bims-proteo Biomed News
on Proteostasis
Issue of 2026–10–11
forty-six papers selected by
Eric Chevet, INSERM
  1. Responses to endoplasmic reticulum stress at a glance.
  2. 40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
  3. MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy.
  4. Cornichon receptors couple membrane adaptation to cargo selection during ER export.
  5. Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
  6. Quasi-continuous cotranslational compaction and folding of a multidomain protein.
  7. Oligo(uridine) tailing and exonucleolytic decay drive 40S ribosome degradation in response to stress.
  8. The cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold.
  9. TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.
  10. Protein homeostasis and inter-organellar signaling under salt stress.
  11. The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics.
  12. Intramembrane proteolysis: principles of substrate recognition and membrane protein fate.
  13. GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.
  14. SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
  15. Loss of Selenot in POMC Neurons Disrupts ER Homeostasis and Induces A Senescent-like Phenotype.
  16. Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.
  17. Global and specific mechanisms stimulate mistranslation in cancer.
  18. Spatially resolved reaction-diffusion modeling reveals effects of intracellular spatial heterogeneity on yeast galactose network dynamics.
  19. Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.
  20. Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression.
  21. Modeling Protein Diffusion Across ER-Nuclear Envelope Junctions Reveals Efficient Transport via Simple Diffusion.
  22. Real-time single-molecule imaging in zebrafish embryos uncovers noncanonical translation.
  23. Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
  24. Small-Molecule Modulators of HIPK4 Activity and Proteostasis.
  25. Targeting ZDHHC15-mediated S-acylation of CD155 reactivates anti-tumor immunity.
  26. Mechanically Regulated Secretion: How Physical Forces Instruct the Secretory Pathway and Remodel the Secretome.
  27. Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
  28. Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.
  29. Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
  30. Synaptic Proteostasis in Health and Disease.
  31. Adipocyte-derived exosomal ANGPTL2 promotes beta cell dysfunction via the EIF2α/ATF4/CHOP stress pathway in mice.
  32. Distinct Regulatory Logic Controls Recruitment and Membrane Dynamics of ESCRT-III Subunit Vps60.
  33. RSL24D1 links ribosome biogenesis to p53 activation in melanoma.
  34. Targeting the Ero1α-PDI oxidative protein folding pathway as a broad-spectrum strategy against coronavirus.
  35. TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.
  36. Molecular basis for the regulation of the SUMOylation activity of the Smc5/6 complex by Esc2.
  37. Bidirectional photoriboswitch for translational regulation in mammalian cells.
  38. Mechanism of spliceosome termination.
  39. Lipid remodeling enables adaptation to chronic hyperosmotic stress.
  40. A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.
  41. Biased stochastic motor dynamics drive bidirectional, processive translocation by the AAA+ disaggregase Hsp104.
  42. The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.
  43. ER-Nε-lysine acetylation machinery in neurological disorders: A context-dependent regulator of proteostasis.
  44. De novo design of autocatalytically forming intra- and intermolecular isopeptide bonds to construct rigid covalent protein assemblies.
  45. Ubiquitination of LMP-1 by UFD-2 regulates apoptotic cell clearance.
  46. EV-SPEC: Decoding the Spatial Proteomic Signature of the Extracellular Vesicle Corona.
  1. J Cell Sci. 2026 Oct 01. pii: jcs264817. [Epub ahead of print]139(19):
    Responses to endoplasmic reticulum stress at a glance.
    Eric Chevet, Céline Philippe, Tony Avril, Elodie Lafont.
      The endoplasmic reticulum (ER) is the gateway to the eukaryotic protein secretory pathway. Beyond its role in protein biogenesis, it is central to Ca2+ homeostasis and lipid biosynthesis. This organelle, which can constitute more than 50% of the cellular membranes in secretory cells, is highly plastic and must adjust to intracellular or extracellular challenges to ensure proper protein secretion. ER stress, resulting from challenges such as accumulation, misfolding or aggregation of proteins or from disrupted ER lipid composition, can deleteriously affect cell function. Thus, the ER has evolved adaptive mechanisms that lead to cellular reprogramming to adjust its capacity to handle stress, including the unfolded protein response (UPR), which engages various ER quality control systems, protein degradation pathways and ER-organelle contacts. If this succeeds, the cell survives; but if it fails, cell death mechanisms are triggered. In this Cell Science at a Glance article and the accompanying poster, we summarize current knowledge on ER stress and control of the UPR in mammalian cells, highlighting aspects that require further attention. We also discuss recent insights that must be considered to better capture the full understanding of the ability of the ER to adjust to biological variation.
    Keywords:  Contact sites; Endoplasmic reticulum; Proteostasis; UPR; Unfolded protein response
    DOI:  https://doi.org/10.1242/jcs.264817
  2. Mol Cell. 2026 Oct 09. pii: S1097-2765(26)00665-9. [Epub ahead of print]
    40S ribosome remodeling triggers 18S rRNA U-tailing and DIS3L2-dependent decay.
    Akruti Shah, Aaztli R Coria, Jennifer T Miller, Emilien Orgebin, Wilfried Guiblet, Acong Yang, Shuo Gu, Colin Chih-Chien Wu.
      Eliminating defective ribosomes through quality control is essential for accurate protein synthesis. However, the mechanisms that commit defective ribosomal subunits to decay remain poorly defined. Here, we identify a tandem mechanism in which ubiquitin-dependent ribosome remodeling and 18S rRNA uridylation lead to 40S ribosomal subunit decay. Specifically, we use an in vitro reconstitution system to show that the atypical kinase RIOK3 remodels 40S ribosomal subunits, thereby exposing the 3' end of 18S rRNA. Nanopore direct RNA sequencing reveals that this remodeling event promotes oligo-uridylation, generating uridylated 18S rRNA decay intermediates. Uridylated 18S rRNA is further degraded by the 3'-5' exoribonuclease DIS3L2. Moreover, DIS3L2-mediated exoribonucleolytic cleavage triggers endoribonucleolytic decay of the 18S rRNA, amplifying turnover. Together, our findings define a stepwise mechanism in which ribosome remodeling and RNA tailing commit defective 40S subunits to elimination, establishing a mechanistic framework for ribosome surveillance in mammalian cells.
    Keywords:  18S rRNA decay; DIS3L2; RIOK3; RNF10; TUT4/7; ribosome turnover; uridylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.022
  3. J Cell Biol. 2026 Nov 02. pii: e202601047. [Epub ahead of print]225(11):
    MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy.
    Yuanjiao Du, Tiantian Zhou, Yazhou Liu, Nanxin Ye, Bing Zou, Weiping Chang, Lin Deng, Wei-Ke Ji.
      ATG2A transfers glycerophospholipids from the endoplasmic reticulum (ER) to the expanding phagophore during autophagy, but how it is anchored to the ER in mammalian cells has been unclear. Here, we identify MOSPD3, an atypical member of the VAP family, as the ER adaptor for ATG2A. Endogenous MOSPD3 occupies ER subdomains adjacent to nascent autophagic structures, and it captures ATG2A through a direct interaction between its major sperm protein (MSP) domain and an FFNT (two phenylalanines in a neutral tract) motif near the ATG2A N terminus. Disrupting either side of this interface abolishes ER recruitment and prevents ATG2A from supporting autophagy. Its paralog MOSPD1 acts redundantly on ATG2B, and cells lacking both adaptors are defective in autophagic flux. MSP-FFNT recognition therefore provides the ER-side anchor that positions the ATG2A lipid-transfer bridge for autophagosome biogenesis.
    DOI:  https://doi.org/10.1083/jcb.202601047
  4. bioRxiv. 2026 Aug 10. pii: 2026.08.07.743479. [Epub ahead of print]
    Cornichon receptors couple membrane adaptation to cargo selection during ER export.
    Jude Tunyi, Oliver Adams, Siân Holton, Martyna Biaduń, Nathan Bernhardt, Gabriel Kuteyi, Omar Pantoja, Lucy R Forrest, Joanne L Parker, Simon Newstead.
      Selective export of membrane proteins from the endoplasmic reticulum (ER) is fundamental for eukaryotic cell biology, yet how trafficking receptors coordinate cargo recognition with membrane adaptation and COPII recruitment remains unknown. Cornichon homolog (CNIH) proteins comprise a conserved family of trafficking receptors that mediate ER export of ion channels, G protein-coupled receptors (GPCRs), ATP-binding cassette (ABC) and solute carrier (SLC) transporters. Here, we determine cryo-electron microscopy structures of the prototypical cornichon receptor Erv14 bound to an SLC transporter in detergent and lipid nanodiscs. We show that cargo recognition is mediated by a dynamic network of interactions, in which structural lipids stabilize the receptor-cargo interface. Nanodisc structures reveal the assembly of a second Erv14 receptor that remodels the receptor-cargo interface in response to membrane architecture, thereby reducing local membrane thickness and providing direct structural evidence that cornichon receptors buffer hydrophobic mismatch during membrane protein biogenesis. Structural and trafficking analyses further show that the second receptor recruits the COPII adaptor Sec24, coupling membrane remodelling to cargo export. Together, our findings establish that cornichon receptors couple lipid-mediated membrane adaptation with cargo selection through sequential receptor assembly, linking membrane protein folding to selective COPII-mediated ER export.
    One sentence summary: Cornichon receptors integrate membrane adaptation with cargo recognition to coordinate membrane protein quality control and selective ER export.
    DOI:  https://doi.org/10.64898/2026.08.07.743479
  5. Mol Cell. 2026 Oct 07. pii: S1097-2765(26)00629-5. [Epub ahead of print]
    Ribosome remodeling drives translation adaptation during viral infection and cellular stress.
    Hsin-Yu Tsai, Luochen Liu, Rebecca H Fleming, Julian Mintseris, Derrick Ekanayake, Jing A Guo, Xin Gu, Steven P Gygi, Amy S Y Lee.
      The ribosome is the highly conserved molecular machine that decodes mRNAs during protein synthesis. Here, we discover that, while traditionally thought to consist of a uniform set of proteins, ribosome composition is reprogrammed to adapt to intrinsic and external cellular perturbations. During infection of human cells by non-segmented negative-sense viruses, viral entry into cells recruits the large ribosomal subunit protein rpL40 to a non-canonical site on the small subunit of 80S ribosomes near the mRNA entry site. These specialized ribosomes preferentially bind viral mRNAs to drive enhanced viral protein synthesis that is critical for replication under host pressures. Unexpectedly, we find that viruses have co-opted this translation pathway from a previously unrecognized endogenous ribosome remodeling program in which metabolic stress alters ribosome structure to promote mRNA translation required for cell survival. Thus, ribosome remodeling is a conserved mechanism that enables dynamic protein synthesis across pathogen and cellular adaptation.
    Keywords:  cell stress; ribosome; ribosome heterogeneity; rpL40; translation regulation; virus
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.008
  6. Nat Commun. 2026 10 05. pii: 10495. [Epub ahead of print]17(1):
    Quasi-continuous cotranslational compaction and folding of a multidomain protein.
    Spyridoula Mitsikosta, Justin M Westerfield, Fátima Pardo-Avila, Michael Levitt, Gunnar von Heijne, Ane Metola.
      Most proteins start to fold cotranslationally as they come off the ribosome. So far, studies of cotranslational folding have focused mainly on small, single-domain proteins. Here, we have used Force Profile Analysis to study the cotranslational folding of Firefly Luciferase, a complex 550-residue protein composed of an N-terminal domain (NTD) encompassing two split Rossmann folds (RF-1, RF-2) and a β-roll, and a flexibly attached C-terminal domain (CTD). The folding process is characterized by a quasi-continuous series of compaction/folding steps that generate intermediate-size pulling forces on the nascent chain, punctuated by a prominent high-force event that represents the folding of the RF-2 domain, and a few low-force instances that likely indicate the formation of distinct folding intermediates. Trigger Factor interacts extensively with the nascent chain when the central part of RF-2 and the early parts of the CTD are synthesized. Our analysis uncovers a cotranslational compaction/folding process that is rich in detail and not just a simple succession of a few distinct, cooperative folding transitions.
    DOI:  https://doi.org/10.1038/s41467-026-78090-y
  7. Mol Cell. 2026 Oct 09. pii: S1097-2765(26)00664-7. [Epub ahead of print]
    Oligo(uridine) tailing and exonucleolytic decay drive 40S ribosome degradation in response to stress.
    Frances F Diehl, Allen R Buskirk, Rachel Green.
      Stresses like starvation trigger degradation of mature 40S ribosomes, requiring the coordinated breakdown of large, stable RNA-protein complexes. The atypical kinase RIOK3 orchestrates degradation by binding ubiquitylated 40S ribosomes and promoting rRNA decay. However, the mechanisms and factors that mediate rRNA decay remain unknown. Here we find that in response to starvation, RIOK3 recruits the terminal uridylyl-transferase TUT7 and the exonuclease DIS3L2 to 40S ribosomes. Sequencing analyses show that TUT7 adds oligo(uridine) tails to the 3' end of 18S rRNA in these ribosomes. DIS3L2 subsequently recognizes uridylated 18S rRNA and carries out 3'-5' decay. We identify major decay intermediates that undergo further uridylation in a process of iterative uridylation and decay. Loss of DIS3L2 impairs 18S rRNA decay during starvation and leads to accumulation of uridylated 18S rRNA. Together these findings define a mechanism for ribosome degradation in human cells in which oligo(uridine) tailing drives decay of rRNA from ribosomes.
    Keywords:  DIS3L2; RIOK3; RNA decay; Ribosome; TUT7; rRNA; starvation; stress response; uridylation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.021
  8. J Biol Chem. 2026 Oct 09. pii: S0021-9258(26)02501-9. [Epub ahead of print] 113629
    The cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold.
    Robert V Williams, Kevin P Guay, Owen Hurlbut Lesk, Daniel N Hebert, Lila M Gierasch.
      Proteins targeted to the secretory pathway are involved in a myriad of biological processes but can only do so when properly folded. Within the endoplasmic reticulum, glycoprotein folding is regulated by the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) and its oxidoreductase partner, the 15-kDa selenoprotein (SEP15 aka SELENOF). The interaction between these two chaperones is poorly understood, limiting understanding of their function. SEP15 is comprised of two domains, a C-terminal thioredoxin-like domain, the structure of which has been reported (PDB 2A4H), and an approximately 50-residue long N-terminal cysteine-rich domain (CRD), of unknown structure. Here, we report the NMR solution structure of SEP15 CRD, which mediates the interaction with UGGT. These data reveal that this domain adopts a dimer in solution and forms a previously undescribed helical fold, stabilized by three disulfide bonds between residues C10-C42, C21-C43, and C24-C39. Furthermore, our results validate a model of the UGGT/SEP15 complex and lay the foundation for future studies of its interaction with glycoprotein substrates.
    Keywords:  Endoplasmic reticulum; disulfide; glycoprotein; protein folding; selenoprotein
    DOI:  https://doi.org/10.1016/j.jbc.2026.113629
  9. Autophagy. 2026 Oct 09.
    TBK1-mediated phosphorylation of WIPI2 links bacteria recognition to autophagosome formation in xenophagy.
    Chuying Qian, Hongtao Zhang, Jin Li, Wei Wan, Wei Liu.
      Xenophagy, a selective autophagy pathway, is a critical innate immune defense mechanism that targets pathogens for lysosomal degradation. However, the molecular mechanisms enabling autophagosomes to specifically recognize and engulf bacteria remain incompletely understood. Here, we identify WIPI2, a core component that drives autophagosome biogenesis, as a novel phosphorylation substrate of TBK1 during Salmonella Typhimurium infection. We demonstrate that TBK1 phosphorylates WIPI2 at Ser96, which enhances its interaction with ATG16L1 and its binding to PtdIns3P. Crucially, the recruitment of WIPI2 to intracellular bacteria is dependent on its interaction with ATG16L1, which is localized to the Salmonella-containing vacuole. Furthermore, TBK1-mediated phosphorylation of WIPI2 is required for efficient bacterial clearance. Collectively, our findings reveal a molecular mechanism whereby TBK1-mediated phosphorylation of WIPI2 directs localized phagophore expansion around invading bacteria, thereby bridging bacterial recognition with autophagosome assembly.
    Keywords:  ATG16L1; PtdIns3P; Salmonella; TBK1; V-ATPase; WIPI2; phosphorylation; xenophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2746965
  10. Plant Signal Behav. 2026 12 31. 21(1): 2744693
    Protein homeostasis and inter-organellar signaling under salt stress.
    Susmita Das, Yamshi Arif, Hesam Mousavi, Henrik Aronsson, Nadia Bazihizina, Mohammad Sarraf.
      Salinity is a major abiotic constraint on plant growth, productivity, and global food security. It disrupts cellular protein homeostasis (proteostasis) at every step, from synthesis to degradation. Plant survival under salt stress therefore depends on the coordinated regulation of protein synthesis, folding, post-translational modification, trafficking, quality control, and turnover. The individual contributions of the nucleus, ribosomes, endoplasmic reticulum (ER), and Golgi apparatus to salinity responses are increasingly well described, but how these compartments communicate remains far less understood. This review synthesizes current evidence on this inter-organellar signaling network, addressing four questions: how salinity-induced osmotic, ionic, and oxidative stress reprograms nuclear transcription and chromatin state; how ribosomes sustain selective translation of protective proteins while clearing stalled or damaged translational products; how the ER expands its folding capacity through the unfolded protein response and removes terminally misfolded proteins by ER-associated degradation; and how the Golgi sustains glycosylation, sorting, and secretion of the transporters needed for ion and osmotic homeostasis. Beyond these organelle-level responses, the review discusses two signaling layers that couple them into a single circuit: post-translational modifications (phosphorylation, ubiquitination, SUMOylation, and redox- and nitrosative/persulfidation-based marks) and phytohormone/gasotransmitter signals, including abscisic acid, nitric oxide, hydrogen sulfide, carbon monoxide, and melatonin. By framing proteostasis as an emergent property of nucleus-ribosome-ER-Golgi coordination rather than of any single compartment, this review identifies specific inter-organellar signaling nodes as candidate targets for breeding or engineering salinity-resilient crops.
    Keywords:  Salt stress; gasotransmitter signaling; inter-organellar signaling; post-translational modification; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1080/15592324.2026.2744693
  11. PLoS Biol. 2026 Oct 08. 24(10): e3004048
    The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics.
    Syeda Kubra, Michelle Sun, William Dion, Yu Bian, Ahmet Catak, Hannah Luong, Haokun Wang, Yinghong Pan, Jia-Jun Liu, Aishwarya Ponna, Lijun Liu, Ian Sipula, Jian-Hua Luo, Michael J Jurczak, Silvia Liu, Bokai Zhu.
      Proteostasis is essential for cellular health, with its disruption contributing to aging, neurodegeneration, and metabolic disorders. While the upstream proteotoxic stress-sensing and protein-folding mechanisms in the ER and cytosol are well studied, the transcriptional regulation of proteostasis remains incompletely understood, particularly concerning the temporal epigenome dynamics, chromatin landscapes, and co-regulatory networks underlying dynamic proteostasis control. Traditionally, proteotoxic stress responses were viewed as acute reactions to noxious stimuli, but recent evidence shows that many proteostasis genes exhibit ~12-hour ultradian rhythms under physiological conditions, driven by an XBP1s-dependent oscillator independent of the canonical circadian clock and cell cycle. By mapping the chromatin landscape of the murine 12-hour oscillator, we identified RBBP5-an essential subunit of the COMPASS complex responsible for H3K4 trimethylation-as a pivotal epigenetic regulator of proteostasis dynamics. In contrast, histone acetyltransferases and H3K9 acetylation were dispensable for dynamic proteostasis gene expression. RBBP5 is not only indispensable for the 12-hour oscillator but also essential for the transcriptional regulation of diverse proteotoxic stresses response, by coactivating XBP1s and promoting H3K4me3 deposition at the promoters of proteostasis genes. As a result, loss of RBBP5 sensitizes cells to proteotoxic stress in part due to impaired autophagy. Proximity labeling of H3K4me3 further uncovered a dynamic chromatin-associated proteomic architecture, including components of COMPASS, the Integrator complex and SWI/SNF remodelers, that constitutes the transcriptional response to proteotoxic stress. Together, these findings establish RBBP5 as a central regulator of proteostasis dynamics, essential for maintaining cellular resilience.
    DOI:  https://doi.org/10.1371/journal.pbio.3004048
  12. Trends Biochem Sci. 2026 Oct 05. pii: S0968-0004(26)00283-5. [Epub ahead of print]
    Intramembrane proteolysis: principles of substrate recognition and membrane protein fate.
    Dönem Avci, Susanne S Steigleder, Marius K Lemberg.
      Intramembrane proteases catalyze peptide bond hydrolysis within cellular membranes, regulating processes including signaling, protein quality control, and membrane protein turnover. Recent advances in cryo-electron microscopy, biochemistry, and molecular dynamics simulations have transformed our understanding of how these enzymes recognize and process substrates within the lipid bilayer. Here, we discuss how dynamic interactions among proteases, substrates, and membranes govern substrate recognition. Structural and biophysical studies reveal how conformational dynamics, membrane remodeling, and specific protease-substrate interactions enable processing of membrane-embedded substrates. Studies of rhomboid pseudoproteases further suggest that transmembrane-domain recognition represents a conserved principle of membrane protein processing that extends beyond proteolysis itself. Finally, we consider how recognition determines membrane protein fate, linking protease activity to signaling, proteostasis, and nonproteolytic scaffolding functions.
    Keywords:  intramembrane proteases; membrane remodeling; protein dislocation; rhomboid pseudoproteases; therapeutic targeting; transmembrane domain recognition
    DOI:  https://doi.org/10.1016/j.tibs.2026.09.005
  13. PLoS Pathog. 2026 Oct 06. 22(10): e1014624
    GlRac regulates an ATG8-independent autophagy-like pathway in Giardia lamblia.
    Angélica Hollunder Klippel, Corryn Newman-Boulle, Grant Reed, Dule Dule, Saanya Kedia, Martin T Kelty, Wai Pang Chan, Han-Wei Shih, Alexander R Paredez.
      Autophagy is a conserved catabolic process essential for cellular homeostasis and adaptation to nutrient stress. The protozoan parasite Giardia lamblia lacks most canonical autophagy-related (ATG) genes, including the hallmark ATG8, raising longstanding questions about whether this deeply divergent parasite can perform autophagy. Here, we identify an ATG8-independent autophagy-like pathway in Giardia regulated by GlRac, the parasite's sole Rho family GTPase. GlRac-positive double-membrane compartments are induced by encystation and nutrient depletion, and their abundance rapidly declines following amino acid replenishment but is unaffected by glucose, indicating amino acid-specific regulation. Giardia Target of Rapamycin (GTOR) levels decrease during nutrient depletion, and GTOR knockdown increases compartment abundance, identifying GTOR as a negative regulator of compartment formation and linking this pathway to nutrient sensing. Time-lapse microscopy revealed that these compartments form through linear and cup-shaped intermediates before becoming spherical and are subsequently cleared upon nutrient replenishment. Of nine putative ATG orthologs examined, none localized as specifically as GlRac to these structures, supporting the existence of a highly divergent pathway. Nevertheless, the compartments exhibit multiple conserved autophagy-associated features, including double-membrane morphology, actin recruitment, acidification, and cysteine protease activity. Pharmacological inhibition of cysteine proteases with E-64d or blocking V-ATPase-mediated acidification with concanamycin A promotes compartment accumulation, consistent with continuous degradative turnover. GlRac regulates compartment biogenesis bidirectionally: constitutive activation increases compartment abundance and size, whereas knockdown reduces them. Finally, quinacrine, an FDA-approved antigiardial drug that accumulates in acidic organelles, perturbs GlRac-positive compartments, consistent with its reported effects on autophagy in other eukaryotes, raising the possibility that this pathway contributes to parasite fitness. Together, these findings establish GlRac as a central regulator of an ATG8-independent autophagy-like pathway in Giardia and demonstrate that this parasite retains key structural, regulatory, and degradation-associated features of autophagy despite the apparent absence of most canonical ATG machinery.
    DOI:  https://doi.org/10.1371/journal.ppat.1014624
  14. FASEB J. 2026 Oct 15. 40(19): e72361
    SIRT1 Regulates Late Stage of Autophagy and Mitophagy via Autophagosome-Lysosome Fusion in Cardiomyocytes.
    Atsushi Kuno, Yukika Saga, Ryusuke Hosoda, Hiroki Aida, Ayuka Kurihara, Yuki Tatekoshi, Koki Abe, Ryo Numazawa, Naotoshi Iwahara.
      Sirtuin-1 (SIRT1) is an NAD+-dependent deacetylase implicated in autophagosome formation; however, whether SIRT1 also regulates autophagosome clearance during late-stage autophagy remains unclear. Here, we investigated the role of SIRT1 in autophagosome clearance during autophagy and mitophagy in cardiomyocytes. Mitochondrial stress induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) decreased mitochondrial protein levels and increased phosphorylation of ubiquitin, a PINK1 target, in H9c2 cardiomyocytes. These CCCP-induced decreases in mitochondrial proteins were prevented by co-treatment with chloroquine, an inhibitor of lysosomal degradation, supporting the induction of CCCP-triggered mitophagy. SIRT1 knockdown similarly prevented the CCCP-induced reduction in mitochondrial proteins and led to the accumulation of autophagosomes containing fragmented mitochondria without attenuating ubiquitin phosphorylation, suggesting that SIRT1 acts downstream of mitochondrial tagging. Tandem GFP-RFP LC3 assay and LC3-LAMP1 colocalization analysis demonstrated impaired autophagosome-lysosome fusion following SIRT1 knockdown. In vivo, cardiomyocyte-specific SIRT1 knockout mice exhibited elevated basal LC3-II levels and a blunted LC3-II response to chloroquine, consistent with impaired autophagic flux. In a doxorubicin (DOX)-treated model, SIRT1 deficiency attenuated autophagosome degradation during the early period after DOX administration. Mechanistically, SIRT1 interacted with Rab7, a key regulator of autophagosome-lysosome fusion, raising the possibility that SIRT1 might regulate fusion through post-translational modification of Rab7 or related components. Collectively, these findings identify SIRT1 as a regulator of autophagosome-lysosome fusion that promotes autophagosome degradation during autophagy and mitophagy in cardiomyocytes.
    Keywords:  Sirtuin‐1; autophagosome–lysosome fusion; autophagy; doxorubicin; mitophagy
    DOI:  https://doi.org/10.1096/fj.202601047R
  15. Antioxid Redox Signal. 2026 Oct 07. 15230864261494912
    Loss of Selenot in POMC Neurons Disrupts ER Homeostasis and Induces A Senescent-like Phenotype.
    Cédric Jehan, Inès Drissa, Dorthe Cartier, Christine Bucharles, Azénor Abgrall, Agathe Prieur, Philippe Chan, Carole Burel, Marie-Laure Walet-Balieu, David Alexandre, Muriel Bardor, Christophe Dubessy, Youssef Anouar, Isabelle Lihrmann.
       AIMS: Selenoprotein T (SELENOT) is an endoplasmic reticulum (ER)-resident thioredoxin-like oxidoreductase implicated in redox and calcium (Ca2+) homeostasis and protein quality control. Although SELENOT is highly expressed in the brain, its role in hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy balance, remains poorly understood. We investigated whether SELENOT is required for maintaining ER homeostasis and neuronal integrity in POMC neurons.
    RESULTS: Using CRISPR-edited and siRNA-silenced POMC neuronal models together with a POMC-specific SELENOT knockout mouse, we demonstrated that SELENOT loss induces a senescent-like phenotype including cellular hypertrophy, loss of neurite outgrowth, senescence-associated β-galactosidase activity, increased P16 and P21 expression, and acquisition of senescence-associated secretory phenotype. Senescence markers were elevated not only in SELENOT-deficient POMC neurons but also throughout the surrounding arcuate nucleus in vivo, suggesting propagation of a pro-inflammatory microenvironment. Mechanistically, prolonged SELENOT deficiency produced selective activation of the ATF6α arm of the unfolded protein response, depletion of ER Ca2+ stores, and profound alterations in N-glycan maturation. Notably, leptin-induced POMC processing and secretion were spared. Glycomics revealed a shift toward immature glycans, whereas thiol-trapping proteomics identified candidate SELENOT interactors linked to ER Ca2+ regulation.
    INNOVATION AND CONCLUSIONS: This study provides the first evidence that SELENOT deficiency is sufficient to trigger cellular senescence in POMC neurons, acting as a central regulator integrating ER proteostasis, Ca2+ homeostasis, redox adaptation, and glycosylation. These results reveal a previously unrecognized mechanism potentially linking neuronal senescence to hypothalamic dysfunction and suggest that SELENOT-dependent pathways may represent therapeutic targets for obesity, metabolic disease, and age-related neuroendocrine disorders. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  arcuate nucleus; energy homeostasis; inflammation; oxidative stress; senescence; unfolded protein response
    DOI:  https://doi.org/10.1177/15230864261494912
  16. Nat Commun. 2026 09 03. pii: 10512. [Epub ahead of print]17(1):
    Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes.
    Dávid Hargitai, Márton Molnár, András Rubics, Iván Bodor, Dóra Baukál, Anikó Nagy, Virág Balogh, Zsófia Simon-Vecsei, Gábor Juhász, Péter Lőrincz.
      Endosomal maturation determines whether internalized cargo is recycled or degraded, yet the logic governing early endosomal fusion remains incompletely defined. Although commonly depicted as a linear Rab5-to-Rab7 transition mediated by a single SNARE pathway, we show that early endosome maturation is driven by multiple parallel, non-interchangeable SNARE complexes. Using Drosophila nephrocytes as a tractable in vivo model, we define a Syx12L-Snap29-Ykt6 complex that mediates homotypic early endosomal fusion and identify two related assemblies-Syx7L-Snap29-Ykt6 and Syx7L-Snap29-Vamp7-that promote later endosomal and lysosomal fusion with distinct Rab requirements. When the canonical Syx12L pathway is disrupted, alternative complexes remain active and generate aberrant endolysosomal swirls which also form in the absence of Rab5 or early endosomal tethers. Thus, Rab5-independent membrane progression toward lysosomes persists but is insufficient to produce fully functional degradative organelles. Together, our findings reveal a network of parallel fusion pathways underlying endosome maturation.
    DOI:  https://doi.org/10.1038/s41467-026-77479-z
  17. Nat Cell Biol. 2026 Oct 05.
    Global and specific mechanisms stimulate mistranslation in cancer.
    Demi Wernaart, Amos Fumagalli, Mrittika Adhikary, Xiaodong Feng, Olaf Geintzer, Edwin S Kyei-Baffour, Onno B Bleijerveld, Liesbeth Hoekman, Ceri Zwart, Alexander Fish, Lisanne Giebel, Artur Burylo, Natalie Proost, Pierre-René Körner, Ferhat Alkan, Chao Yang, Janne Brouwer, Cecilia Anna Henriksen, Eric Westhof, Julien Champagne, Olaf van Tellingen, Marina Rodnina, Reuven Agami.
      Tryptophan codon-specific mistranslation, in the form of ribosomal frameshifting and tryptophan-to-phenylalanine (W > F) codon reassignments (substitutants), is induced in cancer cells by the limiting level of tryptophan imposed by anti-tumour immunity. While the oncogenic mitogen-activated protein kinase pathway drives frameshifting, whether substitutants are genetically regulated remains unknown. Here we screened for genes that control W > F substitutants following interferon-γ-mediated tryptophan shortage. This screen identified ADAR1, an enzyme that converts adenosine to inosine in double-stranded RNA molecules, and FTSJ1, an enzyme that 2'-O-methylates the anticodon region of several tRNAs. We demonstrate that ADAR1 sustains expression of key players in the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W > F mistranslation by methylation of tRNATrp to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan. As ADAR1 and FTSJ1 levels are elevated in many cancer types, we propose that cancer cells deploy global and specific mechanisms to promote mistranslation in response to anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41556-026-02088-3
  18. PLoS Comput Biol. 2026 Oct 05. 22(10): e1014811
    Spatially resolved reaction-diffusion modeling reveals effects of intracellular spatial heterogeneity on yeast galactose network dynamics.
    Tianyu Wu, Marie-Christin Spindler, Abner T Apsley, Emmy Earnest, Zane R Thornburg, Julia Mahamid, Zaida Luthey-Schulten.
      Eukaryotic cells are spatially organized into functionally-distinct compartments. This three-dimensional (3D) organization generates intracellular heterogeneities that can modulate regulatory dynamics. Despite this knowledge of subcellular organization, most quantitative gene-regulation models still assume a well-mixed environment in which molecules can react regardless of their spatial positions. Here, we use the well-established galactose switch in budding yeast (Saccharomyces cerevisiae) to develop spatially-resolved models that integrate experimentally-derived intracellular architectures, including chromosome organization, the endoplasmic reticulum (ER) and spatially distinct ribosome populations. We implement a hybrid stochastic-deterministic framework in which gene expression is modeled using a reaction-diffusion master equation that enforces locality (i.e., reactions occur only when molecules are in physical proximity), while metabolic and transport processes are captured by ordinary differential equations. Guided by electron microscopy and biochemical constraints, we quantify how accounting for intracellular spatial organization alters regulatory predictions in the galactose switch. We show that in present model chromosome geometry has little effect on Gal2p output, whereas ER-associated translation reduces Gal2p delivery to the plasma membrane; the largest decrease of Gal2p abundance occurs when translation of GAL2 mRNA is restricted to a population of ribosomes physically bound to the ER. Together, these results demonstrate that more realistic 3D cellular architectures and local reaction rules can qualitatively change regulatory predictions, motivating integration of intracellular organization in future whole-cell models.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014811
  19. FEBS Lett. 2026 Oct 08.
    Inhibition of dipeptidyl peptidase 7 impairs lysophagy in LLOMe-treated HepG2 cells.
    Na Yeon Park, Inho Kwon, Yong Hwan Kim, Ji-Eun Bae, Joon Bum Kim, Seong Hyun Kim, Sungho Maeng, Doo Sin Jo, Dong-Hyung Cho.
      Lysophagy selectively eliminates damaged lysosomes to preserve lysosomal homeostasis, but its regulatory mechanisms remain incompletely understood. Here, we identify dipeptidyl peptidase 7 (DPP7), a lysosomal serine protease, as a regulator of lysophagy. Inhibition or depletion of DPP7 impaired clearance of LLOMe-damaged lysosomes in HepG2 cells, as evidenced by sustained galectin-3 puncta and reduced lysophagic flux. DPP7 inhibition did not block TFEB activation; however, it markedly reduced ubiquitin accumulation on damaged lysosomes and attenuated the recruitment of SQSTM1 and LC3. This defect was accompanied by impaired lysosomal re-acidification and reduced maturation of cathepsin D and L. Together, our findings identify DPP7 as a novel modulator of ubiquitin-dependent lysophagy and reveal an unexpected role for a lysosomal peptidase in lysosomal quality control.
    Keywords:  DPP7; LLOMe; Lysophagy; Lysosomal integrity; UAMC00039
    DOI:  https://doi.org/10.1002/1873-3468.70482
  20. bioRxiv. 2026 Sep 02. pii: 2026.09.01.748722. [Epub ahead of print]
    Temozolomide Induces Aberrant RNA Alkylation and Widespread Translational Repression.
    Jayden Rhodes, Abigail Grace Johnston, Katherine Marlow Brazell, Xisheng Liu, John L Hartman, Zhangli Su.
      Temozolomide (TMZ) is a frontline alkylating chemotherapy, yet its direct impact on RNA modification and global translation dynamics remains poorly understood. Here, we demonstrate that TMZ induces pervasive RNA alkylation causing severe translational impairment. TMZ directly deposits aberrant methyl groups onto single-stranded mRNA in vitro , creating physical lesions that lower translational efficiency. In glioblastoma cells, acute TMZ exposure triggers a rapid, widespread accumulation of m 7 G on cellular RNAs, leading to the significant attenuation of global protein synthesis. Nanopore direct RNA sequencing identified distinct guanine-specific error signatures and sequence context preferences associated with TMZ-induced damage. Using a quantitative yeast spike-in ribosome profiling strategy, we mapped this translational repression at transcript-level, revealing a global downregulation of translational efficiency. This widespread repression disproportionately targets highly interconnected networks essential for cellular proliferation, specifically chromosome organization. We show that the severity of this translational repression is driven by a transcript's coding guanine density, stability and translation initiation speed. Together, our findings suggest that TMZ-induced alkylation targets stable, highly translated, guanine-rich transcripts. This establishes aberrant RNA methylation and subsequent translational arrest as a potential mechanism of temozolomide cytotoxicity.
    DOI:  https://doi.org/10.64898/2026.09.01.748722
  21. Biophys J. 2026 Oct 06. pii: S0006-3495(26)00694-6. [Epub ahead of print]
    Modeling Protein Diffusion Across ER-Nuclear Envelope Junctions Reveals Efficient Transport via Simple Diffusion.
    Carmela Moschella, Julia Scholz, Sara Merino-Aceituno, Christian Schmeiser, Shotaro Otsuka.
      The endoplasmic reticulum (ER) is the largest continuous membrane-bound organelle in the cell and plays a central role in the synthesis and turnover of lipids and proteins. It connects directly to the nucleus through specialized contact sites known as ER-nuclear envelope (NE) junctions. In a recent study, we showed that these junctions are sparse and highly constricted, measuring less than 20 nm in diameter and occurring at a frequency of approximately 0.1 junctions per square micrometer. However, it remains unclear whether such limited and narrow connections are sufficient to support efficient transport between the ER and NE. Here, we developed a mathematical model of ER-to-NE protein diffusion that incorporates ultrastructural parameters of ER-NE junctions, their spatial frequency, and protein diffusion coefficients within the ER lumen. To validate the model, we experimentally quantified the mobility of ER luminal proteins to the NE using fluorescence recovery after photobleaching (FRAP). Both the model and experimental measurements demonstrate that passive diffusion is sufficient to account for rapid protein exchange between the ER and NE despite the sparse and constricted nature of ER-NE junctions. Furthermore, the model predicts how junction geometry and abundance influence transport efficiency. Together, these findings provide a quantitative framework for understanding ER-NE connectivity and establish that simple diffusion can account for efficient protein transport between the ER and nucleus.
    Keywords:  continuum equations; kinetic equations; mean-field limit
    DOI:  https://doi.org/10.1016/j.bpj.2026.10.002
  22. Sci Adv. 2026 Oct 09. 12(41): eaeb6883
    Real-time single-molecule imaging in zebrafish embryos uncovers noncanonical translation.
    Maëlle Bellec, Jie Liang, Kenny Mattonet, Tatsuya Morisaki, Margaux Lay, Hans-Martin Maischein, Damien Avinens, Vincent Martinet, Delphine Muriaux, Timothy J Stasevich, Jérémy Dufourt, Didier Y R Stainier.
      Precise spatiotemporal control of protein synthesis is essential during embryogenesis, yet directly measuring translation kinetics in vivo remains challenging in vertebrates. In particular, it remains unclear how translation efficiency is determined for key developmental regulators and which kinetic steps limit their production. Here, we used ALFA array-based nascent chain labeling combined with lattice light-sheet microscopy to visualize bmp2b translation in real time and at single-molecule resolution in early zebrafish embryos. When combined with MS2/MCP labeling to visualize all bmp2b messenger RNA (mRNAs), we found that only some of them are being actively translated, suggesting that limited mRNA translation competence contributes to overall translation efficiency. We found that bmp2b translation operates below a maximal initiation regime, as replacement of its untranslated regions (UTRs) with viral UTRs increases ribosome loading. Furthermore, the bmp2b, but not actb2, 5'UTR supports cap-independent translation with ribosome loading comparable to cap-dependent initiation. Together, this approach provides a quantitative in vivo framework to dissect translation kinetics during early vertebrate development.
    DOI:  https://doi.org/10.1126/sciadv.aeb6883
  23. Nat Aging. 2026 Oct 05.
    Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells.
    Rebecca Sereda, Kristen Lindenau, Antonio Diaz, Zhaohui Liu, Olaya Santiago-Fernández, Rabia R Khawaja, Ronald Cutler, Jazmin Calyeca, Mericka McCabe, Sylvére Durand, Fanny Aprahamian, Natalia Del Pilar Vanegas, Hu Chen, Felipe Vilicich, Bhakti Chavda, Yair Botbol, Guido Kroemer, Toren Finkel, Evripidis Gavathiotis, Simone Sidoli, Ana L Mora, Mauricio Rojas, Susmita Kaushik, Ana Maria Cuervo.
      Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
    DOI:  https://doi.org/10.1038/s43587-026-01240-w
  24. J Am Chem Soc. 2026 Oct 05.
    Small-Molecule Modulators of HIPK4 Activity and Proteostasis.
    Zaile Zhuang, Riley K Togashi, Patrick C Kearney, Ian Pass, Steven M Swick, Fu-Yue Zeng, Andrey A Bobkov, Lynn M Fujimoto, Shubhankar Dutta, Athina Zerva, Nicolai D Raig, Debasmita Saha, Atoosa Emami, Martin P Schwalm, Bradley K Moon, Samuel T Howard, Stefan Knapp, Thomas Hanke, Thomas D Y Chung, James K Chen.
      Homeodomain-interacting protein kinase 4 (HIPK4) is a dual-specificity kinase that is predominantly expressed in differentiating spermatids, required for sperm development, and a promising target for nonhormonal male contraception. Genetic and functional studies have established an essential role for HIPK4 in spermiogenesis, where it acts at least in part through regulation of the F-actin-scaffolded acroplaxome during spermatid head shaping. The direct molecular targets of HIPK4 and their downstream effectors remain poorly defined, and small-molecule probes would be versatile tools for further investigating HIPK4 functions. Synthetic HIPK4 ligands could also be valuable leads for the development of nonhormonal male contraceptives. Here, we report the discovery of a cyanoquinoline-based series of HIPK4 inhibitors with nanomolar potency. Our lead compounds are selective for HIPK4, both within the HIPK family and across the broader kinome, establishing this scaffold as a useful starting point for probe and lead development. Unexpectedly, we found that a subset of these cyanoquinolines also perturbs HIPK4 proteostasis in a cell-type-specific manner. In spermatids, these compounds induce the formation of detergent-insoluble HIPK4 aggregates and promote interactions between this kinase and the autophagy receptor Tax1-binding protein 1 (TAX1BP1), potentially reinforcing a native mechanism of HIPK4 regulation. Together, our findings establish cyanoquinoline ligands as a new chemotype for probing HIPK4 biology and advancing male contraceptive discovery.
    DOI:  https://doi.org/10.1021/jacs.6c10097
  25. Cell Chem Biol. 2026 Oct 07. pii: S2451-9456(26)00334-X. [Epub ahead of print]
    Targeting ZDHHC15-mediated S-acylation of CD155 reactivates anti-tumor immunity.
    Xuanpu Zhang, Jie Zou, Jian Lin, Yu Xiao, Yue Zhu, Bokan Chen, Ziye Zhu, Yizhen Ding, Xinmei Zhou, Yinghong Yang, Xiaoyi Wang, Weijie Zhang, Min Zhang, Xia Lin, Pinglong Xu, Baoen Chen.
      The immune checkpoint CD155 is frequently upregulated across multiple malignancies and drives tumor progression and immune evasion, yet the posttranslational mechanisms regulating its stability and activity remain unclear. Here, we identify S-acylation as a key regulator of CD155 stability and immunosuppressive function. Using chemical reporters, we demonstrate that CD155 is S-acylated at three cytoplasmic cysteines by the acyltransferase ZDHHC15 and deacylated by the thioesterases PPT1/APT1. S-acylation protects CD155 from lysosomal degradation and promotes its interaction with Sprouty2 to sustain oncogenic ERK signaling. Genetic inhibition of ZDHHC15 disrupts CD155 S-acylation, triggering CD155 degradation, enhancing CD8+ T cell infiltration, and suppressing tumor growth in syngeneic models. We further show that the FDA-approved CDK4/6 inhibitor abemaciclib promotes CD155 degradation by upregulating PPT1 and enhancing lysosome biogenesis. Our work identifies reversible CD155 S-acylation as a druggable regulatory mechanism that links protein lipidation to immune checkpoint stability and reveals an unexpected immune-potentiating mechanism of abemaciclib.
    Keywords:  APT1; CD155; CDK4/6 inhibitor; PPT1; S-acylation; ZDHHC15; click chemistry; immune checkpoint; palmitoylation; protein lipidation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.09.006
  26. Adv Sci (Weinh). 2026 Oct 06. e78102
    Mechanically Regulated Secretion: How Physical Forces Instruct the Secretory Pathway and Remodel the Secretome.
    Domenico Russo, Seetharaman Parashuraman, Maria Luigia Maresca, Angela Francesca Dinoi, Alessia Calcagnì, Riccardo Rizzo.
      Cells do not secrete in a vacuum: they continuously interpret mechanical and chemical stimuli. This "cell sociology" drives collective behaviors and communication networks, allowing cells to process information from their surroundings. Over the past decade, growing evidence shows that all major secretory organelles are responsive to mechanical cues, overturning the view of secretion as a purely biochemical process. Cues like extracellular matrix (ECM) stiffness, cell shape, membrane tension, and tissue deformation dynamically tune trafficking at every step, remodeling endoplasmic reticulum (ER) exit sites, reshaping Golgi architecture, redirecting sorting at the trans-Golgi network (TGN), repositioning endolysosomes, and controlling exosome release. This mechanical control operates through complementary transcriptional and post-translational mechanisms, including GTPase activation, kinase cascades, cytoskeletal tension, and lipid remodeling, enabling rapid organelle reconfiguration. A mechano-secretory feedback loop exists: the physical microenvironment reorganizes the secretory pathway, and the resulting secretome changes reshape ECM composition and tissue mechanics. While supporting physiological homeostasis, this loop dysregulation drives fibrosis, cancer progression, and immune dysfunction. In this review, we integrate recent major findings to provide a coherent framework for understanding how mechanical forces reshape the secretory pathway and influence tissue function and disease.
    Keywords:  ECM; disease; fibrosis; mechanical cues; mechanosensing; mechanotransduction; secretory pathway; trafficking
    DOI:  https://doi.org/10.1002/advs.78102
  27. Science. 2026 Oct 08. 394(6820): eadx9628
    Golgi-derived vesicles containing PI(3,4)P2 drive mitochondrial fusion.
    Sho Aki, Mayuko Segawa, Vincent Anton, Suvagata R Chowdhury, Shun Nagashima, Isshin Shiiba, Dane M Wolf, Ikuko Koyama-Honda, Ayumu Sugiura, Joe Ganellin, Mark Johnson, Sakie Katsumura, Maki Sugaya, Yasunori Fujita, Koki Nakamura, Kazuaki Yoshioka, Hisamichi Naito, Yoh Takuwa, Ikuroh Ohsawa, Yusuke Hirabayashi, Shigeru Yanagi, Masahiro Morita, Tsuyoshi Osawa, Julien Prudent.
      Mitochondria are dynamic organelles that remodel their shape to regulate cell fate. Mitochondrial division involves interactions with the endoplasmic reticulum (ER), lysosomes, and trans-Golgi network-derived vesicles to facilitate membrane scission. How interorganelle contacts regulate mitochondrial membrane fusion remains largely unknown. Here, we identified a role for Golgi-derived vesicles enriched in phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] in regulating mitochondrial fusion. We found that these vesicles were recruited to ER- and mitofusin-marked fusion sites. Accordingly, loss of class II PI3-kinase isoforms α and β (PI3K-C2α and PI3K-C2β), which generate PI(3,4)P2, led to mitochondrial fragmentation resulting from impaired fusion. Furthermore, cardiomyocyte-specific PI3K-C2α and PI3K-C2β double-deletion mice exhibited mitochondrial fragmentation and heart failure. Thus, subpopulations of Golgi-derived vesicles carrying different phosphoinositides control mitochondrial membrane remodeling and homeostasis.
    DOI:  https://doi.org/10.1126/science.adx9628
  28. Proc Natl Acad Sci U S A. 2026 Oct 13. 123(41): e2614934123
    Pyrrolysine supply and demand shapes the translational landscape in Methanosarcina acetivorans.
    Grace D Britt, Daniel R Utter, Yeonsoo Park, Victoria J Orphan, Rodney Tollerson.
      The amber stop codon (UAG) can encode for pyrrolysine (Pyl) or be read as a stop codon by methylamine-metabolizing organisms including methanogenic archaea. The fate of UAG is decided during the decoding step of translation by competition between the pyrrolysine-aminoacylated transfer RNA (Pyl-tRNAPyl) and release factor. To further understand the consequences of pyrrolysine based genetic code expansion, we integrated RNA sequencing, tRNA charging analysis, and codon-resolved mono- and disome ribosome profiling in Methanosarcina acetivorans. During conditions of high pyrrolysine demand, we observed increased expression of the pyrrolysine biosynthetic operon with a concurrent increase in acylation of tRNAPyl and ribosome occupancy at UAG codons. During low pyrrolysine demand, the population of Pyl-tRNAPyl decreases and we observe a strong ribosome pausing signal during UAG decoding. We find that the dwell time on UAG codons is shorter during high demand, but ribosome collisions increase due to greater ribosome density on UAG-containing transcripts. Together, these results show how pyrrolysine demand modulates tRNA charging and controls elongation dynamics, clarifying the cellular consequences of decoding an ambiguous stop codon.
    Keywords:  Methanosarcina acetivorans; genetic code expansion; pyrrolysine; ribosome pausing; tRNA charging
    DOI:  https://doi.org/10.1073/pnas.2614934123
  29. Nat Rev Mol Cell Biol. 2026 Oct 05.
    Chaperone-mediated autophagy in physiological homeostasis, disease and ageing.
    Susmita Kaushik, Ana Maria Cuervo.
      Chaperone-mediated autophagy (CMA), the first-described selective lysosomal degradation pathway, is distinguished from other degradative pathways by the unique mechanism by which substrates reach the lysosomal lumen: CMA relies on a cytosolic targeting chaperone and a lysosomal membrane receptor that doubles as a translocation complex. In this Review, we highlight recent discoveries of additional molecular components involved in CMA and describe how genetic and pharmacological modulation of CMA in vivo, along with the identification of the subproteome degraded by CMA in different organs, has revealed an expanding range of physiological functions regulated by CMA in an organ-specific manner. CMA not only degrades damaged proteins but also targets fully functional proteins to terminate their physiological roles. Consequently, CMA dysfunction, as observed in ageing and age-related diseases, leads to cellular alterations beyond the mere accumulation of damaged proteins. We summarize recent findings linking CMA to common diseases and discuss efforts to therapeutically target CMA in these conditions.
    DOI:  https://doi.org/10.1038/s41580-026-01023-6
  30. J Neurochem. 2026 Oct;170(10): e70565
    Synaptic Proteostasis in Health and Disease.
    Paul G Donlin-Asp, Emma L Clayton.
      Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.
    Keywords:  autophagy; local translation; neurodegenerative disease; neurodevelopmental disease; proteostasis; synapse
    DOI:  https://doi.org/10.1111/jnc.70565
  31. Diabetologia. 2026 Oct 03.
    Adipocyte-derived exosomal ANGPTL2 promotes beta cell dysfunction via the EIF2α/ATF4/CHOP stress pathway in mice.
    Xiaoqi Zhong, Qiuna Wei, Qi Cheng, Mingwen Weng, Shengxin Wang, Hong Chen, Yuting Ruan.
       AIMS/HYPOTHESIS: Obesity-associated lipotoxicity drives beta cell failure in type 2 diabetes, but the adipose-to-islet signals that promote beta cell dysfunction remain incompletely defined. We hypothesised that angiopoietin-like protein 2 (ANGPTL2) carried by lipotoxic adipocyte-derived exosomes contributes to adipose-to-islet signalling that impairs beta cell function.
    METHODS: Exosomes from palmitate- or PBS-treated 3T3-L1 adipocytes were applied to MIN6 cells and primary mouse islets to assess beta cell function and identity. In vivo, mice underwent adipose-specific Angptl2 knockdown under high-fat diet (HFD) feeding, followed by metabolic phenotyping and assessment of beta cell function. Adipose-derived exosomes from HFD-fed mice with or without adipose Angptl2 knockdown were injected into normal-chow-fed recipient mice, and endocrine marker composition and islet secretory function were evaluated. Mechanistic studies in MIN6 cells used co-immunoprecipitation, pharmacological rescue experiments and Eif2α (also known as Eif2s1) knockdown to interrogate stress signalling.
    RESULTS: Exosomes derived from palmitate-treated adipocytes were efficiently internalised by beta cells and resulted in impaired insulin content and secretion, accompanied by reduced beta cell identity markers and induction of dedifferentiation signatures. ANGPTL2 was enriched in lipotoxic adipocyte-derived exosomes and accumulated in beta cells in an exosome-dependent manner. Angptl2 silencing in adipocytes lowered exosomal ANGPTL2 and mitigated islet dysfunction in vitro. In vivo, adipose-specific Angptl2 knockdown reduced islet ANGPTL2 without changing islet Angptl2 mRNA and improved glucose tolerance, with the AUC of the IPGTT decreasing from 2300.2 ± 165.5 to 1583.7 ± 88.8 mmol/l × min (mean ± SD). In adipose-exosome transfer experiments, recipients of HFD-short hairpin (sh)Angptl2-exosome (Exo) showed lower islet ANGPTL2 abundance and improved ex vivo islet glucose-stimulated insulin secretion (GSIS), with stimulated insulin secretion increasing from 6.0 ± 0.3% (mean ± SD) in the HFD-sh-negative control (NC)-Exo group to 10.9 ± 0.6% in the HFD-shAngptl2-Exo group. Mechanistically, ANGPTL2 associated with eukaryotic translation initiation factor 2α (EIF2α) and increased protein kinase R-like endoplasmic reticulum kinase (PERK)-associated EIF2α by approximately 2.8-fold, whereas this difference was lost after further normalisation to input EIF2α, supporting a substrate-availability model. PERK inhibition and integrated stress response inhibitor both attenuated ANGPTL2-induced activating transcription factor-4 (ATF4)/C/EBP homologous protein (CHOP) signalling and improved GSIS.
    CONCLUSIONS/INTERPRETATION: Lipotoxic adipocyte-derived exosomes increase ANGPTL2 abundance in recipient beta cells and contribute to beta cell dysfunction and identity disruption by amplifying PERK-dependent EIF2α/ATF4/CHOP signalling. Adipose ANGPTL2 and circulating exosome-associated ANGPTL2 represent candidate targets and biomarkers for preserving beta cell function in obesity-associated dysglycaemia.
    Keywords:  ANGPTL2; Adipocyte-derived exosomes; Beta cell dysfunction; EIF2α; Lipotoxicity
    DOI:  https://doi.org/10.1007/s00125-026-06885-1
  32. Mol Biol Cell. 2026 Oct 08. mbcE26040169
    Distinct Regulatory Logic Controls Recruitment and Membrane Dynamics of ESCRT-III Subunit Vps60.
    Tanner Peltier, Richard C Trippe, Matt West, Greg Odorizzi.
      Endosomal Sorting Complexes Required for Transport (ESCRT) machinery drives membrane remodeling and scission events essential for multivesicular body (MVB) biogenesis. The accessory ESCRT-III subunit Vps60 (mammalian CHMP5) shares structural features with the major polymerizing subunit Snf7, including the capacity to form homopolymers in vitro. Here, we demonstrate in Saccharomyces cerevisiae that Vps60 recruitment and polymerization require conditions that permit Snf7 polymer turnover: Vps60 is largely excluded when Snf7 assembly is absent and when Snf7 disassembly is blocked, consistent with recruitment of Vps60 late in the ESCRT-III cycle to Snf7 assemblies that undergo normal turnover. Structure-function analysis reveals that Vps60 regulation diverges fundamentally from core ESCRT-III subunits: while occlusion of the Vps60 C terminus by a GFP tag drives constitutive membrane association and polymer assembly, C-terminal truncation impairs endosomal recruitment, indicating that the Vps60 C terminus is required for membrane recruitment, in contrast to the autoinhibitory C-terminal domains of core ESCRT-III subunits. A C-terminally tagged Vps60 that constitutively associates with membranes phenocopies loss of Vps60 function in both intralumenal vesicle (ILV) formation and cargo sorting. These findings indicate that despite structural similarity to Snf7, Vps60 functions as a late-arriving accessory factor whose recruitment and assembly are tightly coupled to Snf7 dynamics. [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E26-04-0169
  33. Cancer Gene Ther. 2026 Oct 07.
    RSL24D1 links ribosome biogenesis to p53 activation in melanoma.
    Leonie Stahl, Sebastian Staebler, Anja K Bosserhoff.
      Melanoma cells exhibit elevated translation activity and rely on intact ribosomes to sustain their high protein synthesis demand. To support this process, efficient ribosome biogenesis is essential. RSL24D1 is a ribosome biogenesis factor required for late-stage maturation of the 60S ribosomal subunit. By ensuring correct ribosomal assembly, RSL24D1 supports global protein translation and maintains cellular homeostasis. Transcript and protein analyses revealed that RSL24D1 is upregulated in melanoma cells compared to normal human epidermal melanocytes. This overexpression correlates with reduced patient survival, suggesting an oncogenic role. Reduction of RSL24D1 expression impaired protein synthesis, decreased cell growth and resulted in the accumulation of unincorporated ribosomal proteins RPL5 and RPL11, which form the 5S RNP complex and inhibit the binding of MDM2 to p53. This inhibition stabilised p53 and activated downstream targets, including CDKN1A, resulting in G1 phase arrest and a senescence-like phenotype. These findings identify RSL24D1 as a critical component linking ribosome biogenesis to the p53 stress response. Targeting RSL24D1 creates a translational bottleneck, suppressing cell growth in p53 wild-type and p53-mutant cancer cells, highlighting it as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41417-026-01089-6
  34. Redox Biol. 2026 Oct 05. pii: S2213-2317(26)00426-X. [Epub ahead of print]97 104427
    Targeting the Ero1α-PDI oxidative protein folding pathway as a broad-spectrum strategy against coronavirus.
    Xinqian Li, Ping Liu, Xi'e Wang, Xi Wang, Lei Wang.
      The rapid mutation of the SARS-CoV-2 spike (S) protein promotes immune evasion and challenges current therapeutics. However, its cysteine/disulfide bond pattern is highly conserved across coronaviruses and essential for its structure and function. Here, we demonstrate that the folding and maturation of the S protein is a redox-sensitive process managed by sulfhydryl oxidase Ero1α and protein disulfide isomerase (PDI) in the endoplasmic reticulum. Reducing agents or cysteine mutations inhibit furin-processing of the S protein and its transport to the plasma membrane. Genetic or pharmacological disruption of the Ero1α-PDI pathway impairs S protein oxidative folding, furin cleavage and plasma membrane localization, as well as its fusogenic activity. Using a SARS-CoV-2 reverse genetics model, we confirm that targeting the Ero1α-PDI pathway exhibits potent antiviral effect. Moreover, the Ero1α-PDI pathway is essential for S protein maturation across different β-coronaviruses. Thus, our findings highlight the oxidative protein folding machinery as a promising target for developing broad-spectrum anti-coronavirus therapies.
    Keywords:  Endoplasmic reticulum; Ero1α; Oxidative protein folding; PDI; SARS-CoV-2; Spike
    DOI:  https://doi.org/10.1016/j.redox.2026.104427
  35. EMBO Rep. 2026 Oct 05.
    TBK1 eliminates aggregation-prone monomeric TDP-43 through an IFNβ-immunoproteasome pathway in ALS models.
    Shohei Sakai, Kotaro Oiwa, Yohei Iguchi, Izzet Mehmet Akcay, Seiji Watanabe, Okiru Komine, Noriko Nagata, Mai Horiuchi, Jemeen Sreedharan, Masahisa Katsuno, Koji Yamanaka.
      Loss-of-function mutations in TANK-binding kinase 1 (TBK1) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), characterized by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), known as TDP-43 pathology, but the mechanisms beyond impaired autophagy remain undefined. Here, we identify a TBK1-IFNβ-immunoproteasome axis as a novel autophagy-independent proteostatic pathway regulating TDP-43 clearance. TBK1 is activated by aggregation-prone monomeric TDP-43 via physical association, and this activation alleviates TDP-43 pathology in neuronal cells. TBK1 subsequently induces IFNβ expression, which upregulates the immunoproteasome to promote degradation of monomeric TDP-43 in neurons, including human iPSC-derived lower motor neurons. Importantly, IFNβ receptor expression is downregulated in spinal motor neurons from ALS patients with TDP-43 pathology. Furthermore, heterozygous Tbk1 deletion in SOD1G93A mice impairs immunoproteasome induction and increases polyubiquitinated protein accumulation in spinal cords, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that impairment of the TBK1-IFNβ-immunoproteasome axis represents an autophagy-independent mechanism contributing to the development of TDP-43 pathology in ALS and FTD.
    DOI:  https://doi.org/10.1038/s44319-026-00953-8
  36. Commun Biol. 2026 Aug 24. pii: 1305. [Epub ahead of print]9(1):
    Molecular basis for the regulation of the SUMOylation activity of the Smc5/6 complex by Esc2.
    Helena Borràs-Gas, Roger Solé-Soler, Rodolpho do Aido-Machado, Martina Matas, Michael P Williamson, Nathalia Varejão, Jordi Torres-Rosell, David Reverter.
      Post-translational modification by SUMO regulates a wide array of cellular processes. Despite the large number of SUMOylated substrates, only a limited set of SUMO E3 ligases have been identified, raising important questions about how substrate specificity is achieved. In budding yeast, the nuclear protein Esc2 functions as a cofactor in the SUMO pathway through its interaction with the E2 enzyme Ubc9. Esc2 is relevant under conditions of replicative stress, promoting the removal of recombination intermediates during DNA replication. This role has been largely attributed to its ability to enhance the SUMO E3 ligase activity of Nse2, a subunit of the Smc5/6 complex. Here, we uncover the molecular mechanism underlying Esc2-mediated stimulation of Nse2-dependent SUMOylation by identifying a direct interaction between the C-terminal SUMO-interacting motif of Nse2 and the Esc2 SLD2 domain. These coordinated interactions facilitate the formation of a productive E3-E2~SUMO complex and promote efficient SUMO transfer to substrates such as Sgs1 and Top3, thereby enhancing the processing of recombination intermediates and contributing to genome integrity.
    DOI:  https://doi.org/10.1038/s42003-026-10806-8
  37. iScience. 2026 Oct 16. 29(10): 117671
    Bidirectional photoriboswitch for translational regulation in mammalian cells.
    Yaxin Hu, Cheuk Yin Li, Lala Fu, Yiang Sun, Mingji Zhang, Tak Marx Yau, Chuxiao Xiong, Peng Shi, Yi Kuang.
      Photoriboswitches are invaluable tools for synthetic biology because they provide direct, precise, and on-demand control of translation. While most existing photoriboswitches are predominantly one-directional, this study presents a bidirectional photoriboswitch platform capable of mimicking the orthogonal RNA-binding protein-mediated up-/downregulation of multiple mRNAs. Inspired by intein-based split protein reconstitution and light-induced protein dimerization, we first engineered a Light-OFF system that uses photodimerization to block intein reconstitution. We then validated that this Light-OFF system can function orthogonally with a Light-ON system that reconstitutes a different split intein pair under light. Together, a bidirectional photoriboswitch is generated, which senses light to orthogonally reconstitute RNA-binding proteins to tune the translation of their respective target mRNAs. We have demonstrated that the photoriboswitch produces bidirectional translation regulation. Importantly, the functional modules of the photoriboswitch can be easily altered to adapt for different purposes, allowing the bidirectional photoriboswitch to serve as a versatile tool for translation regulation.
    Keywords:  RNA-binding protein; bidirectional regulation; photodimerization; photoriboswitch
    DOI:  https://doi.org/10.1016/j.isci.2026.117671
  38. Nature. 2026 Oct 07.
    Mechanism of spliceosome termination.
    Vytaute Boreikaite, Rupert Faraway, Matthias K Vorländer, Alexander W Phillips, Leonie Opitz, Moritz Wanke, George Yakoub, Gerald Raffl, Laura Fin, Román González-Prieto, Martijn S Luijsterburg, Stefan L Ameres, Clemens Plaschka.
      After excising an intron from pre-mRNA, the spliceosome remains trapped in a non-productive complex bound to the intron1-5. Termination of this complex is critical for spliceosome recycling and intron decay6, but the mechanism remains unknown. Here we present cryo-electron microscopy structures of human spliceosomes at two sequential stages of termination. First, the RNA helicases DHX15 and Aquarius unwind the RNA active site of the spliceosome, releasing bound components including U2 snRNA and extracting the buried intron-lariat branch point. The branch point is then debranched by the spliceosome-tethered enzyme DBR1, generating the previously unknown debranched intron spliceosome. This state recruits the RNA helicase DHX35 with its co-factors GPATCH1-WDR83, assisted by YJU2B. DHX35 ejects the debranched intron from the U6 snRNA-5' splice site duplex, driving spliceosome disassembly and intron turnover. In defective spliceosomes stalled on aberrant introns, YJU2B partners with LENG1 to guide DHX35-GPATCH1-WDR83 for termination through spliceosome quality control. Together, we reveal the mechanism of regular spliceosome termination and its parallels with spliceosome quality control, ensuring accurate and efficient pre-mRNA splicing.
    DOI:  https://doi.org/10.1038/s41586-026-11101-6
  39. J Cell Biol. 2026 Nov 02. pii: e202603154. [Epub ahead of print]225(11):
    Lipid remodeling enables adaptation to chronic hyperosmotic stress.
    Thomas D Williams, Christian Klose, Robert Ernst, Pedro Carvalho.
      Lipid droplets (LDs) accumulate in response to diverse cellular stresses. However, their regulation and physiological roles remain poorly understood in most contexts. Here, we show that in budding yeast, chronic hyperosmotic stress induces sustained LD accumulation. Unlike the transient LD response observed during acute osmotic shock, chronic stress triggers prolonged, Dga1-dependent triacylglycerol synthesis. In the absence of triacylglycerol synthesis, cellular fitness is impaired. Lipidomic profiling reveals extensive membrane remodeling during chronic hyperosmotic stress, most notably an increase in phosphatidylcholine (PC) resulting in changes to membrane properties. In LD-deficient cells, the hyperosmotic stress-induced PC increase is blunted, while enhancing PC synthesis improves the fitness of triacylglycerol-deficient cells. Thus, LD accumulation and phospholipid remodeling underlie an adaptive response to chronic hyperosmotic stress.
    DOI:  https://doi.org/10.1083/jcb.202603154
  40. Sci Adv. 2026 Oct 09. 12(41): eady6048
    A neuronal GPCR modifies neuropeptide signaling to suppress proteostasis in distal tissues.
    Joud Hirbawi, Adam Zaretsky, Huadong Zhu, Uri Goshtchevsky, Gourab Dey, Emmanuelle Merquiol, Atif Ahmed Siddiqui, Irit Cohen, Galia Blum, Ehud Cohen.
      The proteostasis network (PN) safeguards the integrity of proteins by promoting various cellular activities. However, with aging, the PN's competence declines and aggregated proteins accrue within cells. This process underlies the development of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. While the PN functions within cells, proteostasis is regulated across the organism by intertissue communication, which is partially governed by neurons. We previously found that reducing the expression of gtr-1, which encodes a neuronal heterotrimeric guanine nucleotide-binding protein-coupled receptor, mitigates the toxicity of the Alzheimer's disease cause, Aβ peptide. Here, we investigated the mechanism that is acted upon the knockdown of gtr-1 and found that it differentially modulates gene expression profiles, including of neuropeptide-coding genes, and dissimilarly modifies protein aggregation in worms that express distinct proteotoxic proteins. The knockdown of gtr-1 also enhances protein degradation. These findings highlight the roles of neuropeptides as organismal coordinators of proteostasis in the face of distinct proteotoxic challenges.
    DOI:  https://doi.org/10.1126/sciadv.ady6048
  41. bioRxiv. 2026 Aug 10. pii: 2026.08.09.743785. [Epub ahead of print]
    Biased stochastic motor dynamics drive bidirectional, processive translocation by the AAA+ disaggregase Hsp104.
    JiaBei Lin, Jaskamaljot Kaur Banwait, Ayush Saurabh, Kim A Sharp, Daniel R Southworth, Steve Pressé, Aaron L Lucius, Yale E Goldman, James Shorter.
      Protein aggregation disrupts proteostasis and drives neurodegeneration. Hsp104 is a hexameric, ring-shaped AAA+ ATPase that dissolves protein aggregates, yet how hexamers translocate and extract polypeptides trapped in mechanically resistant aggregates remains unclear. Using substrates that recapitulate the physical constraints of aggregates, we establish that Hsp104 is a processive, bidirectional translocase that can dynamically switch direction while threading a single polypeptide. On mechanically restrained substrates and prions, Hsp104 hexamers execute biased stochastic transitions among three conformational states at individual interprotomer interfaces: closed, extended, and a previously unobserved hyperextended form. These transitions follow kinetically favored paths rather than a rigid rotary sequence. The resulting biased stochastic stepping, enabled by the conformational plasticity of Hsp104 hexamers, underpins operational adaptability and redefines the functional logic of AAA+ motors.
    DOI:  https://doi.org/10.64898/2026.08.09.743785
  42. J Cell Mol Med. 2026 Oct;30(19): e71380
    The Unfolded Protein Response as a Modulator of Cancer-Immune Cell Communication in the Tumour Microenvironment.
    Yew Hwang Chee, Matthieu Moncan, Eileen Reidy, Adrienne M Gorman, Afshin Samali.
      The tumour microenvironment (TME) comprises a dynamic network of structural, cellular, and signalling components that interact to influence tumour development. Immune cells play a key role in recognizing and eliminating cancer cells through detection of tumour-derived membrane and secreted proteins processed in the endoplasmic reticulum (ER). These ER-matured proteins on target cells act as critical communication signals, coordinating immune responses against tumour cells. However, during tumorigenesis, accumulation of unfolded or misfolded proteins in the ER of the cancer cells triggers the unfolded protein response (UPR), a transcriptional program that alleviates proteotoxic stress by reshaping the cancer cell proteome and secretome, thereby promoting survival. Activation of UPR disrupts intercellular communication and ultimately impairs immune-mediated tumour clearance. Understanding this crosstalk could inform the development of therapeutics targeting UPR-driven immune modulation. This review discusses how UPR-signalling modulates tumour-immune cell interactions within the TME.
    Keywords:  antigen presentation; anti‐tumour immunity; cancer therapy; endoplasmic reticulum (ER) stress; immune modulation; secretome; tumour microenvironment (TME)
    DOI:  https://doi.org/10.1111/jcmm.71380
  43. Curr Opin Chem Biol. 2026 Oct 07. pii: S1367-5931(26)00135-3. [Epub ahead of print]95 102786
    ER-Nε-lysine acetylation machinery in neurological disorders: A context-dependent regulator of proteostasis.
    Emanuele Di Martino, Raanya De Vos, Sofia Koenig Gimeno, Federica Ricciardi, Antonio Luchicchi, Nicola Salvatore Orefice.
      Despite extensive characterization of cytosolic and nuclear acetylation, the functional relevance of luminal ER-Nε-lysine acetylation in the nervous system remains poorly understood. This modification is mediated by a coordinated metabolic-secretory axis involving acetyl-CoA availability and the ER-resident acetyltransferases ATase-1 (NAT8B) and ATase-2 (NAT8), which depend on acetyl-CoA import into the ER via the transporter SLC33A1 (AT-1). Upstream, the citrate transporters SLC25A1 and SLC13A5 contribute to shaping the cytosolic acetyl-CoA pool. Emerging evidence identifies this pathway as a key regulator of proteostasis within the early secretory pathway, linking cellular metabolism to protein processing, trafficking, and degradation. Recent studies in neurological disease models suggest that excessive activation of this machinery may exert pathogenic effects through distinct mechanisms. In experimental models of autism spectrum disorder (ASD), increased ER acetylation is associated with altered secretory pathway flux, impaired synaptic proteostasis, and abnormal neuronal connectivity, ultimately leading to ASD-like phenotypes. In Alzheimer's disease (AD) models, excessive ER-Nε-lysine acetylation appears to suppress reticulophagic clearance of aggregation-prone proteins within the secretory pathway, whereas genetic or pharmacological reduction of AT-1/ATase activity enhances proteostatic clearance and confers protective effects. In this opinion article, we discuss ER-Nε-lysine acetylation as a context-dependent regulator of proteostasis in neurodevelopmental and neurodegenerative disease models. We highlight key unresolved questions regarding acetylation substrates, relevance to human biology, and future therapeutic opportunities. We further consider its potential relevance to additional disorders, including multiple sclerosis, where its contribution remains largely unexplored.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102786
  44. bioRxiv. 2026 Aug 14. pii: 2026.08.13.744004. [Epub ahead of print]
    De novo design of autocatalytically forming intra- and intermolecular isopeptide bonds to construct rigid covalent protein assemblies.
    Lukas F Milles, Evelyn B Huddy, Ann Carr, Yang Hsia, Xinting Li, Alex Kang, Banumathi Sankaran, Asim K Bera, David Baker.
      Isopeptide bonds are amide bonds between amino acid side chains that can form autocatalytically, notably in the pili of Gram-positive bacteria. Here, we design de novo proteins that form both intramolecular and intermolecular isopeptide bonds entirely autocatalytically. We report over 50 designs that form isopeptide bonds, validated by mass spectrometry and 5 crystal structures. We redesign these constructs as split proteins that form a covalent intermolecular isopeptide crosslink when combined. These split designs are orthogonal to the existing isopeptide-based SpyTag/Catcher system, and their formation can be regulated by temperature, providing control over the timing of crosslinking in protein assemblies. We extend these designs to create rigid domain crosslinks that enable the construction of large well ordered symmetric rings of up to 215 kDa that are irreversibly covalently crosslinked by multiple isopeptide bonds into a single molecule. Our results provide insight into the determinants of isopeptide bond formation, considerably expand the set of isopeptide bond crosslinking systems, and establish a framework to construct fully covalent rigid protein assemblies.
    DOI:  https://doi.org/10.64898/2026.08.13.744004
  45. Cell Death Differ. 2026 Oct 05.
    Ubiquitination of LMP-1 by UFD-2 regulates apoptotic cell clearance.
    Lei Yuan, Peiyao Li, Xinyan Li, Yingying Xi, Fuqiao Liu, Qian Zheng, Hui Wang, Hui Xiao.
      Apoptotic cell clearance, or efferocytosis, is essential for tissue homeostasis and preventing inflammation in multicellular organisms. Through a genome-wide RNAi screen targeting 169 E3 ubiquitin ligases in Caenorhabditis elegans, we identified six ligases involved in efferocytosis regulation, with UFD-2 deletion showing the most significant defect. UFD-2 was found to be critical for phagosome maturation and degradation during apoptotic cell clearance. We identified the lysosomal membrane protein LMP-1 as a direct substrate of UFD-2 and showed that UFD-2 cooperates with UBC-15 to catalyze K63-linked polyubiquitination of LMP-1, essential for efficient apoptotic cell clearance. Loss of UFD-2 resulted in reduced LMP-1 levels within lysosomes and impaired activation of lysosomal DNase NUC-1. The function of UFD-2 in efferocytosis is evolutionarily conserved, as its mammalian homolog UBE4B similarly regulates apoptotic cell clearance in macrophages. These findings establish UFD-2 as a key regulator of efferocytosis, providing therapeutic insights into diseases associated with defective efferocytosis.
    DOI:  https://doi.org/10.1038/s41418-026-01886-4
  46. J Extracell Biol. 2026 Jun;5(6): e70151
    EV-SPEC: Decoding the Spatial Proteomic Signature of the Extracellular Vesicle Corona.
    Camille Menaceur Vandenbroucke, Carsten Scavenius, Yuya Hayashi.
      The concept of protein corona formation around extracellular vesicles (EVs) has given birth to new insights into how cells may recognize EVs by proteins presented at the EV surface. Here we present spatially resolved proteomics using the biotin ligase TurboID to map proteins interacting at the EV surface, without a need for physical isolation of the EV-corona complexes. TurboID promiscuously biotinylates nearby proteins within a few nm distance from the fused 'bait' protein. We genetically engineered EVs by modifying CD63 as the bait protein to which TurboID was fused facing outward to map EV corona proteins. Biotinylated proteins were then analysed by Western blotting and liquid chromatography-mass spectrometry. Western blots revealed protein patterns that are distinct depending on the localization of the fused TurboID. The mass spectrometry analysis identified many of the serum proteins commonly known to form a corona around a synthetic solid nanoparticle, also supporting those previously reported through the physical isolation approaches. Rather striking is, however, the EV corona footprint of endogenous proteins that tells us about the EV biogenesis and what the intrinsic endogenous corona might look like. This approach, which we coined EV-SPEC (Spatial Proteomics of Endogenous Corona), has thus the potential to revolutionize our understanding of EV biology by shifting the focus from the EVs themselves to the proteins that make up the corona, or how the cell 'sees' them, in analogy with the biomolecular corona extensively characterized for synthetic nanoparticles.
    Keywords:  endogenous protein corona; extracellular vesicle biogenesis; genetically engineered extracellular vesicles; proximity labelling; spatial proteomics
    DOI:  https://doi.org/10.1002/jex2.70151
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