form fibrillar aggregates. Although tau aggregation is a hallmark of Alzheimer's disease, the dynamics of its synthesis and degradation are not well characterized. Given that nascent polypeptides are particularly susceptible to misfolding, local control of tau synthesis and degradation may be essential to prevent aggregation. Here we develop STARFISH, a method for visualizing the subcellular site of endogenous mRNA translation in primary neurons and in vivo with single-molecule sensitivity and near-codon resolution, without modifying the nascent polypeptide. Using STARFISH, we show that despite the broad distribution of Mapt mRNA, tau is translated exclusively in neuronal dendrites. About one-third of newly synthesized tau is co-translationally or peri-translationally degraded in dendrites by a neuronal-specific plasma-membrane-associated proteasome, the neuroproteasome. Failure of neuroproteasome-mediated degradation leads to the protein synthesis-dependent accumulation of somatodendritically mislocalized endogenous tau aggregates. These findings define a proteostasis mechanism that counterbalances the constitutive physiological overproduction of tau. We speculate that failure of this proteostasis system contributes to tau aggregation in dendrites in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41593-026-02398-7
  22. Oncogene. 2026 Aug 10.
    Complementary intra- and extracellular AGR2 activities support epithelial ovarian cancer cell aggressiveness.
    Marianne Guilbard, Saïd Taouji, Marc Aubry, Jacques Robert, Raphael Pineau, Valérie Velasco, Romane Florent, Louis-Bastien Weiswald, Cecile Hartog, Coriolan Lebreton, Alix Coulon, Sabrina Croce, Guillaume Babin, Cédric Chaveroux, Stéphanie Beq, Eric Chevet, Delphine Fessart, Frédéric Delom.
      Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.
    DOI:  https://doi.org/10.1038/s41388-026-03938-y
  23. J Mol Biol. 2026 Aug 08. pii: S0022-2836(26)00351-7. [Epub ahead of print] 169978
    Mapping interaction of assembly factor Rpn14 with the proteasome base reveals a bipartite interface and implies ordered remodeling of intersubunit contacts during proteasome biogenesis.
    Quill Thomas, Madison Sterling, Lauren G Carnley, Daniel Betancourt, Taylor A Blount, Danielle J Bitter, Fenglong Jiao, Lan Huang, Antonia A Nemec, Robert J Tomko.
      The 26S proteasome is the largest known protease and an essential mediator of targeted protein degradation, a transformative therapeutic modality for human diseases. Assembly of the 26S proteasome from its 66 cognate subunits depends on nine dedicated assembly chaperones. These chaperones generally function by stabilizing fragile assembly intermediates and/or by regulating the order of subunit association. Whereas the basic functional mechanisms of eight of these nine dedicated chaperones have been at least partially elucidated, the function of Rpn14 (PAAF1 in humans) has remained fully enigmatic. Here, we use a combination of genetics, engineered crosslinking coupled with mass spectrometry, and structural modeling to reveal how Rpn14 interacts with the assembling proteasomal ATPase ring. This model refutes previous Rpn14 binding models and identifies several points of inter-protein steric clash that must undergo remodeling during proteasomal regulatory particle subcomplex maturation. We further show that Rpn14 cooperates with nucleotide to stabilize a known assembly intermediate of the proteasomal base subcomplex. Together, our results illuminate the first known function of Rpn14 during proteasome biogenesis, and provide a framework for detailed mechanistic analyses of how specific interfaces within and between proteasomal subcomplexes are remodeled during their assembly.
    Keywords:  Proteasome; assembly; chaperone; crosslinking; non-natural amino acids; proteolysis; ubiquitin
    DOI:  https://doi.org/10.1016/j.jmb.2026.169978
  24. Mol Cell. 2026 Aug 04. pii: S1097-2765(26)00502-2. [Epub ahead of print]
    The dystonia-associated Torsin1A sustains CLCC1 function in membrane fusion of the nuclear envelope for NPC biogenesis.
    Daria Maslennikova, Harry Baird, Xinyue Ding, Ashutosh Kumar, Alessia Loffreda, Kausthubh Ramachandran, Benjamin Jonas Kösters, Jelmi Uit de Bos, Caroline Ashiono, Katharina Frischer-Ordu, Naemi Luithle, Federico Uliana, Gautam Dey, Volodymyr M Korkhov, Wolfram Antonin, Stefano Vanni, Madhav Jagannathan, Ulrike Kutay.
      DYT1 dystonia is an incurable movement disorder caused by a loss-of-function mutation in Torsin1A, an endoplasmic reticulum (ER)-resident AAA+ ATPase. Here, we use Drosophila and human cells to shed light on Torsins' mode of action. Fly germ cells lacking dTorsin arrest in development with defects in nuclear pore complex (NPC) biogenesis due to impaired nuclear envelope membrane fusion. We identify the conserved membrane protein Chloride Channel CLIC-like protein 1 (CLCC1) as a Torsin1A interaction partner whose absence phenocopies membrane fusion defects caused by Torsin deletion. CLCC1 is enriched at membrane fusion sites, and molecular dynamics (MD) simulations suggest that CLCC1 rings induce bilayer remodeling and lipid flux to initiate fusion of the outer and inner nuclear membranes. Remarkably, CLCC1 overexpression rescues defects associated with loss of Torsins, indicating that a main role of dTorsin/Torsin1A is to sustain CLCC1 functionality. Our findings inform a model of nuclear envelope membrane fusion and imply that modulating CLCC1 expression is a promising therapeutic prospect for DYT1 dystonia.
    Keywords:  AAA+ ATPase; CLCC1; Drosophila spermatogenesis; annulate lamellae; membrane fusion; nuclear envelope; nuclear pore complex; torsin
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.016
  25. Dev Cell. 2026 Aug 04. pii: S1534-5807(26)00276-5. [Epub ahead of print]
    The ARLA1A-NAC089 module coordinates ER phagy with the unfolded protein response to maintain cellular homeostasis in plants.
    Lianming Yang, Weixin Luo, Tingting Huang, Shuo Wang, Zhiran Cao, Dong Jiang, Lei Pang, Jian-Xiang Liu, Sicong He, Ruixi Li.
      The endoplasmic reticulum (ER) is a critical quality-control organelle for protein homeostasis within the cell. The accumulation of misfolded or unfolded proteins triggers ER stress, which can be alleviated through the unfolded protein response (UPR) and ER phagy. These processes work in concert to preserve ER homeostasis, yet the molecular interactions between them remain poorly understood in plants. In this study, we identify the ER-anchored transcription factor NAC089 as an ER-phagy receptor acting downstream of the ADP-ribosylation factor (ARF)-like (ARL) GTPase ARLA1A under carbon starvation. Furthermore, we demonstrate that active ARLA1A inhibits ER phagy by negatively regulating NAC089. Notably, the ARLA1A-NAC089 axis coordinates ER phagy with the UPR to balance cell survival and death. Our findings unveil a multi-layered regulatory network that is essential for maintaining cellular homeostasis and enhancing plant adaptation to environmental stresses.
    Keywords:  ARLA1A; ER phagy; ER stress; NAC089; UPR
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.007
  26. Nat Biotechnol. 2026 Aug 13.
    Proteome-wide identification of the druggable CRBN interactome.
    Pius Galli, Shuhao Xiao, Yanxiang Meng, Alexander Hanzl, Alexandra M Bendel, Regina Baur, Jacob D Aguirre, Anna M Diaz-Rovira, Maximilian R Stammnitz, Georg Kempf, Lukas Kater, Kenji Shimada, Ye Wei, Andreas Scheck, Dominique Klein, Simone Cavadini, Ben Lehner, Guillaume Diss, Bruno E Correia, Nicolas H Thomä.
      Molecular glue degraders (MGDs), such as pomalidomide, induce degradation of non-native substrates by the cullin-RING E3 ligase 4 (CRL4) through its substrate receptor cereblon (CRBN). Here, to explore CRBN programmability, we tested whether reported CRBN-MGD substrates are part of a network of latent CRBN interactors, proteins capable of MGD-induced CRBN binding without detectable degradation. Leveraging a highly parallel protein complementation assay (GluePCA) to measure MGD-induced interaction between CRBN and zinc fingers, we identified ~210 zinc fingers bound to CRBN-pomalidomide, where top binders are already reported as degraded by dedicated MGDs. To map latent CRBN-MGD interactions proteome-wide and define the accessible CRBN interaction space, we combined artificial intelligence-derived protein surface queries (MaSIF-mimicry) with GluePCA. This pipeline identified 6 known and 43 novel CRBN-pomalidomide binders, including orthogonally validated hits. We find that these binders provide privileged starting points for MGD development. We expect this binding-focused workflow to be applicable to other MGD-E3 ligase systems, potentially extending the scope of this emerging drug class.
    DOI:  https://doi.org/10.1038/s41587-026-03237-7
  27. iScience. 2026 Aug 21. 29(8): 117039
    3'UTR-directed, kinase-proximal mRNA decay inhibits C/EBPβ phosphorylation/activation to suppress senescence in tumor cells.
    Jacqueline Salotti, Nida Asif, Srikanta Basu, Aniruddha Das, Linshan Hu, Mei Yang, Baktiar Karim, Karen Saylor, Nancy Martin, David A Scheiblin, Sweta Misra, Brian T Luke, Thorkell Andresson, Ming Yi, Mélissa Galloux, Stephen Lockett, Lino Tessarollo, Peter F Johnson.
      C/EBPβ regulates oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) through activation by ERK1/2 and CK2. In tumor cells, C/EBPβ activity is suppressed by its 3'UTR via a mechanism termed 3'UTR regulation of protein activity (UPA), which spatially segregates CEBPB transcripts from kinase-rich perinuclear endosomes. Here, we identify kinase-proximal mRNA decay as the underlying mechanism. The mRNA decay factors UPF1 and STAU1/2 localize to perinuclear endosomes and promote degradation of CEBPB transcripts, thereby preventing C/EBPβ phosphorylation and activation. Disruption of this pathway restores C/EBPβ activity and induces senescence. In vivo, deletion of a G/U-rich regulatory element (GRE) in the 3'UTR impairs the progression of Kras-driven lung tumors and biases cells toward an AT2-like differentiation state with reduced EMT-associated transcriptional reprogramming. RAS-expressing GRE Δ/Δ fibroblasts show enhanced OIS that requires upregulation of the pro-senescent cytokine S100a9. These findings identify perinuclear mRNA decay as a mechanism suppressing C/EBPβ activity and senescence in cancer.
    Keywords:  3′UTR; 3′UTR regulation of protein activity; RAS signaling; SASP cytokines; cancer; oncogene-induced senescence
    DOI:  https://doi.org/10.1016/j.isci.2026.117039
  28. Methods Mol Biol. 2026 ;3069 247-257
    SsrA-Based Targeted Protein Degradation in Escherichia coli.
    Qichang Nie, Terrence Chi-Kong Lau.
      Targeted protein degradation is an emerging concept of drug discovery to selectively eliminate the pathogenic proteins by activating their degradation in cells. The proteolysis-targeting chimeras (PROTACs) are bifunctional small molecules that induce the degradation of a protein of interest (POI) by proteasome. Here we describe a method that utilizes an ssrA-based BacPROTAC (bacterial PROTACs) to target the drug-resistant proteins CTX-M-14, a class A β-lactamase commonly found in extended-spectrum beta-lactamase (ESBL) plasmids of antimicrobial resistance (AMR) bacteria. This strategy could resensitize the drug-resistant bacteria and revive previously disregarded antibiotics, opens up a new avenue for therapeutic development of AMR bacteria.
    Keywords:  Antimicrobial resistance; BacPROTACs; ESBL plasmids; Escherichia coli; Proteasome; Protein degradation
    DOI:  https://doi.org/10.1007/978-1-0716-5508-5_18
  29. FEBS J. 2026 Aug 14.
    A live-cell autophagy reporter reveals reversible vacuolation in naked mole-rat skin fibroblasts under lysosomal stress.
    Fangze Tong, Mateo P Hoare, Laura J Grundy, Filomena Gallo, Karin H Müller, Ewan St John Smith, Janet R Kumita.
      Naked mole-rats (NMRs, Heterocephalus glaber) display unusual longevity and resistance to age-related decline, and accumulating evidence suggests that their autophagy-lysosome pathway (ALP) is regulated differently from that of conventional mammalian models. However, most studies in NMR cells have relied on static biochemical or ultrastructural readouts, leaving the dynamic organisation of autophagy in living cells poorly defined. Here, we establish a stable tandem fluorescent autophagy reporter in NMR skin fibroblasts using an mCherry-EGFP-LC3NMR construct to enable live-cell, single-cell resolution analysis of ALP dynamics. Under basal conditions, NMR skin fibroblasts exhibit a greater abundance of LC3-positive structures than HeLa cells, together with a mixed population of autophagosomes and autolysosomes, indicating a distinct steady-state organisation of the ALP. Chloroquine (CQ)-induced lysosomal stress caused the expected accumulation of LC3-positive structures but also triggered the formation of large cytoplasmic vacuoles in NMR skin fibroblasts. Importantly, this vacuolation was not associated with acute cytotoxicity and progressively resolved following CQ removal, accompanied by reorganisation of LC3-positive compartments and recovery of lysosomal acidity. Electron microscopy showed that CQ-induced vacuoles are membrane-bound, containing internal material and co-existing with multiple ALP-related vesicular compartments. Primary NMR skin fibroblasts display a similar vacuolation phenotype, indicating that this response is not an artefact of immortalisation or reporter expression. Together, these findings establish a live-cell platform for analysing autophagy in NMR cells and identify a distinctive, reversible vacuolation response to lysosomal stress, consistent with dynamic remodelling of the lysosomal system within NMR skin fibroblasts.
    Keywords:  LC3‐reporter; autophagy–lysosome pathway; long‐lived species; naked mole‐rats; vacuolation
    DOI:  https://doi.org/10.1111/febs.70695
  30. J Mol Biol. 2026 Aug 04. pii: S0022-2836(26)00341-4. [Epub ahead of print] 169968
    Genome-Wide Impact of Human DBR1 Depletion on RNA Processing Networks Reveal a Connection Between Pre-mRNA Splicing, mRNA Surveillance and Stress Granule Dynamics.
    Tiffany Barwell, Caleb M Embree, Robert Reid, Guramrit Singh, Kausik Chakrabarti.
      The RNA lariat debranching enzyme DBR1 is essential for intron turnover and RNA metabolism, yet its broader impact on transcriptome regulation remains incompletely defined. To elucidate the consequences of DBR1 depletion, we performed transcriptome-wide RNA sequencing of DBR1-knockdown and wild-type HEK293 cells. Differential expression analysis revealed widespread perturbations in pathways linked to RNA splicing, mRNA surveillance, translational control, and stress-granule biology. Many of the most significantly altered transcripts encode splicing factors and RNA quality-control components, underscoring DBR1's influence on post-transcriptional regulation. Alternative splicing analysis showed changes across multiple event types, with exon skipping accounting for >50% of events, followed by mutually exclusive exons, alternative 5' and 3' splice sites, and retained introns, indicating that DBR1 depletion induces pervasive splicing defects. Direct spliceosome inhibition using isoginkgetin (blocks tri-snRNP recruitment) and pladienolide B (targets SF3B1) reproduced the DBR1-KD mis-splicing patterns of cell signaling genes and factors involved in RNA metabolism, supporting a functional link between DBR1 activity and alternative splicing. Notably, DBR1 knockdown revealed a subset of transcripts that are both NMD-sensitive and enriched within stress granules. Consistent with this observation, G3BP1 immunopurification and confocal microscopy further support a role for DBR1 and UPF1 in stress-granule dynamics, suggesting that these factors may participate at distinct stages to influence mRNA fate under stress conditions. Together, these findings indicate that DBR1 functions beyond lariat RNA turnover as a common regulator of RNA processing, transcriptome stability, and stress granule homeostasis, revealing intricate crosstalk between RNA splicing and RNA quality control pathways in human cells.
    Keywords:  DBR1; RNA splicing; differential gene expression; mRNA surveillance; siRNA knockdown; stress granules; transcriptomic profiling
    DOI:  https://doi.org/10.1016/j.jmb.2026.169968
  31. Nat Commun. 2026 08 11. pii: 8092. [Epub ahead of print]17(1):
    A ubiquitin chain-feeding mechanism for BRCA1-A.
    Andrea G Murachelli, Farid El Oualid, Titia K Sixma.
      The BRCA1-A complex is a multi-subunit, metallo-deubiquitinating enzyme (metallo-DUB) involved in genome maintenance. BRCA1-A displays strict specificity for K63-linked ubiquitin, with a strong preference for long chains, but the mechanistic basis for this selectivity has remained unclear. To address this, we have developed an activity-based probe that is specific for metallo-DUBs and mimics di- or polyubiquitin chains of any linkage (di- and poly-ubiquitinATA). We have solved cryoEM structures of BRCA1-A bound to K63-linked probe chains of various length, capturing multiple conformational and catalytic states. The structures reveal how allosteric regulation of catalysis occurs within the complex and how BRCA1-A uses auxiliary ubiquitin-binding sites to engage substrate by avidity and to trigger processive cleavage. Crucially, avidity and processivity can only apply to long polyubiquitin chains, explaining BRCA1-A's substrate preference. Together, these results establish BRCA1-A as a chain-shortening DUB specialised for trimming extended K63-linked polyubiquitin chains.
    DOI:  https://doi.org/10.1038/s41467-026-75797-w
  32. Cell Rep. 2026 Aug 03. pii: S2211-1247(26)00870-3. [Epub ahead of print]45(8): 117792
    Phosphatidylserine synthesis tunes IP3R-mediated ER Ca2+ release via phospholipid homeostasis.
    Yifan Zhou, Meng Diao, Yaqiang Liu, Kangmin He, Xiao Yang, Mei Ding, Xun Huang.
      Regulation of phospholipid composition is essential for cellular homeostasis. Phosphatidylserine (PS) synthesized in the endoplasmic reticulum (ER) plays critical roles in the plasma membrane and endolysosomal system. Although aberrant PS metabolism is linked to diseases, its cellular effects remain poorly understood. Here, we reveal a conserved role for PS in maintaining Ca2+ homeostasis. PS deficiency in Drosophila leads to mitochondrial damage, which is reversed by reducing inositol 1,4,5-trisphosphate receptor (IP3R)-mediated ER Ca2+ release. Notably, in mammalian cells with pathological PS levels-either deficiency or excess as in Lenz-Majewski syndrome-IP3R activation leads to oscillatory or reduced ER-surface Ca2+ release, contrasting with steady-state conditions. Manipulating phospholipid composition via the phosphatidylethanolamine (PE)-SREBP axis in Drosophila and the phosphatidylcholine (PC)-SREBP axis in mammals normalizes IP3R-mediated Ca2+ release during PS deficiency. These findings establish modulated ER Ca2+ release as a key function of PS and suggest therapeutic strategies for treating lipid metabolic disorders.
    Keywords:  CP: cell biology; CP: metabolism; Ca(2+); ER; IP(3)R; mitochondrion; phosphatidylserine
    DOI:  https://doi.org/10.1016/j.celrep.2026.117792
  33. Adv Sci (Weinh). 2026 Aug 14. e77190
    Dual-Organelle Secretome Conjugation and Organ-Uptake Tracking (DuO-SCOUT) Enables Deep and Sensitive Mapping of the Secreted Proteins.
    Fenglian Yang, Rui Qian, Jiaxing Song, Xingqi Meng, Jin Young Kim, Kwok On Lai, Li Wang, Liang Zhang.
      Inter-organ communication is governed by a complex "secretome," yet mapping the journey of these factors from their origin to precise cellular destinations remains a fundamental challenge. Proximity labeling emerges as a powerful tool to dissect the secretome, yet conventional workflows typically rely on single-compartment biotinylation at the endoplasmic reticulum (ER), failing to capture proteins that utilize unconventional secretion. Here, we present DuO-SCOUT (Dual-Organelle Secretome Conjugation and Organ-Uptake Tracking), a high-performance platform that simultaneously targets BioID2 to the ER and the trans-Golgi network (TGN). This integrated strategy captures the full secretory maturation relay, increasing protein identification by over 120% compared to traditional ER-anchored methods. We translated this in vivo using an Adipoq-Cre mouse model to map the adipose secretome. To bridge the gap between systemic transport and tissue-specific uptake, DuO-SCOUT integrates BSPA (Biotin-Specific Proximity Amplification), a visualization toolkit detecting biotinylated proteins with sub-nanomolar sensitivity. In obese mice, we identified the piriform cortex (PIR) as a previously unrecognized extra-hypothalamic sink for adipose-derived leptin. This is associated with a localized neuroinflammatory signature, including significant induction of Il6. DuO-SCOUT establishes a broadly applicable framework for dissecting the complex molecular logic of systemic organ-organ communication.
    Keywords:  BioID; adipose; leptin; obesity; secretome
    DOI:  https://doi.org/10.1002/advs.77190
  34. Cell Rep. 2026 Aug 12. pii: S2211-1247(26)00913-7. [Epub ahead of print]45(8): 117835
    Retromer mediates Ypt7-dependent lipid droplet internalization.
    Zixin Xu, Yingyan Zhi, Gongcheng Qu, Yang Liu, Yingyi Zhang, Hei Ting Ngan, Aksel J Saukko-Paavola, Yusong Guo, Christian Ungermann, Robin W Klemm, Lars Langemeyer, Jieqiong Gao.
      Lipid droplets (LDs) are dynamic organelles central to cellular energy homeostasis and stress adaptation. Maintaining LD balance is critical for cell function, yet the mechanisms governing selective LD degradation remain unclear. Here, we reveal a pathway promoting efficient vacuolar sequestering and potential degradation of a Pdr16-marked LD subpopulation, thereby linking LD metabolism to organelle communication. During nutrient limitation, the Rab GTPase Ypt7 and its guanine nucleotide exchange factor (GEF), Mon1-Ccz1, specifically localize to Pdr16-LDs. This targeting relies on a conserved amphipathic helix within Ccz1. Importantly, Ypt7 activation recruits the SNX-BAR retromer complex to the vacuole-LD interface at sites of invagination. There, retromer potentially interacts with its cargo receptor, Vps10, to promote positive membrane curvature that drives the late stage of vacuolar invagination required for LD internalization and degradation. These findings suggest a link between LD turnover, organelle interactions, and cellular adaptation to metabolic stress, providing new insight into lipid homeostasis.
    Keywords:  CP: cell biology; Mon1-Ccz1; Pdr16; Rab GTPase; Ypt7; invagination; lipid droplets; lipophagy; membrane contact sites; retromer; vacuole
    DOI:  https://doi.org/10.1016/j.celrep.2026.117835
  35. J Biol Chem. 2026 Aug 12. pii: S0021-9258(26)02314-8. [Epub ahead of print] 113442
    The Sec11 C-terminal short helix promotes productive engagement of internal signal sequences with the signal peptidase complex.
    Yeonji Chung, Mariia Borbuliak, Sanghun Hwang, Paulo C T Souza, Hyun Kim.
      Proteins destined for secretion typically contain N-terminal signal sequences that target nascent chains to the endoplasmic reticulum (ER). Following targeting, these sequences are cleaved by the heterotetrameric signal peptidase complex (SPC). Despite a conserved N-terminal (n), hydrophobic core (h) and C-terminal (c) tripartite organization, their sequences are highly variable. How SPC subunits contribute to recognition of these diverse sequences remains poorly understood. Sec11, the catalytic subunit of the SPC, contains an N-terminal transmembrane (TM) domain and a C-terminal hydrophobic region. The latter was unresolved in human SPC cryo-EM structures, likely due to intrinsic flexibility, yet AlphaFold predictions of the yeast SPC suggest that this region forms a C-terminal short helix (CTS) strategically positioned within the presumed signal sequence-binding site. This structural arrangement led us to hypothesize its possible role in substrate handling during signal peptide processing and we undertook to investigate its function using biochemical assays combined with molecular dynamics (MD) simulations. Topology mapping confirmed that the Sec11 CTS traverses the ER membrane and MD simulations showed that removal of the Sec11 CTS does not substantially alter overall SPC architecture or the proximal membrane environment. While N-terminal signal sequences of varying hydrophobicity were efficiently cleaved, internal signal sequences with extended n-region were selectively defective in cleavage in the absence of the Sec11 CTS. These data suggest that the Sec11 CTS specifically stabilizes internal signal sequences for productive engagement with SPC.
    Keywords:  Sec11; endoplasmic reticulum (ER); intracellular processing; signal peptidase; signal peptide; signal sequence; substrate specificity; yeast
    DOI:  https://doi.org/10.1016/j.jbc.2026.113442
  36. Cell Rep. 2026 Aug 10. pii: S2211-1247(26)00907-1. [Epub ahead of print]45(8): 117829
    Stress granules confer an early vulnerability in KRAS-driven pancreatic tumorigenesis.
    Matias Estaras, Emma Cosialls, Gareth Pollin, Anass Berkachi, Noriyuki Nishiwaki, Gerardo Blanco, Miguel Fernandez-Bermejo, Antonio Gonzalez, Anil K Rustgi, Gwen Lomberk, Raul Urrutia, Patricia Santofimia-Castaño, Juan Iovanna.
      Pancreatic ductal adenocarcinoma (PDAC) is initiated by activating KRAS mutations, yet most pancreatic cells fail to survive the induced oncogenic stress. How a subset adapts to and initiates malignant transformation remains unclear. Here, we show that stress granules (SGs) formation is a key adaptive mechanism enabling these cells to tolerate oncogenic KRAS signaling. Although we determine that SGs are a generic response in stressed acinar cells, they are required for KRAS-mutant cells to progress to the preneoplastic stage. SGs blocking prevents KRAS-driven acinar-to-ductal metaplasia ex vivo and suppresses preneoplastic lesion formation in vivo. Importantly, SGs inhibition does not affect pancreatic damage during chronic pancreatitis, supporting its safety for selectively targeting KRAS-mutant cells. Finally, SGs are detected in pancreatic tissue from patients with chronic pancreatitis, confirming clinical relevance. Together, these findings identify SGs as a stress adaptation mechanism enabling tumor initiation and highlight them as a target for cancer interception in KRAS-driven PDACs.
    Keywords:  ADM; CP: cancer; mutant KRAS; pancreatic cancer; stress granules; transformation; tumor initiation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117829
  37. BBA Adv. 2026 ;10 100200
    Neddylation-dependent RAB40-Cullin5 E3 ligase complex controls ubiquitin-mediated proteasomal degradation of DNAJC13.
    Kazuki Sato, Naoto Sugeno, Takafumi Hasegawa, Shun Yoshida, Mitsunori Fukuda, Akemi Fujibayashi, Kiyotoshi Sekiguchi, Shun Ishiyama, Takaaki Nakamura, Ako Miyata, Satoshi Watanabe, Kensho Ikeda, Atsushi Takeda, Masashi Aoki.
      DNAJC13 is a member of DNAJ co-chaperone family and its missense mutation causes a rare familial form of Parkinson's disease. DNAJC13 is indispensable for neuronal homeostasis by regulation of autophagy and the regulation of receptor expression on the cell surface. However, the regulatory mechanisms governing DNAJC13 expression remain poorly understood. We previously demonstrated that DNAJC13 binds to RAB40 small GTPase. Unlike other RABs, RAB40 proteins interact with activated Cullin-5 (CUL5) via the SOCS box, forming an Cullin-RING E3 ubiquitin ligase (CRL) complex that regulates ubiquitylation of target proteins. Thus, as a binding partner of RAB40s, DNAJC13 degradation may be regulated by this functional complex. Here, we found that both N-and C-terminal regions of DNAJC13, including IWN1 and IWN3 domains, were essential for its binding to RAB40 A/B/C. Moreover, DNAJC13 degradation of relies predominantly on the ubiquitin-proteasome system rather than on autophagy, and upregulated DNAJC13 ubiquitination in the presence of RAB40A/B/C. Intriguingly, RNAi-mediated silencing of the RAB40 subfamily caused a significant increase in DNAJC13 expression, accompanied by higher autophagic flux. Furthermore, co-immunoprecipitation experiments demonstrated that RAB40C, which is predominantly expressed in midbrain dopaminergic neurons, binds to CUL5 and its activator NEDD8 as well as RBX2 (E2). Finally, DNAJC13 cellular levels were regulated by NEDD8 activity. Taken together, these findings indicate that NEDD8-mediated neddylation plays a key role in RAB40-CUL5-mediated DNAJC13 degradation.
    Keywords:  Cullin5; DNAJC13; Neddylation; Parkinson's disease; RAB40; RME-8; Ubiquitin
    DOI:  https://doi.org/10.1016/j.bbadva.2026.100200
  38. J Mol Biol. 2026 Aug 13. pii: S0022-2836(26)00363-3. [Epub ahead of print] 169990
    The GCN2-ATF4 signaling axis orchestrates the hepatic transcriptional stress response to short-term sulfur amino acid deprivation.
    Valérie Carraro, Maëlle Cherpaz, Lucie Longechamp, Cécile Coudy-Gandilhon, Laurent Parry, Guillaume Voyard, Anne-Catherine Maurin, Céline Jousse, Julien Averous, Lydie Combaret, Isabelle Papet, Alain Bruhat.
      Mammals rely on the integrated stress response (ISR) to maintain essential amino acid (EAA) homeostasis. The kinase GCN2 is a key ISR sensor that is rapidly activated by uncharged tRNAs during EAA deprivation, leading to eIF2α phosphorylation and selective translation of ATF4. ATF4 subsequently orchestrates a transcriptional program regulating amino acid metabolism, redox balance, and autophagy. In this study, we investigated the role of GCN2 in the early hepatic transcriptional response to dietary sulfur amino acids (SAA; methionine and cysteine) deprivation. Using ATF4-luciferase reporter mice, we demonstrate that short-term SAA deprivation rapidly activates the eIF2α-ATF4 pathway within 3 hours, with activation primarily localized to the liver. Complementary in vivo and ex vivo approaches revealed that genetic deletion or pharmacological inhibition of GCN2 abolishes early eIF2α phosphorylation and induction of ATF4 target gene, while PERK is dispensable for this response. Furthermore, GCN2 controls the induction of multiple adaptive transcriptional programs involved in amino acid transport, aminoacyl-tRNA synthesis, autophagy, serine biosynthesis, one-carbon metabolism and glutathione degradation highlighting a coordinated adaptive response to acute SAA deprivation. These findings establish GCN2 as a major sensor mediating the early hepatic response to SAA deprivation, and define a transcriptional program essential for maintaining amino acid homeostasis. In contrast, Fgf21 induction occurs independently of GCN2, indicating the existence of parallel adaptive mechanisms. Collectively, this work provides new insight into the early dynamics and molecular specificity of ISR activation in response to acute dietary SAA deprivation.
    Keywords:  ATF4 signaling; GCN2 kinase; Integrated Stress Response; liver transcriptional response; short-termsulfur amino acid deprivation
    DOI:  https://doi.org/10.1016/j.jmb.2026.169990
  39. Nat Commun. 2026 08 11. pii: 8091. [Epub ahead of print]17(1):
    Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex.
    Martina Foglizzo, Arindam Datta, Oksana Degtjarik, Hirunika Perera, Jordan Liburd, Upasana M Sykora, Sri Ranjani Ganji, Gemma Wildsmith, Francesca Chandler, Lisa J Campbell, Antonio N Calabrese, Roger A Greenberg, Elton Zeqiraj.
      Deubiquitylases modulate cellular processes by removing monoubiquitin or cleaving polyubiquitin chains. The ARISC-RAP80 complex partners with BRCA1-BARD1 to form the BRCA1-A supercomplex, which recognises K63-linked ubiquitin chains at DNA damage sites. ARISC-RAP80 contains multiple ubiquitin-binding sites, yet how these influence recognition and cleavage of K63-polyubiquitylated substrates remains unknown. We discover that a composite three-subunit interface allows ARISC-RAP80 to position K63-linked polyubiquitin chains in its catalytic site. Substrate recognition is further supported by RAP80 and non-catalytic ubiquitin-binding sites that impose a compact conformation on K63-polyubiquitylated substrates. This mechanism exploits the inherent flexibility of long ubiquitin chains and differs considerably from other deubiquitylases. Structure-guided mutageneses validate ubiquitin chain interactions, and cell-based assays demonstrate a functional role of the observed interfaces in chromatin recruitment. Our findings define mechanisms of polyubiquitin chain decoding and cleavage by ARISC-RAP80, linking ubiquitin reading and erasing functions to BRCA1-A mediated DNA damage responses.
    DOI:  https://doi.org/10.1038/s41467-026-75795-y
  40. Cell. 2026 Aug 14. pii: S0092-8674(26)00872-X. [Epub ahead of print]
    Polyamines buffer labile iron to suppress ferroptosis.
    Pushkal Sharma, Heather R Keys, Ryan P Mansell, Jillian Stark, Louisa Girard, Christalyn Ausler, Rachel Anderson, Sebastian Müller, Shinya Imada, Ivan S Pires, Tenzin Kunchok, Millenia Waite, Bingbing Yuan, Amy Deik, Luke Ferro, Paula T Hammond, Raphaël Rodriguez, Maria-Eirini Pandelia, Whitney S Henry, Ankur Jain.
      Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
    Keywords:  GPX4; ferroptosis; genetically encoded iron sensor; iron homeostasis; labile iron pool; polyamines; redox-active iron; spermidine; spermine
    DOI:  https://doi.org/10.1016/j.cell.2026.07.040
  41. Drug Discov Today. 2026 Aug 12. pii: S1359-6446(26)00174-1. [Epub ahead of print] 104769
    Deubiquitinase-targeting chimeras (DUBTACs): a game-changing approach for targeted protein stabilization in drug discovery.
    Gebremedhin Solomon Hailu, Emanuele Fabbrizi, Andrea Mancini, Francesco Fiorentino, Antonello Mai, Dante Rotili.
      Targeted protein degradation (TPD) has transformed drug discovery by enabling event-driven elimination of pathogenic proteins, but many diseases arise from protein insufficiency and require restoration rather than removal. Deubiquitinase (DUB)-targeting chimeras (DUBTACs) offer a complementary proximity-pharmacology approach for targeted protein stabilization (TPS), recruiting DUBs to remove degradative ubiquitin chains and prevent proteasomal turnover. These heterobifunctional molecules link a protein-binding ligand to a DUB recruiter, enabling functional rescue. Notably, DUBTACs provide opportunities to stabilize proteins previously considered undruggable. Here, we summarize design principles, emerging applications, and translational challenges and outline priorities for advancing DUBTACs toward therapeutic development.
    Keywords:  DUBTAC; deubiquitinase recruitment; drug design; drug discovery; heterobifunctional molecules; targeted protein stabilization; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.drudis.2026.104769
  42. EMBO J. 2026 Aug 10.
    In-situ cryo-ET of mouse embryos reveals cytoplasmic lattices contain ubiquitin-charged E2-E3 ligase assemblies.
    Kashish Singh, Katarina Harasimov, Kathy K Niakan, Andrew P Carter.
      Cytoplasmic lattices (CPLs) are filamentous assemblies essential for mammalian embryonic development. They are known to regulate organelle organization, spindle assembly, and protein homeostasis, but their molecular functions remain unclear. Here, we develop a strategy combining cryo-focused ion beam milling and cryo-electron tomography to resolve macromolecular complexes directly in mammalian embryos. Using this approach, we determine the in situ structure of cytoplasmic lattices within 6/8-cell mouse embryos at ~4.7 Å resolution. CPL filaments are built from multiple copies of at least fourteen proteins arranged into a ~4.5 MDa repeating unit. The repeat contains a central cavity that is open at the back and lined with multiple FBXW-SKP1 complexes and three modules, each containing the E2 ubiquitin-conjugating enzyme UBE2D and the E3 ligase UHRF1. We resolve two CPL states: one is consistent with a ubiquitin-charged UBE2D, where ubiquitin is held in an open, inactive conformation by binding the scaffold protein PADI6; the second lacks discernible ubiquitin density and shows structural changes compatible with ubiquitin becoming available for transfer. Our findings support a model in which CPLs function as large ubiquitin ligase assemblies during early embryonic development.
    DOI:  https://doi.org/10.1038/s44318-026-00895-w
  43. J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02302-1. [Epub ahead of print] 113430
    Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation.
    Johan Panek, Edward Fielder, Congsing Sun, Steph Crabtree, Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura Booth, Wyatt Yue, Gavin Richardson, Lauren Holder, Gavin J Miller, Jóhannes Reynisson, Sovan Sarkar, Viktor I Korolchuk.
      Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.
    Keywords:  Autophagy; Mitophagy; Niemann-Pick type C1 disease; Oligomerisation; ROS; p62
    DOI:  https://doi.org/10.1016/j.jbc.2026.113430
  44. Leukemia. 2026 Aug 11.
    USP8 controls proteostasis pathways in B cells and multiple myeloma.
    Almut Dufner, Fabien Thery, Gianni Monaco, Jelena Lazarevic, Oliver Gorka, Nina Chevalier, Marta Campos Alonso, Maximilian Frosch, Gerbrand J van der Heden van Noort, Kira Allmeroth, Marco Prinz, Olaf Groß, Huib Ovaa, Paul P Geurink, Wolfgang W Schamel, Martin S Denzel, Vigo Heissmeyer, Benedikt Jacobs, Mirle Schemionek, Francis Impens, Heiko Bruns, Klaus-Peter Knobeloch.
      Ubiquitin-specific protease 8 (USP8) plays a pivotal role in the regulation of endosomal and lysosomal trafficking and is critically involved in the pathogenesis of various tumor entities. USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific Usp8 deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.
    DOI:  https://doi.org/10.1038/s41375-026-03086-y
  45. Autophagy. 2026 Aug 11. 1-21
    Senecavirus a 3C protease cleaves RETREG1 to antagonize ER-phagy and promote viral replication via endoplasmic reticulum calcium signaling.
    Jingyu Mao, Ju Yu, Penghui Zeng, Xiaoyu Yang, Yongyan Shi, Yunjie Qu, Jianwei Zhou, Dedong Wang, Jiangwei Song, Yong Wang, Jue Liu, Lei Hou.
      Co-evolution between viruses and autophagy has led to the emergence of viral strategies that manipulate host endoplasmic reticulum (ER) homeostasis, ultimately promoting viral replication. ER turnover is achieved through selective autophagy, also referred to as ER-phagy, which is regulated by the RETREG1/FAM134B (reticulophagy regulator 1) family of reticulon proteins. Nevertheless, how viruses target RETREG1, a receptor for ER-phagy, remains largely unclear. In this study, we demonstrate that infection with Senecavirus A (SVA), an emerging picornavirus, triggers the cleavage of RETREG1, which functions as a negative regulator of viral replication. By screening viral proteins, we identified the SVA 3C protease (3C[pro]) as the executor of this cleavage event. Detailed mapping revealed that residues Q428, E430, and G431 of RETREG1 are involved in its cleavage by the 3C[pro], and the resulting two fragments fail to suppress viral replication. Furthermore, proteolytic cleavage of RETREG1 by 3C[pro] impairs its ability to relieve ER stress and mediate ITPR1 degradation via RETREG1-dependent ER-phagy. This disruption leads to increased ER calcium (Ca2+) release and subsequent activation of autophagy through the CAMKK2-PRKAA2-MTOR axis, which ultimately facilitates SVA replication. Taken together, these findings indicate that SVA antagonizes the antiviral function of RETREG1-mediated ER-phagy via its 3C[pro], highlighting RETREG1 as a potential therapeutic target for combating SVA infection.Abbreviations: 2-APB: 2-aminoethyl diphenylborinate; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; ATL3: atlastin GTPase 3; BHK-21: baby hamster kidney-21; CAMKK2: calcium/calmodulin dependent proteinkinase kinase2; CCPG1: cell cycle progression 1; CKAP4/CLIMP63: cytoskeleton associated protein 4; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DM: double mutant; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; eGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; GFP: green fluorescent protein; HSPA5/GRP78/BiP: heat shock protein family A (Hsp70) member 5; HA: hemagglutinin; HDAC4: histone deacetylase 4; HEK-293T: human embryonic kidney 293T; hpi: hours post-infection; IFA: indirect immunofluorescence assay; ITPR1/IP3R1: inositol 1,4,5-trisphosphate receptor type 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; mCherry: monomeric cherry; MTOR: mechanistic target of rapamycin kinase; REEP5: receptor accessory protein 5; RETREG1/FAM134B: reticulophagy regulator 1; RTN3: reticulon 3; SD: standard deviation; SEC61B: SEC61 translocon subunit beta; SEC62: SEC62 preprotein translocation factor; SERP1/RAMP4: stress associated endoplasmic reticulum protein 1; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; ST: swine testis; SVA: Senecavirus A; TEM: transmission electron microscopy; TEX264: testis expressed 264, ER-phagy receptor; Tm: tunicamycin; U2OS: human osteosarcoma epithelial cells; UV: ultraviolet; ZVAD-FMK: benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone; μg: microgram; μm: micrometer; μM: micromole.
    Keywords:  CAMKK2-PRKAA2-MTOR axis; Calcium (Ca2+); ER-phagy; RETREG1 cleavage; SVA 3C[pro]; viral replication
    DOI:  https://doi.org/10.1080/15548627.2026.2714544
  46. J Biol Chem. 2026 Aug 11. pii: S0021-9258(26)02304-5. [Epub ahead of print] 113432
    The zinc metalloprotease ZMPSTE24 binds a distinct topological isoform of the tail-anchored protein IFITM3.
    Eric D Spear, Khurts Shilagardi, Sonia Sarju, Susan Michaelis.
      The biogenesis of integral membrane proteins is complex, as revealed by an ever-growing number of cellular components dedicated to the insertion, folding, surveillance, rectification, or quality control of specific client membrane proteins. The zinc metalloprotease ZMPSTE24 and its yeast homolog Ste24 have well-established roles in the proteolytic maturation of the nuclear scaffold protein lamin A and yeast a-factor, respectively. Additionally, Ste24 has been implicated through yeast genetic screens in a variety of membrane processes, including ER- associated degradation (ERAD), Sec61 translocon "unclogging," and potentially as a membrane protein topology determinant. Recently, an interaction was demonstrated between ZMPSTE24 and the antiviral interferon induced transmembrane protein IFITM3, although the functional significance of this interaction is poorly understood. IFITM3 is a tail-anchored protein with a cytoplasmic N-terminus, a single transmembrane span, and a lumenal/exocellular C-terminus. Here, we show that a catalytic-dead version of ZMPSTE24, ZMPSTE24E336A, exhibits enhanced binding to IFITM3, and this bound species of IFITM3 is hypo-palmitoylated. Using a split fluorescence topology reporter, we demonstrate that ZMPSTE24E336A "traps" and stabilizes a subpopulation of IFITM3 molecules with an atypical membrane topology, whose C-terminus is cytosolic instead of lumenal. Such inverted forms of IFITM3 are also detected in the presence of ERAD inhibitors or for a lysineless version of IFITM3. We hypothesize the ZMPSTE24E336A trap mutant reveals a normally transient isoform of IFITM3 whose transmembrane span is inverted and that ZMPSTE24 is involved in the quality control of IFITM3 topology, either inverting, correcting or assisting in removal of aberrant IFITM3 molecules.
    Keywords:  IFITM; ZMPSTE24/FACE-1; palmitoylation; protein quality control; transmembrane topology; trapping mutant; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.jbc.2026.113432
  47. Proc Natl Acad Sci U S A. 2026 08 18. 123(33): e2610420123
    Sorcin couples Annexin A11 recruitment to ESCRT-III assembly for plasma membrane repair.
    Jordan Matthew Ngo, Justin Krish Williams, Abinayaa Murugupandiyan, Randy Schekman.
      The absence of a cell wall affords animal cells diverse functionality at the cost of acute sensitization to plasma membrane (PM) damage. Thus, animal cells tightly monitor and maintain PM integrity to prevent cell death. Genetic loss of PM repair factors is associated with human diseases such as muscular dystrophy. Despite evidence that annexin and endosomal sorting complex required for transport (ESCRT) proteins are required for PM repair, the extent to which their recruitment is coordinated at sites of membrane damage remains unclear. Here, leveraging quantitative organellar proteomics and genome-wide CRISPR interference screens, we identify sorcin as a PM repair factor that couples annexin A11 (ANXA11)-mediated sensing of PM damage to ESCRT-III assembly. We show that sorcin directly binds ANXA11 and ALIX in the presence of Ca2+ via its penta-EF-hand domain and flexible N terminus, respectively, and is required for ESCRT-III recruitment to PM lesions and membrane resealing. Our data support a model in which ANXA11, recruited to the PM upon damage-induced Ca2+ influx, serves as an anchor that facilitates the sequential recruitment of sorcin and ESCRT-III at PM lesions. Together, these findings establish a Ca2+-dependent scaffolding mechanism that couples PM damage sensing to ESCRT-III assembly for PM repair.
    Keywords:  annexin; endosomal sorting complex required for transport (ESCRT); membrane repair; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2610420123
  48. Methods Mol Biol. 2026 ;3069 53-72
    UbiSite Approach: Global Site-Specific Profiling of Canonical and Non-Canonical Ubiquitination in Cells and Tissues.
    Nicoline Kingo Pedersen, Vyacheslav Akimov, Blagoy Blagoev.
      Ubiquitination is a complex post-translational modification that regulates a wide range of cellular processes through the covalent attachment of ubiquitin to substrate proteins. While canonical ubiquitination occurs on lysine residues, non-canonical modifications on serine, threonine, and the protein N-terminus are increasingly recognized. This chapter describes the UbiSite approach, a refined strategy for site-specific mapping of global ubiquitination using mass spectrometry-based proteomics. The method relies on digestion of the proteome of interest with LysC endopeptidase. LysC digestion leaves a 13 amino acid remnant on the ubiquitinated site of modified peptides, and this remnant is recognized by the monoclonal UbiSite antibody allowing selective enrichment of ubiquitinated peptides. Tens of thousands modification sites are readily identified from cells or tissue extracts in a single UbiSite experiment with the workflow described here. The 13 amino acid remnant is unique to ubiquitin and the UbiSite antibody thereby discriminates ubiquitin from other ubiquitin-like modifiers and enables detection of both canonical and non-canonical ubiquitination. The UbiSite procedure can be automated and combined with label-free quantification as well. UbiSite offers a robust and versatile platform for comprehensive ubiquitinome profiling with enhanced specificity and depth, enabling new insights into the regulatory roles of ubiquitin across diverse biological contexts.
    Keywords:  Affinity purification; Canonical ubiquitination; Mass spectrometry; N-terminal ubiquitination; Non-lysine ubiquitination; UbiSite; Ubiquitin; Ubiquitylation
    DOI:  https://doi.org/10.1007/978-1-0716-5508-5_4
  49. Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2519615123
    Mapping the architecture of protein complexes in Arabidopsis using cross-linking mass spectrometry.
    Cao Son Trinh, Ruben Shrestha, Pengzhi Mao, William C Conner, Andres V Reyes, Sumudu S Karunadasa, Annie Yu, Grace Liu, Ken Hu, Shou-Ling Xu.
      Capturing molecular machines in action is essential for understanding protein complex architecture, cellular regulation, and gene function. Here, we present a large-scale structural proteomics resource for Arabidopsis thaliana generated using an optimized cross-linking mass spectrometry workflow. Using the trifunctional cross-linker PhoX, whose phosphonic acid moiety enables immobilized metal affinity chromatography-based enrichment, we selectively enriched cross-linked peptides from whole-cell lysates, chloroplasts, and nuclei. Analysis with pLink 3.2 identified 52,944 unique cross-linked peptide pairs, corresponding to 37,531 residue-level contacts across 5,064 proteins. These data define 3,083 protein-protein interactions, including 2,385 heteromeric and 698 homomultimeric interactions. Comparison with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database showed that 676 interactions are supported by STRING scores ≥0.9. Structural mapping to Protein Data Bank and AlphaFold models showed that most cross-links were within the expected 35 Å distance constraint. The dataset further enabled the analysis of protein connectivity and complex topology across diverse molecular assemblies, including the Rubisco holoenzyme, chloroplast 70S ribosome, photosystem complexes, and the cytosolic 80S ribosome together with associated biogenesis and regulatory factors. We also identified histone-associated complexes, including interactions involving an O-acyltransferase. By providing residue-level structural constraints for a substantial portion of the Arabidopsis proteome, this study provides a resource for exploring plant molecular machines and their spatial organization.
    Keywords:  cross-linking mass spectrometry (XL-MS); gene annotation; protein–protein interaction network mapping; structural analysis
    DOI:  https://doi.org/10.1073/pnas.2519615123
  50. MedComm (2020). 2026 Aug;7(8): e70892
    Cardiovascular Diseases and Cancer: Convergent Proteostasis Networks at the Crossroads of Mechanisms and Therapeutic Opportunities.
    Jacob Eli García Torres, Norbert Frey, Ashraf Yusuf Rangrez.
      Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment-related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress-response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer-cardiovascular interface. We analyze how the ubiquitin-proteasome system, autophagy-lysosome pathway, endoplasmic reticulum stress-induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy-induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio-oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.
    Keywords:  CVDs; ER stress; autophagy; cancer; cardiotoxicity; cardio‐oncology; drug repurposing; proteostasis; ubiquitin–proteasome system; unfolded protein response
    DOI:  https://doi.org/10.1002/mco2.70892
  51. Proc Natl Acad Sci U S A. 2026 Aug 18. 123(33): e2606609123
    Codon optimization depletes stop codons in alternative reading frames of protein-coding nucleic acid therapeutics.
    Zheling Liu, Zhenguang Ying, Luoan Shen, Weirui Ma.
      Out-of-frame translation events, arising from ribosomal frameshifting or noncanonical initiation, are an unavoidable feature of translation. Their consequences depend on the distribution of stop codons in alternative reading frames, which determines the permissiveness of those frames: whether out-of-frame translation terminates quickly or generates extended products. Using quantitative dual-fluorescence reporters, we show that these stop codons function as molecular checkpoints that terminate out-of-frame translation. Genome-wide analysis across 10 organisms reveals that natural coding sequences maintain dense stop codon distributions in alternative frames, with a median spacing of approximately 20 amino acids. Codon optimization, the standard method for enhancing translation, systematically depletes this safeguard. Because all three stop codons (UAA, UAG, UGA) begin with uridine, and optimal human codons exclude uridine from third positions, stop codons in the -1 reading frame become structurally impossible in codon-optimized sequences. Analysis of 120 therapeutic sequences, including FDA-approved COVID-19 messenger RNA (mRNA) vaccines, confirms widespread -1 frame stop codon depletion: out-of-frame products average 164 amino acids, sixfold longer than in natural human genes. Strategic restoration of stop codons through synonymous substitutions eliminates detectable out-of-frame products by mass spectrometry while preserving the intended protein. Although such products and immune responses have been detected in COVID-19 mRNA vaccine recipients, there is no evidence they cause clinical harm; nonetheless, our approach offers a simple way to eliminate them through informed sequence design alone, without changes to manufacturing or regulatory frameworks. Our findings establish stop codon distribution as a critical design parameter for protein-coding nucleic acid therapeutics.
    Keywords:  alternative reading frames; codon optimization; mRNA therapeutics; out-of-frame translation; stop codons
    DOI:  https://doi.org/10.1073/pnas.2606609123
  52. Traffic. 2026 Sep;27(3): e70045
    Mechanism of Autophagic Extracellular Vesicles Revealed.
    Constantinos Demetriades, Thierry Galli.
      Recent work by Mao and colleagues identifies a distinct class of small extracellular vesicles, termed autophagic extracellular vesicles (AEVs), generated from amphisomes upon autophagy induction. In this commentary, we discuss how this study provides important mechanistic insight into the coupling between autophagy and secretion. AEVs are molecularly and functionally distinct from canonical exosomes, being enriched in autophagy-related components such as LC3 and p62, and dependent on core ATG machinery for their biogenesis. Notably, their secretion is enhanced by autophagy induction and contributes to intercellular communication, particularly in the context of viral infection. These findings position amphisomes as critical sorting hubs that direct cargo toward either degradation or secretion, thereby integrating autophagic and endolysosomal pathways. We further highlight how these results intersect with prior evidence implicating SNARE-dependent mechanisms, including VAMP7 and stress-responsive regulators such as GRASP55, in unconventional secretion. Finally, we discuss key unresolved questions, particularly the mechanisms underlying the generation of small intraluminal vesicles within amphisomes and the role of ESCRT machinery in this process. Overall, the identification of AEVs adds a new layer of complexity to extracellular vesicle biology and opens new avenues for understanding how autophagy contributes to intercellular signaling in health and disease.
    DOI:  https://doi.org/10.1111/tra.70045
  53. Nucleic Acids Res. 2026 Aug 10. pii: gkag761. [Epub ahead of print]54(15):
    Sparsomycin inhibits translation through a conserved mechanism across all domains of life.
    Madhura N Paranjpe, Elodie C Leroy, Egor A Syroegin, Laurin Flemmich, Julia Thaler, Mélanie Gillard, Anthony Bougas, Georgia Kournoutou, George P Dinos, Thibaud T Renault, Ronald Micura, C Axel Innis, Yury S Polikanov.
      Sparsomycin (SPA) is a broad-spectrum inhibitor of protein synthesis with activity across all three domains of life. Although SPA has long been known to target the ribosomal peptidyl transferase center (PTC), previous structural studies suggested that SPA binds differently to bacterial ribosomes compared to their archaeal and eukaryotic counterparts-an unexpected conclusion given the high evolutionary conservation of the ribosomal catalytic center. Here, we show that SPA inhibits a majority of elongation-competent bacterial ribosomal complexes and present X-ray crystal structures of Thermus thermophilus 70S ribosomes stalled by SPA at the initiation and early elongation stages of translation. These structures reveal that SPA binds to the bacterial ribosome in a manner essentially identical to that observed in archaeal and eukaryotic ribosomes, establishing a unified structural mechanism of SPA action across all domains of life. In this conserved binding mode, SPA occupies the A-site cleft of the PTC and forms an extensive network of interactions with universally conserved ribosomal RNA nucleotides and the CCA-end of the P-site transfer RNA (tRNA), thereby stabilizing the peptidyl-tRNA substrate while sterically blocking accommodation of an incoming aminoacyl-tRNA. By clarifying the mode of action of SPA on the bacterial ribosome, our work provides a structural framework for the rational design of SPA derivatives with improved potency and bacterial specificity.
    DOI:  https://doi.org/10.1093/nar/gkag761
  54. Autophagy Rep. 2026 ;5(1): 2705631
    FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer.
    Halvor Ullern, Julie Aarmo Johannessen, Feyza Kasikci, Miriam Formica, Naghmeh Karimi Melve, Siri Andresen, Andreas Brech, Karol Axcrona, Kjersti Jørgensen, Lorant Farkas, Jorrit M Enserink, Helene Knævelsrud.
      Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation were unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate aberrant p62 accumulation in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate that FLCN loss is characterized by SQSTM1/p62 accumulation, although SQSTM1/p62 appears dispensable for anchorage-independent growth in cell models.
    Keywords:  Autophagy; BHD; FLCN; SQSTM1/p62; renal cell carcinoma
    DOI:  https://doi.org/10.1080/27694127.2026.2705631
  55. Free Radic Biol Med. 2026 Aug 11. pii: S0891-5849(26)01023-3. [Epub ahead of print]255 830-842
    Protein persulfidation emerges as a conserved component of the redox response to DNA damage.
    Damián Ramírez-Robles, Emilio Espinoza-Simón, Marijose López-Miranda, Karen Juárez-Meléndez, Elías Nieto-Zaragoza, Kevin Torres-Marcial, Emmanuel Ríos-Castro, Milos Filipovic, Francisco Torres-Quiroz.
      Genotoxic stress is frequently accompanied by alterations in cellular redox homeostasis; however, the mechanisms linking redox regulation to the DNA damage response (DDR) remain incompletely understood. Here, we investigated the early redox response to DNA damage induced by methyl methanesulfonate (MMS) in Saccharomyces cerevisiae, focusing on cysteine oxidative post-translational modifications (PTM). We show that activation of the DNA damage response is accompanied by rapid redox changes that occur in the absence of a generalized oxidative stress response. MMS exposure promotes selective remodeling of cysteine oxidative modifications, characterized by decreased free thiols, robust induction of protein persulfidation, and comparatively modest changes in sulfenylation. These alterations are accompanied by increased intracellular hydrogen sulfide levels, supporting the involvement of reactive sulfur species in the cellular response to DNA damage. Proteome-wide analyses revealed that cysteine oxidative modifications preferentially target proteins involved in central metabolism, nucleotide biosynthesis, and genome maintenance. Consistent with these observations, MMS-induced genotoxic stress promotes metabolic adaptation characterized by increased mitochondrial respiration, elevated ATP production, and mitochondrial morphological remodeling, linking bioenergetic adaptation to redox regulation. Importantly, perturbation of intracellular redox balance using N-acetylcysteine compromises survival under DNA-damaging conditions, supporting a functional role for redox signaling during the DDR. Finally, MMS treatment also induces protein persulfidation in mammalian cells. Moreover, exposure to etoposide, a mechanistically distinct genotoxic agent that induces DNA double-strand breaks through topoisomerase II inhibition, showed a similar trend, suggesting that protein persulfidation may not be restricted to alkylation-induced DNA damage. Together our findings identify protein persulfidation as a prominent component of the redox response to DNA damage and provide new insight into the functional interplay between mitochondrial metabolism, cysteine-based redox regulation, and genome maintenance.
    Keywords:  DNA damage response; MMS; Persulfidation; Sulfenylation; Yeast
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.021
  56. FEBS Lett. 2026 Aug 10.
    Peripheral lysosomes recruit PLEKHG3 to focal adhesions and restrain protrusion dynamics.
    Rainer Ettelt, Ana-Maria Sandru, Georg Vucak, Sebastian Didusch, Biljana Riemelmoser, Karin Ehrenreiter, Markus Hartl, Lukas A Huber, Manuela Baccarini.
      Lysosomes are dynamic organelles regulating metabolic signaling by recruiting cytosolic molecules to protein platforms on their limiting membrane. We used proximity labeling to define interactors and vicinal proteins of LAMTOR3, a component of the Ragulator scaffold that controls mTORC1 signaling and lysosome positioning. The screen has yielded several previously unappreciated interactors, including an actin remodeling network. Here, we characterize the RhoGEF PLEKHG3 as a LAMTOR3 vicinal protein colocalizing with peripheral lysosomes and cortical F-actin at focal adhesion sites. Forced peripheral dispersion of lysosomes drives PLEKHG3 accumulation at focal adhesions and decreases protrusive activity in both wild-type and PLEKHG3-deficient cells. Thus, lysosome positioning governs both PLEKHG3 localization and protrusive activity, yet the protrusion changes can occur independently of PLEKHG3.
    Keywords:  LAMTOR; PLEKHG3; cell motility; cytoskeleton; focal adhesions; lysosomes
    DOI:  https://doi.org/10.1002/1873-3468.70428
  57. Plant Physiol. 2026 Aug 11. pii: kiag587. [Epub ahead of print]
    RING-type E3 ligase RhSAREL promotes flower senescence by differentially regulating two TMBIM family members, RhTMBIM1 and RhTMBIM7, in Rosa hybrida.
    Jin Chen, Wentong Zhou, Siqi Zhao, Yubi Su, Yuhan Fan, Yuanyuan Wang, Jiaqi Zhao, Yiqing Liu, Feifei Yu, Changqing Zhang.
      Flower senescence significantly impacts the postharvest quality of cut roses (Rosa hybrida). E3 ligases orchestrate a diverse array of processes in plants, including organ development and stress responses. However, the molecular mechanisms of E3 ligases in flower senescence remain largely unknown. Here, we report that Senescence-associated RING-type E3 ligase (RhSAREL), a RING-H2 E3 ligase gene, is highly expressed at the early stage of flower senescence. RhSAREL-RNAi transgenic rose plants showed increased flower longevity. We confirmed that RhSAREL interacts individually with two Transmembrane BAX Inhibitor-1 Motif-containing (TMBIM) family proteins, RhTMBIM1 and RhTMBIM7, both in vivo and in vitro. Both RhTMBIM1 and RhTMBIM7 showed stable transcript levels during flower senescence, while silencing RhTMBIM1 or RhTMBIM7 accelerated flower senescence. Biochemical assays revealed that RhSAREL ubiquitinates RhTMBIM7 and promoted its degradation via the 26S proteasome pathway, but not so for RhTMBIM1. Protein docking and interface analysis showed that RhSAREL blocks RhTMBIM1's calcium (Ca2+) leakage channel through its key N-terminal 26-amino-acid region. This interaction conformation disrupts RhTMBIM1-mediated Ca2+ homeostasis, thereby accelerating petal programmed cell death and senescence. Taken together, the RING-H2 E3 ligase RhSAREL promotes rose flower senescence by differentially regulating RhTMBIM1 and RhTMBIM7 via E3 ligase activity-independent and -dependent pathways, respectively.
    DOI:  https://doi.org/10.1093/plphys/kiag587
  58. Curr Res Microb Sci. 2026 ;11 100653
    Stress-induced remodeling of membrane-bound organelles in budding yeast.
    Peng Sheng, Mengna Sun, Xinyue Wang, Lizhe Bai, Hong Cao, Dan Li.
      Membrane-bound organelles undergo extensive remodeling during environmental stress, yet systematic side-by-side comparisons of organelle responses in budding yeast remain limited. Here, a panel of fluorescent markers was used to examine multiple organelles in Saccharomyces cerevisiae exposed to heat, hydrogen peroxide, acetic acid, or ethanol. Across all conditions, mitochondria consistently shifted from tubular networks to fragmented puncta, representing a common stress response. Quantitative scoring showed that heat stress induced mitochondrial fragmentation in more than 90% of cells within 20 min, and GFP-HDEL redistribution was detected in a substantial fraction of cells under all four stress conditions, with the strongest effect under heat stress. In contrast, overall endoplasmic reticulum (ER) morphology remained largely preserved, although redistribution of GFP-HDEL indicated altered ER retention and/or endomembrane homeostasis. Heat and oxidative stress also induced Ire1 puncta. Several nuclear proteins exhibited stress-dependent redistribution from the nucleus, indicating dynamic remodeling of nuclear protein localization. Vacuoles generally appeared enlarged and fused, whereas acetic acid induced a distinct phenotype with Ybh3 enrichment at the vacuolar membrane and redistribution of Prc1 and Pep4 to cytoplasmic puncta. Markers of the early and late Golgi and the late endosome showed stress-specific loss, clustering, or relocalization. Lipid droplets, peroxisomes, and autophagy-related structures were also altered. Additionally, Yca1, Aif1, and Mmi1 formed puncta under heat and ethanol stress. Together, these findings provide a comparative imaging framework defining shared and stress-specific features of organelle remodeling in budding yeast.
    Keywords:  Budding yeast; Endoplasmic reticulum; Environmental stress; Fluorescence imaging; Mitochondria; Organelle remodeling
    DOI:  https://doi.org/10.1016/j.crmicr.2026.100653
  59. STAR Protoc. 2026 Aug 10. pii: S2666-1667(26)00427-2. [Epub ahead of print]7(3): 104774
    Protocol for proteomic profiling of hypusinated protein candidates using a clickable spermidine probe.
    Tian Zhang, Jianlong Li, Xinbo Hu, Hua Zhu, Xin Zhou, Zheng-Jiang Zhu, Li Tan, Zhaoyin Wang, Yaoyang Zhang, Junying Yuan, Bing Shan.
      Hypusination is a unique posttranslational modification in which deoxyhypusine synthase (DHPS) transfers an aminobutyl moiety from spermidine to specific lysine residues, followed by deoxyhypusine hydroxylase (DOHH)-mediated hydroxylation. Here, we present a protocol that enables proteome-wide identification of candidate hypusinated proteins. We describe steps for the synthesis of a clickable alkynyl-spermidine probe, DHPS-dependent metabolic labeling in cells, click chemistry-mediated biotinylation, streptavidin-based enrichment, and subsequent mass spectrometry analysis of probe-labeled proteins. We also describe the procedures for data processing and statistical analysis. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.
    Keywords:  Cell Biology; Mass Spectrometry; Molecular/Chemical Probes
    DOI:  https://doi.org/10.1016/j.xpro.2026.104774
  60. FEBS J. 2026 Aug 11.
    p62/SQSTM1: From an autophagy receptor to a condensate organizer of selective autophagy and stress signaling.
    Jun-Ichi Sakamaki, Masaaki Komatsu.
      Upon exposure to stress, cells activate a variety of stress-response and quality-control mechanisms to maintain homeostasis. Dysregulation of these processes is implicated in numerous diseases, including cancer, liver disorders, and neurodegenerative diseases. p62/Sequestosome 1 (SQSTM1) is a multifunctional protein that plays a central role in protein homeostasis and stress responses by regulating autophagy and signal transduction pathways. Through its multiple protein-interacting domains, p62 functions both as a scaffold for selective autophagic degradation and as a signaling hub. Since our previous review of p62 a decade ago, substantial progress has been made in elucidating its molecular functions and physiological roles. Notably, p62 undergoes liquid-liquid phase separation with ubiquitinated proteins to form membraneless condensates, termed p62 bodies, when cells are exposed to proteotoxic stress. By sequestering specific proteins, p62 bodies act as platforms for autophagy-dependent degradation and stress signaling. These findings have substantially revised our view of p62 function, which was previously considered primarily as a receptor simply linking ubiquitinated substrates to autophagic membranes and connecting signaling molecules. This conceptual shift from one-to-one molecular interactions to multivalent, multimolecular, higher-order assemblies has fundamentally redefined the functional landscape of p62. In this review, we highlight how p62 bodies integrate selective autophagy and stress signaling, with a particular emphasis on their emerging roles in disease pathogenesis and their potential as therapeutic targets.
    Keywords:  KEAP1‐NRF2 pathway; liquid–liquid phase separation; p62 body; p62/SQSTM1; selective autophagy; ubiquitination
    DOI:  https://doi.org/10.1111/febs.70689
  61. J Biol Chem. 2026 Aug 10. pii: S0021-9258(26)02299-4. [Epub ahead of print] 113427
    E3 ligase RNF145 regulates airway smooth muscle cell proliferation via the PP2A-p70S6K signaling axis.
    Vijaya Kumar Gangipangi, Erin O Curley, Deepak A Deshpande, Pawan Sharma.
      Airway smooth muscle (ASM) is a key determinant of airway caliber and a major contributor to structural remodeling in obstructive lung diseases, including asthma and COPD. ASM proliferation is regulated by transcriptional and post-transcriptional mechanisms, including ubiquitin-dependent protein turnover mediated by E3 ubiquitin ligases. Here, we investigated the role of the RING-type E3 ligase RNF145 in mitogenic signaling and ASM cell proliferation. Human ASM cells were transfected with RNF145 shRNA or treated with the E3 ligase inhibitor SMER3, followed by stimulation with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF). RNF145 knockdown or SMER3 treatment dose-dependently inhibited mitogen-induced ASM cell proliferation without inducing cytotoxicity, supporting a pro-mitogenic role for RNF145. Both interventions reduced phosphorylation of p70S6K at Thr421/Ser424 and Thr389 without affecting ERK MAPK signaling. Inhibition of PP2A and PP1 with okadaic acid or calyculin A restored p70S6K phosphorylation in RNF145-deficient cells, while SMER3 increased serine/threonine phosphatase activity. Mechanistically, RNF145 promoted K48-linked ubiquitination and proteasomal degradation of the PP2A scaffold subunit Aα, thereby limiting PP2A holoenzyme assembly during mitogenic signaling. Re-expression of RNF145 in RNF145-deficient cells reduced PP2A Aα abundance and restored p70S6K activation and ASM cell proliferation. These findings identify RNF145 as a positive regulator of ASM cell proliferation that sustains p70S6K signaling by suppressing PP2A. The RNF145-PP2A-p70S6K axis may therefore represent a therapeutic target for airway remodeling in chronic obstructive airway diseases.
    Keywords:  E3 ubiquitin ligase; airway remodeling; airway smooth muscle; cell proliferation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113427
  62. Cell Death Differ. 2026 Aug 10.
    RNF5 promotes acute lung injury through HSPA5 ER-to-cytosol translocation and resultant PERK activation.
    Ya-Zhou Sun, Xin-Yan Li, Jia Wang, Meng-Liu Zeng, Wei-Yi Qu, Xu Cheng, Lei Luo, Wei Wang, Juan Yang, Jun Zhang, Han Tian, Peng Zhang, Zhi-Gang She, Hongliang Li, Xiao-Jing Zhang.
      Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions lacking specific pharmacological treatments. Endoplasmic reticulum (ER) stress plays a pivotal role in their pathophysiology, yet the precise regulatory mechanisms remain elusive. In this study, we identify the E3 ubiquitin ligase ring finger protein 5 (RNF5) as a critical driver of ALI/ARDS. RNF5 is markedly upregulated in response to ALI and significantly exacerbates lung injury by stabilizing HSPA5 (heat shock protein family A member 5), a master regulator of the unfolded protein response (UPR). Notably, in vivo Rnf5 ablation effectively attenuated pulmonary edema, inflammatory cell infiltration, and apoptosis, whereas lung-specific Rnf5 overexpression worsened inflammation and cell death in mice. Mechanistically, RNF5 interacts with HSPA5 and competitively blocks its binding to PERK, facilitating PERK release. Furthermore, RNF5 promotes the retro-translocation of HSPA5 from the ER lumen to the cytosol. In the cytosol, RNF5 mediates the K6- and K63-linked polyubiquitination of HSPA5, enhancing its thermal stability and preventing its re-entry into the ER. This spatial sequestration sustains the persistent dissociation of the PERK-HSPA5 complex, leading to the hyperactivation of the pro-apoptotic and pro-inflammatory PERK-eIF2α-CHOP signaling cascade. The ability of RNF5 to promote ALI is strictly dependent on its E3 ligase activity. In conclusion, our findings uncover a compartment-specific regulatory mechanism of HSPA5, suggesting that the RNF5-HSPA5-PERK axis represents a promising therapeutic target for ALI/ARDS.
    DOI:  https://doi.org/10.1038/s41418-026-01843-1
  63. Dev Cell. 2026 Aug 12. pii: S1534-5807(26)00277-7. [Epub ahead of print]61(8): 1593-1594
    Wiring autophagy: Neural circuits regulate lysosomal homeostasis in muscle.
    Min Chen, Congcong He.
      Autophagy is commonly viewed as a cell-autonomous degradative process governed by intracellular metabolic and stress signals,1 but how autophagy is coordinated across tissues in multicellular organisms remains unclear. Zheng et al. 2 identify two parallel neuronal circuits that non-cell-autonomously regulate muscle autophagy in C. elegans, revealing an unexpected role for the nervous system in orchestrating peripheral autophagy.
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.008
  64. Acta Crystallogr F Struct Biol Commun. 2026 Sep 01.
    Molecular insights into NLRP1 Gly/N-degron recognition by CRL2ZER1.
    Bing Zhang, Tao Wang, Liuyu Wang, Junlin Li, Quanyan Liu, Cheng Dong.
      The Gly/N-degron pathway is a branch of the proteasomal degradation pathway that specifically targets proteins initiated with an N-terminal glycine. The E3 ligase substrate adaptors ZYG11B and ZER1 have been identified as being responsible for recognizing the target proteins of the Gly/N-degron pathway. Previously, it has been shown that the Gly/N-degron pathway activates the human NLRP1 inflammasome by degrading the autoinhibitory N-terminal fragment of NLRP1 after cleavage by the enteroviral 3C protease. However, the recognition of the NLRP1 Gly/N-degron is not yet fully understood. Here, we determined the X-ray crystal structure of ZER1 bound to the NLRP1 Gly/N-degron at a resolution of 2.2 Å. The structural information revealed that ZER1 uses its ARM repeats to form a conserved cavity that engages the N-terminal glycine (G1) through hydrogen bonds to Asp556, Asn597 and Glu600. Structural comparisons show a shared recognition mode for Gly/N-degrons despite subtle differences in side-chain interactions. However, ZER1 exhibits weaker affinity for the NLRP1 Gly/N-degron than ZYG11B, likely due to distinct local environments surrounding position 3. This study elucidates the molecular basis of NLRP1 recognition by ZER1 and provides insights into targeting this pathway in inflammatory diseases.
    Keywords:  E3 ligases; NLRP1 Gly/N-degron; ZER1; crystal structure
    DOI:  https://doi.org/10.1107/S2053230X26007715
  65. Dev Cell. 2026 Aug 13. pii: S1534-5807(26)00283-2. [Epub ahead of print]
    Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors.
    Shota Nakanoh, Despina Stamataki, Lorena Garcia-Perez, Chiara Azzi, Hayley L Carr, Alexandra Pokhilko, Loukik Doshi, Giulia L M Boezio, Hilary Knowles, Adriana Lamas Bancalari, Manuela Melchionda, Lu Yu, Steven Howell, Mark Skehel, David Oxley, Simon Andrews, James Briscoe, Teresa Rayon.
      The pace of embryonic development differs between mammalian species, yet the molecular basis for this remains unknown. By comparing protein dynamics in mouse and human neural progenitors (NPs), we show that protein turnover is faster in mouse NPs, driven by higher rates of protein synthesis and degradation. Human NPs exhibit longer protein half-lives, reduced proteasomal activity, and lower proteasome abundance. These differences persist in post-mitotic neurons and are also observed in the embryonic spinal cord in vivo. Pharmacological inhibition of proteasomal activity slows differentiation in mouse NPs. Conversely, enhancing proteasomal activity accelerates neuronal output in human NPs. Moreover, accelerating the degradation of the key transcriptional repressor IRX3 in mouse NPs speeds the activation of its target gene. Together, these results provide evidence that species-specific regulation of proteasome-mediated proteolysis influences the timing of neural development and suggest that evolutionary tuning of proteasomal activity contributes to differences in embryonic developmental pace.
    Keywords:  UPS; developmental tempo; dynamic SILAC proteomics; gene regulatory network; neural progenitors; post-transciptional regulation; proteasome; protein degradation; proteostasis; spinal cord; stem cells; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.devcel.2026.07.014
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