bims-proteo Biomed News
on Proteostasis
Issue of 2026–03–15
forty-nine papers selected by
Eric Chevet, INSERM
  1. ZAP targets aberrant mRNA transcripts encoding proteins with defective signal peptides for degradation.
  2. PRRC2A, PRRC2B and PRRC2C are Stress Granule Proteins that Promote Translation Through Association with the eIF3 complex.
  3. IRE1α regulates macrophage phagocytosis in immune thrombocytopenia through NR1D1 mRNA decay and lysosomal biogenesis.
  4. TMEM259/MEMBRALIN is a non-canonical ER-phagy receptor that associates with MAN1B1 and VCP to eliminate viral glycoproteins.
  5. Standing on the Shoulders of Giant Ribosomes: UPF1-dependent Surveillance of Translation Dynamics to Proteostasis.
  6. Targeted Protein Degradation by Repurposing Transmembrane E3 Ubiquitin Ligases.
  7. Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
  8. Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
  9. Cardiomyopathy and aging integrally contribute to the unfolded protein response collective pathways.
  10. SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay.
  11. Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
  12. Stress-induced nucleolar rejuvenation via chaperone-mediated segregation in a filamentous fungus.
  13. Ageing promotes metastasis via activation of the integrated stress response.
  14. NAA40 and NAC cooperate in co-translational histone acetylation in humans.
  15. Endocytome profiling uncovers cell-surface protein dynamics underlying neuronal connectivity.
  16. Cullin-RING receptors in rare disease biology.
  17. Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
  18. Molecular insights into the regulation of GNPTαβ by LYSET.
  19. Translational regulation by oxidative desulfuration of tRNA modifications.
  20. Biochemical insights into the conserved interactions of NMD factors from budding yeast to humans.
  21. Degradation factor 1, Def1, regulates mRNA translation and decay through Ccr4-Not-dependent ubiquitylation of the ribosome.
  22. Advancing Targeted Protein Degradation Through Immunoproteasome-Caged N-Degrons.
  23. Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
  24. A guide to mapping ubiquitin and ubiquitin-like E3 ligases to their substrates.
  25. A paired sequence language model for protein-protein interaction modeling.
  26. Desmosomes compartmentalize mRNA and translation in the skin.
  27. A druggable redox switch on SHP1 controls macrophage inflammation.
  28. Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
  29. Switching of the c-Myc protein degradation pathway depending on the PP2A-B55α complex levels.
  30. Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer.
  31. Reversibility and β-sheet formation are decoupled in tau condensate aging.
  32. Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
  33. DeepDegradome: A structure-aware deep learning framework for PROTAC and ligand generation against protein targets.
  34. Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.
  35. Checking in on proteostasis.
  36. Rapid Proteome-Wide Discovery of Protein-Protein Interactions With ppIRIS.
  37. CF2H: a cell-free two-hybrid platform for rapid protein binder screening.
  38. Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
  39. Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukaemia.
  40. Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet induced steatotic liver disease.
  41. Protocol for the quantification of digestive exophagy in cell culture.
  42. Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core.
  43. The UFM1 Conjugation System: A Master Regulator of Cellular Stress Surveillance in Human Disease.
  44. G4-Ligand-Directed PROTACs Unveil DR1 as a Novel Ligand-Co-Binding G4-Protein and Reshape G4-Dependent Transcription.
  45. Exon inclusion signatures enable accurate estimation of splicing factor activity.
  46. Bacterial Schlafen proteins mediate phage defence.
  47. Bioengineered ferritin-based lysosome-targeting chimera platform for tumor-targeted therapy.
  48. MSH6 regulates cGAS activity in antiviral and antitumor signaling pathways by governing its cytosolic/nuclear distribution.
  49. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  1. EMBO J. 2026 Mar 12.
    ZAP targets aberrant mRNA transcripts encoding proteins with defective signal peptides for degradation.
    Akruti Shah, Aaztli R Coria, Britnie Santiago Membréno, Emilien Orgebin, Jennifer T Miller, Wilfried Guiblet, Colin Chih-Chien Wu.
      The endoplasmic reticulum (ER) is an important site for accurate folding and processing of secretory and membrane proteins. Signal peptides within such proteins are recognized by the signal recognition particle (SRP), which guides them to the ER. When this process is impaired, cells rely on quality control mechanisms to prevent the accumulation of misfolded or mislocalized proteins. One of these mechanisms, known as regulation of aberrant protein production (RAPP), detects nascent proteins with aberrant signal peptides and degrades their mRNA templates. Using functional genetic screens, we identify the zinc finger antiviral protein (ZAP) as a key component of the RAPP pathway. Proteomics and enhanced UV-crosslinking and immunoprecipitation (eCLIP) experiments reveal that the short isoform ZAP-S associates with SRP components and facilitates degradation of aberrant mRNAs. ZAP-S recognizes faulty proteins early in their biogenesis and targets their corresponding mRNAs for degradation. Loss of ZAP activates the unfolded protein response and the downstream integrated stress response, highlighting its central role in safeguarding protein targeting and maintaining cellular homeostasis.
    Keywords:  GRN; RAPP; Signal Peptide; ZAP; mRNA Quality Control
    DOI:  https://doi.org/10.1038/s44318-026-00720-4
  2. bioRxiv. 2026 Feb 25. pii: 2026.02.24.707808. [Epub ahead of print]
    PRRC2A, PRRC2B and PRRC2C are Stress Granule Proteins that Promote Translation Through Association with the eIF3 complex.
    Jie Qi Huang, Eileigh Kadijk, Karl J Schreiber, Zi Hao Liu, Rachel W Chiang, Zhixin Zhang, Kevin Guttman, Tian Hao Huang, Sylvia M T Almeida, Olena Zhulyn, Alan Moses, Julie D Forman-Kay, John L Rubinstein, Ji-Young Youn.
      Regulation of mRNA translation is essential for cellular homeostasis, and its dysregulation contributes to cancer, neurodegeneration, and developmental disorders. Stress granules are cytosolic condensates that form during stress-induced translation arrest and are enriched in mRNAs, translation factors, and RNA-binding proteins, but how stress granule proteins modulate translation remains poorly understood. Here, we identify the stress granule components Proline-Rich Coiled-Coil A, B, and C (PRRC2 proteins) as translation regulators. PRRC2 proteins are large, intrinsically disordered paralogs conserved across jawed vertebrates. Functional proteomics revealed that all PRRC2 proteins associate with the 48S translation initiation complex (PIC), whereas PRRC2B additionally interacts with nuclear proteins. Under stress, the proximal interaction network of PRRC2 proteins undergoes dynamic remodeling, including increased interactions with the stress granule scaffold G3BP1. Genetic perturbation shows that the PRRC2 proteins influence stress granule assembly in a context-specific manner, and are collectively required for cell growth in basal conditions due to their essential role in translation. Cells with reduced PRRC2 proteins exhibit a significant reduction in the abundance of more than half of the proteome, with a bias toward translational targets of eIF3d and eIF4G2. Interaction domain mapping and AlphaFold3 modeling revealed that an α helix within the putative coiled-coil domain of PRRC2C mediates interactions with the eIF3 core complex. This modeling places the PRRC2C α helix in a previously unassigned region of a published cryo-EM density map, validating the protein interaction and the mechanistic role of PRRC2C in translation control. Together, these findings establish PRRC2 proteins as components of the translation initiation machinery that regulate translation through their interactions with the eIF3 complex and other components of the 48S PIC factors, providing a direct mechanistic link between stress granule proteins and translational control.
    DOI:  https://doi.org/10.64898/2026.02.24.707808
  3. Cell Rep. 2026 Mar 12. pii: S2211-1247(26)00161-0. [Epub ahead of print]45(3): 117083
    IRE1α regulates macrophage phagocytosis in immune thrombocytopenia through NR1D1 mRNA decay and lysosomal biogenesis.
    Yushan Xu, Fangling Zhao, Mengjiao Lin, Zhewen Qin, Yi Zheng, Ni Yao, Xingxing Chen, Bei Zhang, Dawei Cui, Ziyin Yang, Bo Shan, Jue Xie.
      Macrophage phagocytosis is essential for immune homeostasis but must be tightly constrained to prevent pathological tissue damage. How cellular stress pathways enforce phagocytic homeostasis remains incompletely understood. Here, we show that phagocytosis selectively activates the endoplasmic reticulum stress sensor IRE1α in macrophages, which functions as a negative regulator of lysosome-driven phagocytic amplification. Using myeloid-specific IRE1α-deficient mice and pharmacological inhibition, we demonstrate that loss of IRE1α RNase activity leads to excessive phagocytosis through unchecked lysosomal biogenesis. Mechanistically, phagocytosis-activated IRE1α directly degrades Nr1d1 mRNA via regulated IRE1α-dependent decay (RIDD), thereby restraining NR1D1-driven lysosomal expansion. Disruption of this IRE1α-NR1D1 axis exacerbates macrophage-mediated platelet clearance and accelerates disease progression of immune thrombocytopenia (ITP). Reduced ERN1 expression and IRE1α activity are observed in monocytes from patients with ITP. Pharmacological inhibition of NR1D1 or lysosomal activity rescues thrombocytopenia. Together, these findings establish the IRE1α-NR1D1-lysosome axis as a therapeutically actionable pathway in phagocytosis-driven diseases.
    Keywords:  CP: immunology; IRE1α; IRE1α-dependent decay; Nr1d1; SR8278; endoplasmic reticulum stress; immune thrombocytopenia; lysosomal biogenesis; macrophage phagocytosis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117083
  4. Autophagy Rep. 2026 ;5(1): 2639256
    TMEM259/MEMBRALIN is a non-canonical ER-phagy receptor that associates with MAN1B1 and VCP to eliminate viral glycoproteins.
    Jim Maurice Camilleri, Jing Zhang, Tao Wang, Iqbal Ahmad, Sunan Li, Yong-Hui Zheng.
      Selective autophagy of the endoplasmic reticulum (ER-phagy/reticulophagy) is essential for organelle homeostasis and host defense, yet how ER quality control (ERQC) pathways distinguish viral glycoproteins from misfolded host proteins remains poorly understood. Recent work identifies TMEM259/MEMBRALIN (transmembrane protein 259) as a selective ER-phagy receptor containing a non-canonical LC3-interacting region (LIR) motif that assembles a dedicated ER-to-lysosome-associated degradation (ERLAD) complex targeting viral class I fusion glycoproteins. TMEM259 is a multi-pass ER membrane protein with luminal domains that recruit MAN1B1 (mannosyl-oligosaccharide 1,2-α-mannosidase) and cytosolic regions that engage VCP/p97 (valosin-containing protein). This TMEM259-MAN1B1-VCP axis directs diverse viral glycoproteins, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, Ebola virus (EBOV) glycoprotein, influenza A virus (IAV) hemagglutinin (HA), and human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein, to lysosomes in a ubiquitin-independent manner. In contrast, misfolded host glycoproteins are primarily cleared through canonical ER-associated degradation (ERAD) or alternative ERLAD pathways. Preferential recognition of densely glycosylated viral substrates suggests that MAN1B1 may function as a glycan-density sensor, enabling TMEM259 to couple ER proteostasis with intrinsic antiviral immunity. These findings expand the conceptual framework of selective autophagy and uncover a specialized ER-phagy pathway dedicated to eliminating viral glycoproteins.
    Keywords:  ER-phagy; MAN1B1; Membralin; TMEM259; VCP; class I fusion proteins
    DOI:  https://doi.org/10.1080/27694127.2026.2639256
  5. J Mol Biol. 2026 Mar 10. pii: S0022-2836(26)00125-7. [Epub ahead of print] 169752
    Standing on the Shoulders of Giant Ribosomes: UPF1-dependent Surveillance of Translation Dynamics to Proteostasis.
    Heeju Park, Chunghun Lim.
      Up-frameshift 1 (UPF1) is best known as a key factor in nonsense-mediated mRNA decay (NMD), a well-conserved surveillance pathway that degrades mRNAs harboring premature termination codons (PTCs). The ATP-dependent RNA helicase UPF1 is recruited to ribosomes terminating at PTCs and triggers mRNA decay. Canonical NMD thereby limits the accumulation of truncated, potentially harmful polypeptides by rapidly eliminating faulty transcripts after the initial rounds of translation. However, emerging evidence from yeast to mammals indicates that UPF1 activity extends beyond simple degradation of PTC-containing mRNAs. Recent work links UPF1 to translating ribosomes, connecting translation dynamics with mRNA surveillance, co-translational quality control of nascent polypeptides, and aggresome targeting of aberrant translation products. These UPF1 functions beyond canonical NMD are increasingly recognized as important for cellular homeostasis. This review focuses on how UPF1 engages ribosomes to influence translation dynamics and coordinates the quality control of mRNA substrates and aberrant translation products. We further discuss the implications of these ribosome-coupled activities for diverse aspects of cellular physiology and disease.
    Keywords:  UPF1; co-translational quality control; nonsense-mediated mRNA decay (NMD); proteostasis; ribosome surveillance
    DOI:  https://doi.org/10.1016/j.jmb.2026.169752
  6. Chembiochem. 2026 Mar 13. 27(5): e202500870
    Targeted Protein Degradation by Repurposing Transmembrane E3 Ubiquitin Ligases.
    Jibin Cui, Qian Qu, Man Pan.
      Targeted protein degradation (TPD) is an emerging therapeutic strategy that leverages the cell's native degradation machinery to eliminate disease-causing proteins. An advanced approach in this field operates by mediating proximity-induced ubiquitination between E3 ubiquitin ligases and proteins of interest, thereby triggering their proteasomal destruction. Recent advances have expanded this paradigm to cell-surface proteins, opening a new frontier in targeting the undrugged proteome. This review highlights the development of TPD technologies that exploit cell-surface E3 ligases for the degradation of membrane proteins.
    Keywords:  bispecific chimeras; cell‐surface E3 ligases; membrane proteins; targeted protein degradation
    DOI:  https://doi.org/10.1002/cbic.202500870
  7. iScience. 2026 Mar 20. 29(3): 115056
    Loss of DDI2 rewires proteostasis through CCN1-driven compensatory autophagy.
    Nayyerehalsadat Hosseini, Ahmed M Elshazly, Holly A Byers, Madison A Ward, Amy N Brooks, Janakiram R Vangala, Senthil K Radhakrishnan.
      The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP) are the primary mechanisms for protein degradation, yet the molecular mechanisms linking them remain unclear. We show that loss of the UPS shuttle-protease DDI2 in diverse human and murine cells leads to a proteotoxic stress response driven by the intracellular accumulation of the secretory protein CCN1. Misfolded CCN1 is normally extracted from the endoplasmic reticulum by a DDI2-p97 complex and directed to lysosomes for degradation. In the absence of DDI2, CCN1 builds up, produces reactive oxygen species, and triggers compensatory autophagy; CCN1 knockout or ROS scavenging attenuates this response. Loss of DDI2 also impairs CCN1-LAMP1 colocalization, suggesting that DDI2 functions as a selective cargo receptor linking the UPS and ALP. These findings reveal a stress-responsive DDI2-CCN1 axis that reshapes proteostasis and highlight DDI2 as a potential therapeutic vulnerability in proteasome-dependent cancers.
    Keywords:  Biochemistry; Biological sciences; Cancer; Cancer systems biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115056
  8. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2514355123
    Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.
    Yan Yan, Xinming Wang, Hanna Jeon, Teresa R Kee, Khoi D Tran, Hyunkyoung Lee, Xingyu Zhao, Tian Liu, Simon S Wing, Jung-A A Woo, David E Kang.
      Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP (FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by several posttranslational modifications, including ubiquitination. While multiple E3 ubiquitin ligases are known to facilitate TDP-43 clearance, little is known about the role of deubiquitinases (DUBs) in controlling TDP-43 proteostasis. Through an unbiased discovery screen of DUBs, here we identify and demonstrate using in vitro and in vivo models, as well as human brain tissue, that ubiquitin-specific peptidase-19 (USP19) acts as a TDP-43-directed DUB that removes K48- and K63-linked ubiquitin conjugates from TDP-43 and preferentially promotes cytoplasmic aggregation of TDP-43 C-terminal fragments (TDP-CTFs) through its catalytic activity. Specifically, the endoplasmic reticulum (ER)-anchored USP19 isoform (USP19-ER) exhibits superior activity in deubiquitinating TDP-CTFs, enhancing its phase separation and aggregation, compared to its cytosolic isoform (USP19-Cyto). Furthermore, as TDP-CTFs are generated at the ER, USP19 acts to couple the aggregation of TDP-CTFs to ER stress (ATF6, ATF4, IRE1, & CHOP). In humans, USP19 protein levels increase in FTLD-TDP brains, which extensively colocalize with cytoplasmic phospho-TDP-43 (pTDP-43) pathology. Importantly, we demonstrate in vivo that genetic reduction of usp19 mitigates pTDP-43 pathology, astrogliosis, and ER stress while reversing long-term potentiation (LTP) and motor deficits in a mouse model of TDP-43 pathogenesis (TAR4 mice). These findings establish a critical role of USP19 at the nexus of TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.
    Keywords:  ALS; ER stress; FTD; TDP-43; USP19
    DOI:  https://doi.org/10.1073/pnas.2514355123
  9. J Mol Cell Cardiol. 2026 Mar 10. pii: S0022-2828(26)00040-4. [Epub ahead of print]
    Cardiomyopathy and aging integrally contribute to the unfolded protein response collective pathways.
    Camilla Bacchin, Marco Luciani, Luca Troncone, Cristina Balla, Stefano Berto, Bethany Jacobs Wolf, Federica Del Monte.
      Proteins are essential elements controlling cellular processes. Their synthesis and assembly are vital to the cell as their defect would have deleterious consequences. A finely tuned conserved biological machinery known as the protein quality control (PQC) is in place to correct the defect. The PQC includes the unfolded protein response (UPR), devoted to recognizing, unfolding and refolding abnormally arranged proteins, and the clearance apparatuses composed of the Ubiquitin Proteasome System (UPS) and the Endoplasmic Reticulum Associated Protein Degradation (ERAD). Abnormally folded proteins accumulate in idiopathic dilated cardiomyopathy (iDCM). In this study we investigated the transcriptional and translational landscapes of the UPR and UPS systems using polymerase chain reaction (PCR) and western blotting (WB) of myocardial tissues from iDCM patients and age, ethnicity and biological sex matched control cases. Our results show an increase of the three main UPR axis at the transcription and translational levels, suggesting an activation/inactivation of all axes, with altered PTM/cleavage/splicing eliciting abnormal downstream function. Notably, aging independently affects this machinery in diseased and control individuals. In addition, mutation in presenilin gene associated with Alzheimer's disease led to post-translational changes of the UPR components suggesting that genetic risk may exacerbate the natural age and disease-driven protein dyshomeostasis. In conclusion, our findings highlight that abnormalities of UPR are a still largely unexplored feature in heart failure to be view in its entirely. The combined alteration of several target proteins of these pathways configures defective proteostasis as a condition of misfolded peptides accumulation ultimately exhausting the cell survival capabilities.
    Keywords:  Aging; Heart failure; Proteostasis; Unfolding protein response
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.03.001
  10. Nucleic Acids Res. 2026 Feb 24. pii: gkag193. [Epub ahead of print]54(5):
    SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay.
    Sabrina Kueckelmann, Sophie Theunissen, Fenja Meyer Zu Altenschildesche, Leonie von Ondarza, Jan-Wilm Lackmann, Marek Franitza, Kerstin Becker, Volker Boehm, Niels H Gehring.
      Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA turnover pathway, which degrades transcripts containing premature termination codons. NMD activation depends on phosphorylation of the RNA helicase UPF1 by the SMG1 kinase, which acts in a complex with SMG8 and SMG9. Structural and biochemical studies have implicated SMG8 and SMG9 as regulators of SMG1 activity, but their contributions to NMD in human cells remain incompletely defined. Here, we systematically dissect the roles of SMG8 and SMG9 in NMD using genetic and pharmacological perturbations in multiple human cell lines. Deletion of the kinase inhibitory domain (KID) of SMG8 did not affect UPF1 phosphorylation or NMD efficiency, demonstrating that this domain is dispensable in vivo. Complete loss of SMG8 or SMG9 resulted in only modest NMD impairment and was accompanied by moderately increased UPF1 phosphorylation. However, SMG8- or SMG9-deficient cells exhibited pronounced hypersensitivity to partial pharmacological inhibition of SMG1, leading to synergistic, transcriptome-wide stabilization of NMD targets. These effects were reproducible across different cellular contexts, underscoring a general regulatory role for SMG8 and SMG9. Together, our results establish SMG8 and SMG9 as nonessential modulators that safeguard the efficiency and perturbation tolerance of the NMD pathway in human cells.
    DOI:  https://doi.org/10.1093/nar/gkag193
  11. J Cell Biol. 2026 May 04. pii: e202506039. [Epub ahead of print]225(5):
    Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
    Li Hao, Tomoki Midorikawa, Yuta Ogasawara, Takuma Tsuji, Takuma Kishimoto, Yutaro Hama, Huichao Lang, Nobuo N Noda, Kuninori Suzuki.
      Bridge-like lipid transfer proteins (LTPs) contain a repeating β-groove domain and long hydrophobic grooves that act as bridges at membrane contact sites (MCSs) to efficiently transfer lipids. Atg2 is one such bridge-like LTP essential for autophagosome formation, during which a newly synthesized isolation membrane (IM) emerges and expands through lipid supply. However, studies on Atg2-mediated lipid transfer are limited to in vitro studies due to the lack of a suitable probe for monitoring phospholipid dynamics in vivo. Here, we characterized the lipophilic dye octadecyl rhodamine B (R18), which internalizes and labels the endoplasmic reticulum (ER) in a manner that requires flippases and oxysterol-binding protein-related proteins. Using R18, we demonstrated phospholipid transfer from the ER to the IM during autophagy in vivo. Upon autophagy termination, our data suggested the reversible phospholipid flow from the IM to the ER in response to environmental changes. Our findings highlight the critical role of bridge-like LTPs in MCS-mediated phospholipid homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202506039
  12. J Cell Biol. 2026 May 04. pii: e202508066. [Epub ahead of print]225(5):
    Stress-induced nucleolar rejuvenation via chaperone-mediated segregation in a filamentous fungus.
    Audra M Rogers, Brenna K Broussard, Rachel Taylor, Martin J Egan.
      How the nucleolus recovers from acute proteostatic stress, particularly in multinucleate syncytia, remains poorly understood. In the highly polarized hyphae of the model filamentous fungus Magnaporthe oryzae, we uncover a novel stress-induced spatial quality control pathway that promotes the inheritance of rejuvenated nucleolar material during nuclear division. This pathway discriminates between newly formed and damaged nucleolar compartments, selectively partitioning and sequestering the latter. Our findings reveal a previously unrecognized mechanism for chaperone-mediated segregation of a membraneless nuclear organelle, extending principles of protein quality control to the unique demands of highly polarized syncytia.
    DOI:  https://doi.org/10.1083/jcb.202508066
  13. Nature. 2026 Mar 11.
    Ageing promotes metastasis via activation of the integrated stress response.
    Angana A H Patel, Jozefina J Dzanan, Kevin X Ali, Ella A Eklund, Samantha W Alvarez, Dorota Raj, Martin Dankis, Ilayda Altinönder, Maria Schwarz, Kristell Le Gal, Emre Bedel, Ahmed Ezat El Zowalaty, Emma Jonasson, Heba Albatrok, Nadia Gul, Jozef P Bossowski, Ray Pillai, Patrick Micke, Johan Botling, Levent M Akyürek, Davide Angeletti, Sama I Sayin, Anetta Härtlova, Thales Papagiannakopoulos, Roger Olofsson Bagge, Anders Ståhlberg, Andreas Hallqvist, Clotilde Wiel, Volkan I Sayin.
      Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.
    DOI:  https://doi.org/10.1038/s41586-026-10216-0
  14. Nat Commun. 2026 Mar 12.
    NAA40 and NAC cooperate in co-translational histone acetylation in humans.
    Dandan Guan, Timo Denk, Ariel Klavaris, Matthias Thoms, Otto Berninghausen, Birgitta Beatrix, Antonis Kirmizis, Roland Beckmann.
      N-terminal acetylation is an abundant and predominantly co-translational modification in eukaryotes that profoundly affects folding, compartmentalization fidelity and turnover of target proteins. Unlike other N-acetyltransferases, human NatD is composed solely of the catalytic subunit NAA40 and exclusively modifies histone proteins H2A and H4. However, the molecular details of co-translational NAA40 activity have remained elusive. Here, we show biochemically and by cryo-EM how NAA40 activity is coordinated at the ribosomal peptide tunnel exit involving the NAC complex. We demonstrate that the NAA40-NAC interaction is required for efficient ribosome binding and histone acetylation. Furthermore, we provide insights on the potential coordination of methionine removal and subsequent NAA40-mediated acetylation by formation of a multienzyme complex on the ribosome involving METAP1. Therefore, our results illustrate the details of N-terminal histone acetylation by NAA40 and highlight the role of NAC as a general coordinator of nascent protein modification.
    DOI:  https://doi.org/10.1038/s41467-026-70279-5
  15. Neuron. 2026 Mar 12. pii: S0896-6273(26)00052-8. [Epub ahead of print]
    Endocytome profiling uncovers cell-surface protein dynamics underlying neuronal connectivity.
    Colleen N McLaughlin, Hui Ji, Katherine X Dong, Chuanyun Xu, Kenneth Kin Lam Wong, Zhuoran Li, David J Luginbuhl, Charles Xu, Cheng Lyu, Wei Qin, Jiefu Li, Namrata D Udeshi, Steven A Carr, Alice Y Ting, Liqun Luo.
      Endocytosis actively remodels the neuronal surface proteome to drive diverse cellular processes, yet its global extent and effects on neural circuit development have defied comprehensive interrogation. Here, we introduce endocytome profiling: a systematic, cell-type-specific approach for mapping cell-surface protein (CSP) dynamics in situ. Quantitative proteomic analysis of developing Drosophila olfactory receptor neuron (ORN) axons generated an endocytic atlas comprising over 1,000 proteins and revealed the extent to which the cell-surface proteome is remodeled to meet developmental demands. Targeted interrogation of a junctional CSP showed that its endosome-to-surface ratio is precisely balanced to enable developmental axon pruning while preserving mature axon integrity. Multi-omic integration uncovered widespread transcellular signaling and identified a growth factor secreted by neighboring neurons to direct ORN axon targeting via endocytic regulation of its receptor. Endocytome profiling provides unprecedented access to cell-surface proteome dynamics and offers a platform to dissect proteome-scale remodeling across diverse cell types and contexts.
    Keywords:  Drosophila; axon targeting; cell-surface protein; endosome; olfactory receptor neuron; proteomics; proximity labeling; remodeling
    DOI:  https://doi.org/10.1016/j.neuron.2026.01.027
  16. Trends Cell Biol. 2026 Mar 12. pii: S0962-8924(26)00003-6. [Epub ahead of print]
    Cullin-RING receptors in rare disease biology.
    Natalia A Szulc, Wojciech Pokrzywa.
      The ubiquitin-proteasome system governselective protein turnover in all eukaryotes, and its cullin-Really Interesting New Gene (RING) ligases represent the largest class of E3 ligases. Their substrate receptors (SRs) act as the 'specificity engines' of degradation, yet their contribution to human genetic disease has only recently come into focus. In this review, we provide the first systematic catalogue of 267 SRs, of which 93 are now linked to germline disorders. We synthesise emerging mechanisms, from altered degron recognition to noncanonical SR functions, and highlight how patient variants illuminate pathways for diagnosis and therapy. By connecting proteostasis, rare-disease genetics, and targeted protein degradation, SRs emerge as central nodes with broad implications for precision medicine.
    Keywords:  E3 ubiquitin ligases; cullin–RING ligases; germline variants; rare genetic diseases; substrate receptors; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1016/j.tcb.2026.01.003
  17. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708335. [Epub ahead of print]
    Single-Cell Spatial Proteomics Uncovers Molecular Interconnectivity among Hallmarks of Aging.
    Seungmin Yoo, Christopher Young, Liying Li, Lingraj Vannur, Junming Zhuang, Fan Zheng, Meiying Wu, Julie K Andersen, Chuankai Zhou.
      Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context. We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.
    DOI:  https://doi.org/10.64898/2026.02.26.708335
  18. Nat Commun. 2026 Mar 11.
    Molecular insights into the regulation of GNPTαβ by LYSET.
    Xi Yang, Balraj Doray, Danielle Henn, Varsha Venkatarangan, Benjamin C Jennings, Zhongzheng Dong, Jiaxuan Liang, Weichao Zhang, Bokai Zhang, Linchen Yu, Liang Chen, Stuart Kornfeld, Ming Li.
      In vertebrates, newly synthesized lysosomal enzymes traffic to lysosomes through the mannose-6-phosphate (M6P) pathway. The Golgi membrane protein LYSET was recently discovered to regulate lysosome biogenesis by controlling the level of GlcNAc-1-phosphotransferase (GNPT). However, its working mechanism remained unclear. In this study, we demonstrate that LYSET is a two-transmembrane protein essential for GNPT stability, cleavage by Site-1 Protease (S1P), and enzymatic activity. We reconcile conflicting models by showing that LYSET enhances GNPT cleavage and prevents its mislocalization to lysosomes for degradation. We further establish that LYSET achieves this by interacting with GOLPH3 and retromer complexes to anchor the LYSET-GNPT complex at the Golgi. Alanine mutagenesis identified an F4XXR7 motif in LYSET's N-tail for GOLPH3 binding. The retromer further promotes Golgi retention by binding to the C-terminal of LYSET and recycling it from endolysosomes. Together, our findings reveal LYSET's multifaceted role in stabilizing GNPT, retaining it at the Golgi, and ensuring the fidelity of the M6P pathway, thereby providing insights into its molecular function.
    DOI:  https://doi.org/10.1038/s41467-026-70402-6
  19. Nat Commun. 2026 Mar 10. pii: 2125. [Epub ahead of print]17(1):
    Translational regulation by oxidative desulfuration of tRNA modifications.
    Yufeng Mo, Kensuke Ishiguro, Kenjyo Miyauchi, Yuriko Sakaguchi, Yosei Hanzawa, Naho Akiyama, Ayaka Murayama, Kodai Machida, Hiroaki Imataka, Akio Yamashita, Takayuki Ohira, Mikako Shirouzu, Tsutomu Suzuki.
      Modifications in the anticodon region of transfer RNA (tRNA) are essential for accurate and efficient protein synthesis. 5-Methyl-2-thiouridine derivatives (xm5s2U) are major modifications at the wobble position of tRNA anticodons decoding purine-ending two-codon sets. Although the thiocarbonyl group of xm5s2U enhances decoding efficiency, it is chemically susceptible to oxidative desulfuration, yielding 4-pyrimidinone derivatives (xm5h2U). Here, we identify xm5h2U derivatives in human cells and mouse tissues and confirm their cellular formation by spike-in experiments. Desulfurized tRNAs carrying 5-methoxycarbonylmethyl-4-pyrimidinone (mcm5h2U) show impaired codon recognition in a human reconstituted in vitro translation system. The mcm5h2U modification reduces aminoacylation of tRNAs for lysine, glutamate, and glutamine, but not arginine. Cryogenic electron microscopy reveals the structural basis of altered AAA/AAG decoding by mcm5h2U at the ribosomal A-site. These findings reveal a mechanism by which oxidative desulfuration of tRNA modifications dynamically regulates codon recognition and protein synthesis under oxidative stress conditions in human and mammalian cells.
    DOI:  https://doi.org/10.1038/s41467-026-70126-7
  20. J Mol Biol. 2026 Mar 10. pii: S0022-2836(26)00124-5. [Epub ahead of print] 169751
    Biochemical insights into the conserved interactions of NMD factors from budding yeast to humans.
    Nadia Ruiz-Gutierrez, Marc Graille, Hervé le Hir, Cosmin Saveanu.
      Nonsense-mediated mRNA decay (NMD) is one of the most extensively studied pathways of cytoplasmic mRNA degradation. It plays a critical role in diverse cellular processes by eliminating aberrant transcripts containing premature stop codons and by regulating the stability of physiological mRNAs. NMD factors were initially identified through genetic screens in S. cerevisiae (UPF1, 2, 3) and C. elegans (SMG-1, SMG5-7). Subsequent biochemical and genetic studies revealed the composition of NMD complexes and identified additional factors. A major protein hub for NMD is Upf1, an ATP-dependent RNA helicase that is part of two mutually exclusive NMD assemblies, the Upf1-Upf2-Upf3 complex and the Upf1-decapping complex, which contains the decapping enzyme and its co-factors. Here, we discuss recent findings, primarily from budding yeast, on the protein-protein interactions driving NMD complexes dynamics and their similarities to human NMD. Together, the N-terminal cysteine and histidine rich (CH) and helicase domains (HD) of Upf1 act as a hub for binding multiple partners. Upf1 is required for binding to NMD substrates and for the initiation of RNA degradation through decapping (yeast) or endonucleolytic hydrolysis (humans). We focus on the interplay between Upf2, Dcp2 and Nmd4 (yeast SMG6), which ensures the mutually exclusive formation of Upf1-bound subcomplexes modulating Upf1's affinity for RNA. Thus, the study of NMD factors interactions in different organisms sheds new light on the remarkable conservation of NMD molecular mechanisms.
    Keywords:  NMD; Nonsense-Mediated mRNA Decay; Protein interactions; RNA decapping; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.jmb.2026.169751
  21. RNA. 2026 Mar 10. pii: rna.080884.125. [Epub ahead of print]
    Degradation factor 1, Def1, regulates mRNA translation and decay through Ccr4-Not-dependent ubiquitylation of the ribosome.
    Oluwasegun T Akinniyi, Aswathy Sebastian, Shardul Kulkarni, Istvan Albert, Joseph C Reese.
      Yeast Def1 is well known for its role in regulating RNA polymerase II elongation and degrading the large subunit of polymerase during transcriptional stress. It is an abundant cytoplasmic protein that undergoes stress-induced processing and is then transported to the nucleus. Previous research from our lab has shown that Def1 interacts with various proteins involved in mRNA decay and translation control, and that it regulates mRNA half-lives, suggesting an important role in the cytoplasm. In this study, we report that Def1 binds polyribosomes and that its null mutant strain exhibits phenotypes indicating a role in translation. Ribo-seq analysis revealed that deleting DEF1 altered ribosome footprints on mRNAs and increased the dwell time of ribosomes at non-optimal codons in the A-site. Additionally, results from a codon-optimality reporter assay suggest that Def1 facilitates the degradation of mRNAs containing non-optimal codons. The Ccr4-Not complex links codon optimality to mRNA decay, and Def1's binding to ribosomes depends on its ubiquitin-binding domain, as well as the ubiquitylation of eS7a in the small ribosomal subunit by the Ccr4-Not complex. Moreover, the polyglutamine-rich, unstructured C-terminus of Def1 is crucial for its interaction with RNA decay and translation factors. This indicates that Def1 functions as a ubiquitin-dependent scaffold that connects translation status to mRNA decay. In summary, we have identified a cytoplasmic function for Def1 in translation and established it as a regulator of gene expression that spans both transcription and translation processes.
    Keywords:  Ccr4-Not; Def1; co-translational decay; posttranscriptional control; ubiquitylation
    DOI:  https://doi.org/10.1261/rna.080884.125
  22. Chembiochem. 2026 Mar 13. 27(5): e202500715
    Advancing Targeted Protein Degradation Through Immunoproteasome-Caged N-Degrons.
    Jack White, Michael M Shahid, Mohamed Eldeeb.
      Proteolysis-targeting chimeras (PROTACs) are a promising therapeutic modality that induces the degradation of proteins of interest, yet continue to be limited by metabolic instability and nonoptimal selectivity. N-degron-based PROTACs, while compact and effective recruiters of N-recognins (E3 ubiquitin ligases), are particularly prone to premature degradation and off-target effects. To address this challenge, Loy et al. introduced a "caged" N-degron PROTAC in which a tetrapeptide-morpholine fragment shields the arginine degron. This sequence is specifically recognized by the immunoproteasome (iCP), an inducible proteasome isoform highly expressed in cancer and inflammatory cells, while absent in most healthy tissues. Upon iCP-mediated cleavage, the degron is unmasked, allowing for the degradation of ABL tyrosine kinase via dasatinib-linked PROTAC activity. This protease-gated strategy integrates endogenous proteolytic specificity into degrader activation, enhancing functional stability while allowing context-dependent specificity. Despite these elegant improvements, some challenges remain regarding cell permeability and disease-dependent iCP expression. Nevertheless, immunoproteasome-gated degron represents a compelling framework for the next generation of N-degron PROTACs. Herein, we highlight these recent findings in the context of the design principles, mechanistic insights, and therapeutic implications of this approach and briefly discuss some key challenges and opportunities for future development.
    Keywords:  N‐degrons; N‐terminal dependent degradation; proteasomes; protein degradation; proteolysis‐targeting chimera
    DOI:  https://doi.org/10.1002/cbic.202500715
  23. Cell Death Dis. 2026 Mar 09.
    Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.
    Erin M Kropp, Sho Matono, Olivia Y Wang, Aaron M Robida, Malathi Kandarpa, Jineigh L Grant, Bryndon J Oleson, Andrew Alt, Moshe Talpaz, Matthew J Pianko, Qing Li.
      Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum-associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD has been proposed as a therapeutic strategy to overcome proteasome inhibitor resistance; however, the identification of novel inhibitors has been limited. To address this, we conducted a cell-based high-throughput screen using the FDA repurposing library and identified omaveloxolone (RTA408) as a potent ERAD inhibitor that selectively impairs the degradation of ER luminal and membrane substrates, without affecting the degradation of key cytosolic proteins that are implicated in disease relapse. Surprisingly, although ER stress response pathways are activated after ERAD inhibition in MM, we find that apoptosis is mediated by altered lipid raft organization, leading to aberrant activation of the death-inducing signaling complex (DISC) and caspase 8 in the extrinsic apoptotic pathway. Notably, ERAD inhibition by RTA408 is cytotoxic to primary malignant plasma cells, including those resistant to proteasome inhibitors, and demonstrates in vivo anti-myeloma activity. Our findings establish a novel ERAD inhibitor, which is a valuable tool to dissect ERAD biology, and provide pre-clinical evidence for RTA408 as a therapeutic agent in MM.
    DOI:  https://doi.org/10.1038/s41419-026-08526-2
  24. FEBS J. 2026 Mar 11.
    A guide to mapping ubiquitin and ubiquitin-like E3 ligases to their substrates.
    Laura Merino-Cacho, Claudia Guinea-Pérez, Mónica Pozo-Rodríguez, Sandra Cano-López, Juanma Ramirez, Orhi Barroso-Gomila, Ugo Mayor, James D Sutherland, Rosa Barrio.
      Ubiquitination is a post-translational modification that plays a key role in the maintenance of protein homeostasis. Ubiquitin is covalently attached to the target proteins through a three-step enzymatic cascade in which substrate specificity is conferred by the E3 ligases. However, to match more than 600 E3s with their specific substrates is one of the major challenges in the field. The dynamic and reversible nature of ubiquitination requires the development of techniques to systematically address this question. Here we provide a comprehensive overview of the current methodologies used to reveal targets of E3 ligases, discussing their strengths and limitations. This is particularly relevant in light of emerging pharmacological strategies for targeted protein degradation.
    Keywords:  E3 ligases; post‐translational modifications; substrate identification; ubiquitin; ubiquitin‐like proteins
    DOI:  https://doi.org/10.1111/febs.70479
  25. Nat Commun. 2026 Mar 10.
    A paired sequence language model for protein-protein interaction modeling.
    Jun Liu, Hungyu Chen, Yang Zhang.
      Understanding protein-protein interactions (PPIs) is crucial for deciphering cellular processes and guiding therapeutic discovery. While recent protein language models have advanced sequence-based protein representation, most are designed for individual chains and fail to capture inherent PPI patterns. Here, we introduce a Protein Pair Language Model (PPLM) that jointly encodes paired sequences, enabling direct learning of interaction-aware representations beyond what single-chain models can provide. Building on this foundation, we develop PPLM-PPI, PPLM-Affinity, and PPLM-Contact for binary interaction, binding affinity, and interface contact prediction. Large-scale experiments show that PPLM-PPI achieves state-of-the-art performance across different species on binary interaction prediction, while PPLM-Affinity outperforms both ESM2 and structure-based methods on binding affinity modeling, particularly on challenging cases including antibody-antigen and TCR-pMHC complexes. PPLM-Contact further surpasses existing contact predictors on inter-protein contact prediction and interface residue recognition, including those deduced from cutting-edge complex structure predictions. Together, these results highlight the potential of co-represented language models to advance computational modeling of PPIs.
    DOI:  https://doi.org/10.1038/s41467-026-70457-5
  26. Dev Cell. 2026 Mar 12. pii: S1534-5807(26)00078-X. [Epub ahead of print]
    Desmosomes compartmentalize mRNA and translation in the skin.
    Alec D'Alessandro, Kwabena Badu-Nkansah, Sophia Link, Daniel Hlavaty, Glenn Bjerke, Christopher V Nicchitta, Rui Yi, Terry Lechler.
      Subcellular compartmentalization allows cells to spatially control molecular functions. We show that in mouse and human epidermal cells, translational machinery is enriched at the cell cortex, where a large subset of mRNAs is also localized, defining a previously unrecognized axis of mRNA organization. The desmosomal protein desmoplakin is required for the cortical recruitment of both ribosomes and mRNAs via distinct mechanisms. Surprisingly, many cortex-localized transcripts are not actively translated but instead are translationally repressed. This spatially restricted regulation involves the RNA-induced silencing complex (RISC), which is also enriched at the cortex in a desmoplakin-dependent manner. Under homeostatic conditions, cortical RISC associates with mRNAs encoding cell adhesion and cytoskeletal proteins. Following wounding, these RISC-associated transcripts become translationally activated. Together, our findings reveal a dynamic, desmosome-dependent cortical compartmentalization of translation that responds to epithelial barrier disruption.
    Keywords:  RISC; compartmentalization; desmoplakin; desmosome; mRNA localization; ribosome; translation; translatome
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.013
  27. Nat Chem Biol. 2026 Mar 12.
    A druggable redox switch on SHP1 controls macrophage inflammation.
    Mei Ying Ng, Meredith N Nix, Guangyan Du, Ivan Davidek, Nils Burger, Sanghee Shin, Sean Toenjes, Haruna Takeda, Megan Cheah Xin Yan, Bingsen Zhang, Haopeng Xiao, Shelley M Wei, Hyuk-Soo Seo, Sirano Dhe-Paganon, Thomas E Wales, John R Engen, Evanna L Mills, Jianwei Che, Tinghu Zhang, Nathanael S Gray, Edward T Chouchani.
      Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.
    DOI:  https://doi.org/10.1038/s41589-026-02163-8
  28. Nat Commun. 2026 Mar 13.
    Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
    Michel Kahi, Abigail Mazzu, Ludovic Batistic, Marc Pujalte-Martin, Victor Tiroille, Anne Vincent, Joseph Murdaca, Loic Trapani, Paraskevi Kousteridou, Oumayma Benaceur, Amine Belaid, Marie Irondelle, Emilie Thomas, Christelle Boscagli, Pierre Bertrand, Heather S Carr, Frédéric Larbret, Emilie Baudelet, Stéphane Audebert, Didier F Pisani, Silvère Baron, Luc Camoin, Mathieu Carlier, Matthieu Durand, Damien Ambrosetti, Yu Chen, Jean-Jacques Diaz, Arnaud Jacquel, Issam Ben-Sahra, Nathalie M Mazure, Pascal Peraldi, Frédéric Bost.
      Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5Ahyp) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5Ahyp controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5Ahyp regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5Ahyp. Together, we uncover a critical role for eIF5Ahyp in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-70566-1
  29. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2509374123
    Switching of the c-Myc protein degradation pathway depending on the PP2A-B55α complex levels.
    Sana Ando, Shunta Ikeda, Keiko Tanaka, Yuri Tomabechi, Atsushi Yamagata, Mikako Shirouzu, Ryouichi Tsunedomi, Hiroaki Nagano, Shunya Tsuji, Koichi Sato, Takashi Ohama.
      The transcription factor c-Myc is a master oncoprotein that regulates over 15% of all genes. Protein phosphatase 2A (PP2A), a crucial tumor suppressor, destabilizes c-Myc protein. Classically, PP2A-mediated dephosphorylation of Ser62 followed by Thr58 phosphorylation was thought to promote ubiquitination of c-Myc by the E3 ligase F-box and WD repeat domain containing 7 (FBXW7). However, recent evidence indicates that FBXW7 preferentially recognizes c-Myc when both Thr58 and Ser62 are phosphorylated, leaving the mechanism underlying PP2A-induced c-Myc degradation unsolved. Here, we demonstrate that the PP2A-B55α complex, which directly dephosphorylates c-Myc at Thr58, regulates two distinct degradation pathways in a biphasic manner: B55α suppression increases Thr58 phosphorylation and enhances FBXW7-dependent degradation, whereas B55α overexpression promotes Thr58-independent, ubiquitin-protein ligase E3 component N-recognin 5 (UBR5)-mediated degradation. We further show that the PP2A-B55α complex binds and dephosphorylates UBR5. In contrast, B55δ, which belongs to the same B55 family and shares a common core structure, exhibits weaker UBR5 binding affinity and fails to induce c-Myc degradation. Our findings identify PP2A-B55α as a context-dependent molecular switch for c-Myc degradation and provide a unified framework that resolves the paradox linking PP2A activation to c-Myc destabilization.
    Keywords:  PPP2R2A; PPP2R2D; UBR5; c-Myc; protein phosphatase 2A
    DOI:  https://doi.org/10.1073/pnas.2509374123
  30. Sci Adv. 2026 Mar 13. 12(11): eaea9061
    Integrative analysis of mRNA stability regulation uncovers a metastasis-suppressive program in breast cancer.
    Heather Karner, Tabea C Mittmann, Vicky W Chen, Ashir A Borah, Andreas Langen, Hassan Yousefi, Lisa Fish, Balyn W Zaro, Albertas Navickas, Hani Goodarzi.
      Heterogeneity in cancer gene expression is typically linked to genetic and epigenetic alterations, yet the extent of contribution from posttranscriptional regulation remains unclear. Here, we systematically measured messenger RNA (mRNA) dynamics across diverse breast cancer models, revealing that mRNA stability substantially shapes gene expression variability. To decipher these dynamics, we developed GreyHound, an interpretable multimodal deep-learning framework integrating RNA sequence features and RNA binding protein (RBP) expression. GreyHound identified an extensive network of RBPs and their regulons underlying variations in mRNA stability, including a regulatory axis centered on RBP RBMS3 and redox regulator TXNIP. RBMS3 depletion resulted in targeted transcript destabilization-associated with poor clinical outcomes and enhanced metastatic potential in xenograft models. In vivo epistasis studies confirmed that RBMS3-mediated regulation of TXNIP mRNA stability drives this metastasis-suppressive program. These findings identify a key posttranscriptional mechanism in breast cancer and illustrate how interpretable models of RNA dynamics can uncover regulatory programs in disease.
    DOI:  https://doi.org/10.1126/sciadv.aea9061
  31. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2522993123
    Reversibility and β-sheet formation are decoupled in tau condensate aging.
    Charlotte M Fischer, Irina A Edu, Tomas Šneideris, Ieva Baronaite, Zenon Toprakcioglu, Leif-Thore Deck, Daoyuan Qian, Rob Scrutton, Lasse Dreyer, Jitao Wen, Daniel E Otzen, Si Wu, Sarah Perrett, Tuomas P J Knowles.
      Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, β-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are β-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack β-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention.
    Keywords:  biophysics; intrinsically disordered proteins; liquid–liquid phase separation; microfluidics; protein aggregation
    DOI:  https://doi.org/10.1073/pnas.2522993123
  32. Science. 2026 Mar 12. 391(6790): eaec1778
    Autophagolysosomal exocytosis inverts Src kinase onto the cell surface in cancer.
    Corleone S Delaveris, Rita P Loudermilk, Apurva Pandey, Soumya G Remesh, Trenton M Peters-Clarke, Snehal D Ganjave, William J N Dougherty, Henry M Delavan, Chunyue Wang, Jesse Ling, Juan Antonio Camara Serrano, Fernando Salangsang, Chien-Kuang Cornelia Ding, Nancy Greenland, Carissa E Chu, Sima Porten, Veronica Steri, Jonathan Chou, Michael J Evans, Kevin K Leung, James A Wells.
      Overexpression of the proto-oncogene Src is common to a wide variety of cancers. In this work, we found that Src is noncanonically translocated and inverted onto the cell surface in cancer, both in vitro and in vivo. We identified autophagolysosomal exocytosis (ALE) as a secretory mechanism prominent in cancer cell lines. Src represents the prototypical example of a family of membrane-anchored proteins that are transported by this process. Furthermore, this extracellular membrane-associated Src (eSrc) was found in primary tumors, and anti-Src antibody-based therapies mediated tumor cell killing in cell culture systems and in mouse xenograft models. Thus, intracellular N-myristoylated proteins, prototypically Src, can be topologically inverted onto the cell surface in cancer and targeted with antibody therapeutics.
    DOI:  https://doi.org/10.1126/science.aec1778
  33. Proc Natl Acad Sci U S A. 2026 Mar 17. 123(11): e2518248123
    DeepDegradome: A structure-aware deep learning framework for PROTAC and ligand generation against protein targets.
    Qiaoyu Hu, Yu Cao, PengXuan Ren, Xianglei Zhang, Fenglei Li, Xueyuan Zhang, Fengyu Cai, Ran Zhang, Yongqi Zhou, Lianghe Mei, Fang Bai.
      Targeted protein degradation is a promising strategy for drug discovery, but designing effective PROTACs remains challenging, especially for proteins without well-defined binding sites. Current methods rely on modifying linkers between fixed ligands, which limits the diversity and innovation of the overall molecular architecture of PROTAC. Here, we introduce DeepDegradome, an AI-powered method that automates the structure-aware design of both small-molecule ligands and PROTACs. It employs a large fragment library constructed from public databases and applies an in-house docking method (iFitDock) to obtain initial binding fragments. DeepDegradome builds ligands by assembling these fragments based on the shape and physicochemical features of the target protein pocket. It can further construct PROTACs from these generated ligands, eliminating the dependency on predefined warheads or E3 ligands. Compared to other AI models, DeepDegradome produces more valid, drug-like molecules with higher predicted binding affinity. We demonstrate DeepDegradome's effectiveness by designing and validating multiple potency inhibitors and PROTACs for two protein targets: WDR5 and CDK9. One synthesized compound showed excellent agreement between predicted and actual binding conformation confirmed by X-ray crystallography. By combining ligand and PROTAC design in one system, DeepDegradome offers a scalable and reliable tool for discovering new drugs against protein targets.
    Keywords:  PROTACs; deep learning; fragment-based drug design; molecular generation
    DOI:  https://doi.org/10.1073/pnas.2518248123
  34. Mol Syst Biol. 2026 Mar 11.
    Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.
    Tetiana Serdiuk, Virginie Redeker, Jimmy Savistchenko, Sandesh Neupane, Walther Haenseler, Yanick Fleischmann, Viviane Reber, Sabrina Keller, Cinzia Tiberi, Ruxandra Bachmann-Gagescu, Matthias Gstaiger, Thomas Braun, Roland Riek, Steve Gentleman, Adriano Aguzzi, Natalie de Souza, Ronald Melki, Paola Picotti.
      The aggregation of the protein alpha-synuclein (αSyn) is a common feature of multiple neurodegenerative diseases collectively called synucleinopathies, for which the pathobiology is not well understood. The different phenotypic characteristics of the synucleinopathies Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) have been proposed to originate from the distinct structures adopted by αSyn in its amyloid forms. Here, using covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS) in vitro and in situ within neuronal cells and directly in native patient brain homogenates, we show that pathogenic αSyn from distinct synucleinopathies (PD, DLB and MSA) are structurally different. Further, we found that fibril structural differences are associated with different putative fibril interactomes and neuronal responses. We discovered disease-specific ubiquitination patterns and turnover profiles for pathogenic αSyn species, detected molecular pathways responding specifically to the uptake of different αSyn fibrillar polymorphs, and identified a subset of the involved proteins as putative interactors of αSyn. In particular, components of the ubiquitin-proteasomal System (UPS), including E3 ubiquitin ligases, chaperones, and deubiquitinating proteins, showed disease/polymorph-specific putative interaction patterns, possibly accounting for different resistance of patient-derived αSyn fibrils to degradation. Genetic modulation with CRISPR-based tools showed that members of the UPS degradation pathway (three E3 ligases: UBE3A, TRIM25, HUWE1 and the AAA+ ATPase VCP) reduced αSyn inclusions, in a strain-specific manner. LiP-MS also identified sets of proteins with altered protease susceptibility in postmortem brain homogenates of PD, DLB, and MSA patients. These sets were largely disease-specific and included proteins altered in cells treated with fibrils derived from patients with the matching disease. Our findings provide insight into cellular processes involved in the accumulation and turnover of αSyn pathogenic aggregates in PD, DLB and MSA in a disease/specific manner and constitutes a resource of potential novel drug targets in these synucleinopathies.
    Keywords:  Alpha-Synuclein; Amyloid Strains; Limited Proteolysis-Coupled to Mass Spectrometry; Parkinson’s Disease; Structural Proteomics
    DOI:  https://doi.org/10.1038/s44320-026-00199-5
  35. Nat Struct Mol Biol. 2026 Mar 13.
    Checking in on proteostasis.
    Eri Sakata, Ramanujan S Hegde, Yan G Zhao, Takuhiro Ito, Sheena E Radford, Maria Hatzgolou, Ursula Jakob, Eunyong Park, Yi Lin, Elke Deuerling, Peiguo Yang, Young-Jun Choe.
      
    DOI:  https://doi.org/10.1038/s41594-026-01772-0
  36. Adv Sci (Weinh). 2026 Mar 12. e21310
    Rapid Proteome-Wide Discovery of Protein-Protein Interactions With ppIRIS.
    Luiz Felipe Piochi, Di Tang, Johan Malmström, Yasaman Karami, Hamed Khakzad.
      Protein-protein interactions (PPIs) are central to cellular processes and host-pathogen dynamics across all domains of life, yet comprehensive interactome mapping remains challenging at the proteome scale. Experimental approaches provide only partial coverage, while existing computational methods often lack generalizability across species or are too resource-intensive for large-scale screening. Here, we introduce ppIRIS (protein-protein Interaction Regression via Iterative Siamese networks), a lightweight deep learning framework that integrates evolutionary and structural embeddings to predict PPIs directly from sequence. Evaluated on multi-species benchmarks, ppIRIS achieves state-of-the-art accuracy while enabling proteome-wide screening in minutes. Trained on curated bacterial datasets and applied to the Group A Streptococcus (GAS) proteome, ppIRIS identified functional clusters associated with virulence pathways, such as nutrient transport, stress response, and metal scavenging. Extending to cross-species prediction, ppIRIS recovered 56.2% of known GAS-human plasma interactions with enrichment in complement, coagulation, and protease inhibition pathways. Experimental validation confirmed novel predictions, demonstrating the applicability of ppIRIS for systematic discovery of bacterial and cross-species PPIs. The model together with a Google Colaboratory is freely available at github.com/lupiochi/ppIRIS.
    Keywords:  cross species interactions; deep learning; group A streptococcus; protein language models; protein‐protein interactions; proteome‐wide analysis; virulence factors
    DOI:  https://doi.org/10.1002/advs.202521310
  37. Nat Commun. 2026 Mar 10.
    CF2H: a cell-free two-hybrid platform for rapid protein binder screening.
    Julien Capin, Pauline Mayonove, Angelique DeVisch, Amon Becher, Giang Ngo, Alexis Courbet, Robert J Ragotte, Martin Cohen Gonsaud, Julien Espeut, Jerome Bonnet.
      Protein binders that detect, activate, inhibit, or otherwise modulate their targets are pivotal for biomedical applications. With the increasing accuracy and accessibility of de novo protein design, faster and cheaper experimental screening methods would democratize and accelerate the identification of high-affinity binders. Here we present Cell-Free Two-Hybrid (CF2H), a rapid and sensitive method for detecting high-affinity protein-protein interactions (PPI) that does not require cloning, protein purification nor high-end laboratory equipment. CF2H uses a dimerization-activated DNA binding domain (DBD) fused to prey and bait proteins to trigger transcription upon protein-protein interaction. We demonstrate that CF2H enables the detection of interactions between various types of target and binder proteins such as single-domain antibodies, DARPins, and de novo designed binders. We benchmark CF2H as a screening platform by validating previously reported binders for Mdm2 and discovering high-affinity binders targeting the checkpoint inhibitor PD-L1 in less than 24 hours. Finally, we show that CF2H can be used to characterize small-molecule modulators of PPI and detect protein biomarkers, opening the door for a new class of cell-free biosensors.
    DOI:  https://doi.org/10.1038/s41467-026-69741-1
  38. Neuron. 2026 Mar 11. pii: S0896-6273(26)00086-3. [Epub ahead of print]
    Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
    Zhilong Zheng, Wangju Yang, Zhen Chen, Panpan Chen, Mengdan Tao, Shengda Wang, Bowei Cui, Zeyue Yang, Yanqing Yan, Xiao Han, Yongjie Zhang, Zijian Ren, Xiaoxin Yan, Yueqing Jiang, Jing Wang, Tingyou Li, Yan Liu, Xing Guo.
      Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.
    Keywords:  ALS; NMJ; PGAM5; VCP; amyotrophic lateral sclerosis; mitochondrial integrated stress response; mitochondrial phosphatase phosphoglycerate mutase 5; mtISR; neuromuscular junction; valosin-containing protein
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.003
  39. Biochem J. 2026 Mar 12. pii: BCJ20253463. [Epub ahead of print]
    Inducing TRIB2 Targeted Protein Degradation to Reverse Chemoresistance in Acute Myeloid Leukaemia.
    Evie Rigby, Francesca Fasanella Masci, Akshara Narayanan, Elzbieta Kania, John A Harris, Jamie Williams, Binghua Zhang, Lijun Liu, Laura Richmond, Fengtao Zhou, Ke Ding, Ruaidhrí J Carmody, Patrick A Eyers, Karen Keeshan.
      The myeloid oncogene TRIB2 is a key driver of acute myeloid leukaemia (AML) pathogenesis, promoting chemoresistance and blocking differentiation through ubiquitin-mediated degradation of the C/EBPα transcription factor. Despite its stable and sometimes elevated expression across AML subtypes, TRIB2 remains a clinically-untargeted vulnerability. Here, we present a comprehensive investigation into TRIB2 degradation mechanisms using multimodal approaches, including CRISPR knockout, mutational protein stability, small molecule TRIB2 engagement and evaluation of a novel targeted protein degrader (TRIB2-PROTAC). We identify Afatinib, a multi-ERBB covalent inhibitor, as a rapid inducer of TRIB2 degradation, triggering AML cell death potentially via signalling pathways distinct from ERBB. Importantly, TRIB2 degradation synergized with cytarabine, the frontline AML chemotherapy, amplifying therapeutic efficacy. Mapping of TRIB2 ubiquitination sites revealed Lys-63 as critical for its own proteolytic turnover, and a Lys to Arg degradation-resistant mutant (KallR) conferred enhanced chemoresistance and increased leukaemic engraftment in vivo. CRISPR-mediated TRIB2 knockout validated an essential role in AML cell survival. Consistently, the novel TRIB2-PROTAC (compound 5K) achieved robust TRIB2 degradation and AML cell killing at low micromolar concentrations. These findings establish TRIB2 as a compelling therapeutic target in AML and demonstrate that leveraging the ubiquitin-proteasome system to degrade TRIB2 offers a promising strategy to overcome chemoresistance. This work provides strong preclinical rationale for the development of TRIB2-targeting therapies in AML.
    Keywords:  Acute myeloid leukaemia; Chemotherapy resistance; Pseudokinases; Tribbles; Ubiquitin proteasome system
    DOI:  https://doi.org/10.1042/BCJ20253463
  40. J Clin Invest. 2026 Mar 10. pii: e197719. [Epub ahead of print]
    Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet induced steatotic liver disease.
    Abhishek K Singh, Balkrishna Chaube, Kathryn M Citrin, Joseph Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C Lowery, Sonal Shree, Keira E Mahoney, Nabil E Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T Ross, Stacy A Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A Grabińska, William C Sessa.
      Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from Metabolic dysfunction-associated steatotic liver disease (MASLD) to HCC remains unclear. We explored the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme, in chronic liver disease. Hepatocyte-specific NgBR deletion in mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Similarly, liver-specific knockout of DHDDS (D-LKO) NgBR's cis-PTase partner and a knock-in model carrying a human NgBR mutation that impairs cis-PTase activity developed HCC under high-fat diet conditions, although with lower penetrance. Single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Mechanistically, NgBR deficiency promotes excessive hepatic TAG accumulation by enhancing lipid uptake and impairing very-low-density lipoprotein (VLDL) secretion. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish cis-PTase as a critical suppressor of MASLD-HCC conversion and suggest DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in advanced metabolic dysfunction-associated steatohepatitis (MASH).
    Keywords:  Hepatology; Lipoproteins; Liver cancer; Metabolism; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/JCI197719
  41. STAR Protoc. 2026 Mar 11. pii: S2666-1667(26)00008-0. [Epub ahead of print]7(1): 104355
    Protocol for the quantification of digestive exophagy in cell culture.
    Lucy Funes, Frederick R Maxfield, Santiago Solé-Domènech.
      Microglia use digestive exophagy to partially degrade, extracellularly, Alzheimer's amyloid-beta aggregates that are too large to be phagocytosed. Here, we present a protocol to quantify this mechanism in cell culture. We describe steps for extracting primary microglial cells and preparing amyloid-beta model aggregates. We then detail procedures for measuring lysosomal exocytosis toward, and extracellular degradation of, these deposits using quantitative fluorescence microscopy. We also provide guidance on quantifying the data using digital image analysis. For complete details on the use and execution of this protocol, please refer to Jacquet et al.1.
    Keywords:  Cell biology; Cell culture; Cell isolation; Cell-based assays; Microscopy; Molecular/chemical probes; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2026.104355
  42. Nat Chem Biol. 2026 Mar 10.
    Structures of ALG3/9/12 reveal the assembly logic of the N-glycan oligomannose core.
    J Andrew N Alexander, Shu-Yu Chen, Somnath Mukherjee, Mario de Capitani, Rossitza N Irobalieva, Lorenzo Rossi, Parth Agrawal, Julia Kowal, Matheus A Meirelles, Markus Aebi, Jean-Louis Reymond, Anthony A Kossiakoff, Sereina Riniker, Kaspar P Locher.
      Asparagine-linked glycans are essential for the maturation and function of most eukaryotic secretory proteins. The biosynthesis and transfer of dolichylpyrophosphate-anchored GlcNAc2Man9Glc3 glycan is a highly conserved process occurring in the endoplasmic reticulum (ER) membrane and involving over a dozen membrane proteins whose dysfunction is linked to congenital disorders of glycosylation (CDGs). Three membrane-integral mannosyltransferases, ALG3, ALG9 and ALG12, mediate four consecutive mannosylation reactions that convert GlcNAc2Man5 to GlcNAc2Man9. Here, using chemoenzymatically synthesized lipid-linked glycan donor and acceptor analogs, we recapitulated this biosynthetic pathway in vitro. High-resolution cryo-electron microscopy structures of pseudo-Michaelis complexes of each step revealed how the branched glycan is accurately synthesized and unwanted side products are averted. Molecular dynamics simulations and mutagenesis studies uncovered a subtle but precise mechanism selecting the dolichylphosphomannose donor substrate over dolichylphosphoglucose, which is also present in the ER membrane. Our results also provide mechanistic explanations for enzyme dysfunction in CDGs and offer opportunities for N-glycan engineering.
    DOI:  https://doi.org/10.1038/s41589-026-02164-7
  43. Biology (Basel). 2026 Feb 26. pii: 382. [Epub ahead of print]15(5):
    The UFM1 Conjugation System: A Master Regulator of Cellular Stress Surveillance in Human Disease.
    Meiqian Kuang, Haigang Xu, Hongjun Huang, Caifang Ren, Pan Huang, Aihua Gong.
      Post-translational modification (PTM) encompasses diverse modifications, including phosphorylation, methylation, ubiquitin-like modifications (UBLs), and so on, which profoundly influence cellular functions. UFMylation is a recently identified ubiquitin-like modification, which is mediated by the Ubiquitin-like Ubiquitin Fold Modifier 1 (UFM1) conjugation system. The UFM1 conjugation system comprises UFM1, Ubiquitin-like protein activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1), UFM1-specific ligase 1 (UFL1), UFM1-specific protease 1 (UFSP1), UFM1-specific protease 2 (UFSP2), UFM1-binding protein 1 (UFBP1), and CDK5 regulatory subunit-associated protein 3 (CDK5RAP3). Accumulating research has demonstrated that the UFM1 conjugation system regulates various cellular stress responses, including endoplasmic reticulum (ER) stress, protein trafficking, DNA damage repair, and autophagy. Additionally, abnormal stress adaptations of the UFM1 conjugation system contribute to the pathophysiological complications of inflammatory diseases and cancer, underscoring its significance as a key regulatory node in human health and disease. Therefore, this review provides a comprehensive exploration of the structural characteristics of UFM1 conjugation system members and the mechanistic roles of UFMylation by UFM1 conjugation system-mediated diseases related to cellular stress responses, which will not only facilitate the identification of novel diagnostic and prognostic indicators but also enable the identification of specific therapeutic targets for UFM1 conjugation system-related diseases.
    Keywords:  UFM1; UFM1 conjugation system; UFMylation; cancer; diseases; stress response
    DOI:  https://doi.org/10.3390/biology15050382
  44. Adv Sci (Weinh). 2026 Mar 09. e23819
    G4-Ligand-Directed PROTACs Unveil DR1 as a Novel Ligand-Co-Binding G4-Protein and Reshape G4-Dependent Transcription.
    Mao-Lin Li, Shu-Min Xu, Xin-Chen Jiang, Le-Tian Dai, Yu-Tao Hu, Kai-Bo Wang, Jia-Heng Tan, Zhi-Shu Huang, Shuo-Bin Chen.
      G-quadruplexes (G4s) are dynamic nucleic acid structures whose biological impact is largely mediated by G4-binding proteins (G4BPs). While numerous G4BPs have been catalogued, the subset that specifically co-bind G4s in the presence of small-molecule ligands remains unexplored, limiting our understanding of ligand pharmacology. Here, we introduce G4-Ligand-Directed PROTACs (G4L-TACs), a chemical biology platform that couples high-affinity G4 ligands with E3 ubiquitin ligase recruiters to selectively degrade ligand-co-binding G4BPs. Using PDS-derived G4L-TACs, we identified the transcription factor DR1 as a previously unrecognized G4BP recruited to ligand-stabilized promoter G4s. G4L-TAC-mediated DR1 degradation relieved transcriptional repression at G4-rich oncogenic promoters, providing mechanistic insights into how G4 ligands influence gene expression beyond simple nucleic acid stabilization. These results establish G4L-TACs as a novel platform to discover ligand-co-binding G4BPs and reveal DR1 as a new regulatory node in G4-dependent transcription, offering a versatile tool for mechanistic dissection and therapeutic exploration.
    Keywords:  G4 binding proteins; G‐quadruplexes; targeted protein degradation; transcription factor DR1
    DOI:  https://doi.org/10.1002/advs.202523819
  45. Nat Commun. 2026 Mar 12. pii: 1994. [Epub ahead of print]17(1):
    Exon inclusion signatures enable accurate estimation of splicing factor activity.
    Miquel Anglada-Girotto, Carolina Segura-Morales, Daniel F Moakley, Chaolin Zhang, Samuel Miravet-Verde, Andrea Califano, Luis Serrano.
      Splicing factors control exon inclusion in messenger RNAs, shaping transcriptome and proteome diversity. Their catalytic activity is regulated by multiple layers, making single-omic measurements on their own fall short in identifying which splicing factors underlie a phenotype. Here, we posit that splicing factor activity, defined as a splicing factor's ability to modulate exon inclusion, can be estimated from changes in exon inclusion signatures. To test this hypothesis, we benchmark methods for constructing splicing factor→exon networks and estimating splicing factor activity. We find that combining RNA-seq perturbation-based networks with VIPER (Virtual Inference of Protein Activity by Enriched Regulon analysis) accurately captures splicing factor activity as modulated by multiple regulatory layers. This approach integrates splicing factor regulation into a single score derived solely from exon inclusion signatures, allowing functional interpretation of heterogeneous conditions. As a proof of concept, we identify recurrent cancer splicing programs, revealing associations with oncogenic- and tumor suppressor-like splicing factors missed by conventional methods. These programs correlate with patient survival and key cancer hallmarks: initiation, proliferation, and immune evasion. Altogether, we show splicing factor activity can be accurately estimated from exon inclusion changes, enabling comprehensive analyses of splicing regulation with minimal data requirements.
    DOI:  https://doi.org/10.1038/s41467-026-69642-3
  46. Nat Microbiol. 2026 Mar 09.
    Bacterial Schlafen proteins mediate phage defence.
    Veronica Perez Taboada, Yimo Wu, Riley Cassidy, Kirill E Medvedev, Luuk Loeff, Anna Nemudraia, Artem Nemudryi.
      Human Schlafen proteins restrict viral replication by cleaving tRNA, thereby suppressing protein synthesis. Although the ribonuclease domain of Schlafen proteins is conserved across all domains of life, its function in prokaryotes has remained unclear. Here we demonstrate that prokaryotic Schlafen nucleases are widespread antiviral effectors that protect bacteria from bacteriophages and are fused to a diverse array of phage-sensing domains. We expressed seven Enterobacterales Schlafen systems in Escherichia coli, identifying two that confer defence against coliphages. We focused on a system where Schlafen nuclease is fused to a previously unknown immunoglobulin-like sensor domain and demonstrated that it recognizes tail assembly chaperones of T5-like phages. Upon activation, the Schlafen nuclease cleaves both E. coli and phage-encoded tRNAs and restricts T5 phage by reducing its burst size. Our findings redefine Schlafens as an ancient, mechanistically conserved family of immune effectors, revealing the deep evolutionary origin of tRNA-targeting antiviral immunity in humans.
    DOI:  https://doi.org/10.1038/s41564-026-02277-8
  47. Nat Commun. 2026 Mar 09.
    Bioengineered ferritin-based lysosome-targeting chimera platform for tumor-targeted therapy.
    Shuai Zhang, Yiliang Jin, Yaxin Hou, Guoheng Tang, Zhuoran Wang, Xuehui Chen, Xiyun Yan, Kelong Fan.
      Lysosome-targeting chimeras (LYTACs) hold therapeutic potential by degrading pathogenesis-associated proteins. However, current LYTAC systems often require considerable effort for case-by-case construction and are devoid of a convenient and efficient modular platform. Here, we develop a modular LYTAC platform based on human heavy chain ferritin (HFn), leveraging its peptide-display function and TfR1-mediated lysosomal endocytosis. This system comprises a bioengineered HFn scaffold with enhanced TfR1 affinity and target-specific affibodies conjugated to the HFn via SpyTag-SpyCatcher system. Using this approach, HFn-LYTACs efficiently degrade epidermal growth factor receptor, epidermal growth factor receptor-2 and programmed death-ligand 1. Mechanistic studies indicate that the HFn-LYTAC platform mediates the degradation of membrane proteins via two distinct mechanisms: a TfR1-dependent endocytic pathway as well as the nanoparticle size and multivalent ligand effect of HFn-LYTAC. In vivo, HFn-LYTACs inhibit tumor growth with favorable safety. Therefore, the modular HFn-LYTAC platform represents a versatile, efficient, and promising strategy for tumor-targeted therapy.
    DOI:  https://doi.org/10.1038/s41467-026-70383-6
  48. Cell Rep. 2026 Mar 12. pii: S2211-1247(26)00137-3. [Epub ahead of print]45(3): 117059
    MSH6 regulates cGAS activity in antiviral and antitumor signaling pathways by governing its cytosolic/nuclear distribution.
    Qili Yang, Jinming Kang, Lin Li, Wan Zhang, Dahua Chen, Qinmiao Sun.
      While the cytosolic localization of cGAS is critical for cells to initiate immune responses and protect cells from viral infections, the activity of cGAS in the nucleus is inhibited to prevent autoimmune responses triggered by self-DNA. Therefore, the dynamically regulated distribution of cGAS in the cytosol and nucleus ensures its precise role in maintaining immune homeostasis. However, the molecular mechanism governing this spatial distribution of cGAS remains unclear. Here, we identify MSH6 as a regulator promoting cGAS nuclear localization by enhancing its association with importin-α proteins, consequently reducing cGAS condensation and activity. We further show that MSH6 attenuates antitumor immunity and that its deficiency in tumor cells leads to an effective tumor eradication by heat-inactivated modified vaccinia virus Ankara. Collectively, our results not only provide insights into understanding how cGAS activity is regulated but also suggest a therapeutic potential for treating MSH6-mutated tumors through the cGAS-mediated signaling pathway.
    Keywords:  CP: cancer; CP: immunology; MMR; MSH6; cGAS; cancer therapy; innate immunity; nuclear localization
    DOI:  https://doi.org/10.1016/j.celrep.2026.117059
  49. Nat Struct Mol Biol. 2026 Mar 13.
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Colin J Delaney, Amr Al-Farhan, Alyssa J Mathiowetz, Cody E Doubravsky, Derek A Pratt, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens using a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase and flavin adenine dinucleotide (FAD) synthase, enzymes that are essential for synthesizing FAD from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for both FSP1 activity and stability. FAD deficiency and mutations blocking FSP1-FAD binding triggered FSP1 degradation through a ubiquitin-proteasome pathway involving the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance, with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1038/s41594-026-01759-x
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