bims-proteo Biomed News
on Proteostasis
Issue of 2026–08–30
fifty-four papers selected by
Eric Chevet, INSERM
  1. hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
  2. Pocket-PROTACs: an interpretable pocket-aware deep learning framework for predicting PROTAC-induced protein degradation.
  3. Remaking an exit: dynamic regulation of ER exit sites by post-translational modifications.
  4. BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.
  5. Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
  6. Zinc increases stress granule formation by promoting RNA condensation.
  7. Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.
  8. The dual role of Rpt3 in protecting cells from proteotoxic damage.
  9. The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression.
  10. Translophagy-A potential link between autophagy impairment and translational errors.
  11. Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations in vitro and in vivo.
  12. Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
  13. DirectContacts2: a wiring diagram of human physical protein interactions.
  14. Semi-Synthetic LC3-Interacting Degrader for Visualizing Macroautophagic Activity and Targeted Degradation.
  15. An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation.
  16. Proximal Proteomics Reveals Potential Regulators of Programmed Death-Ligand 1 in Human Cancer.
  17. Heat shock-induced autophagy has cargo selectivity in Saccharomyces cerevisiae.
  18. Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.
  19. G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.
  20. RNF213-dependent lytic destruction of Chlamydia-containing vacuoles activates host cell death pathways.
  21. Direct phospho-proteoform delivery reveals a degradation-prone monomeric state of 14-3-3.
  22. The N-terminal Extension of Ribosomal Protein Rps2 Shapes Its Early Fate through Chaperone-Importin Competition and Arginine Methylation.
  23. The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.
  24. Cannabinoid tolerance relies on CB1 receptor ubiquitination by NEDD4L.
  25. Ubiquitination-driven proteostasis remodeling underlies oxidative stress and actin degradation in citrus Huanglongbing.
  26. The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
  27. Dual localization of PDI5 couples endoplasmic reticulum proteostasis to meristem organization and meiotic fidelity in Arabidopsis.
  28. Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
  29. Harnessing the E3 Ligase KLHL12 for Tumor-Selective Protein Degradation.
  30. Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation.
  31. Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.
  32. Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology.
  33. A programmable lipid-triggered allosteric site modulates LC3 LIR receptor binding activity.
  34. Sequential restriction of SNARE-mediated fusion by the COPII inner coat and SNARE chaperones.
  35. Heat-shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss.
  36. Tau-Targeted PROTACs Degrade Pathology-Associated Tau and Improve Memory in Alzheimer's Disease Models.
  37. Endolysosomal inhibition uncouples tau uptake from intracellular seeding.
  38. Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
  39. Prefoldin function links meiotic chromosome segregation with cellular remodeling and reveals tubulin sensitivity of the meiotic spindle.
  40. Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.
  41. Multi-subunit collaboration enables Smc5/6 to function as a composite SUMO E3 complex.
  42. ESCRT-I complex enhances therapeutic efficacy of ASO drugs by regulating endosomal escape and glucose homeostasis.
  43. IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.
  44. Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
  45. Regulation of ubiquitination and degradation of the gap junction channel protein Connexin43 involves the concerted action of multiple members of the NEDD4 family of E3 ubiquitin ligases.
  46. The proteasome promotes cytokinetic abscission by relieving an Aurora B-dependent inhibition of ESCRT-III dynamics.
  47. Ribosome heterogeneity provides a translational barrier against protein misfolding disease in Saccharomyces cerevisiae.
  48. IP3R2-mediated inter-organelle calcium signaling suppresses melanosome degradation.
  49. Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.
  50. TRIM32-mediated ubiquitination of STING promotes glycolysis and tumor progression.
  51. 16S ribosomal RNA modification drives transcript-specific translation efficiency.
  52. Stoic: fast and accurate protein stoichiometry prediction.
  53. The integrated stress response in immune thrombocytopenia: from cellular stress to hematopoietic adaptation.
  54. Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy.
  1. Nucleic Acids Res. 2026 Aug 24. pii: gkag832. [Epub ahead of print]54(16):
    hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
    Valentina Pecoraro, EunBin Kong, Puneet Sharma, Yulia Gonskikh, Marek Żywicki, Fabian Nagelreiter, Markus Schosserer, Katrin Freiburghaus, Jean-Marc Nuoffer, Johannes Grillari, Norbert Polacek.
      Cells adapt to metabolic stress by orchestrating gene expression to mitigate cellular damage, sustain homeostasis, and promote survival. Within this framework, translational control provides a rapid and efficient layer of regulation. Non-coding RNAs have recently emerged as effective modulators of translation, partly by targeting the ribosome. The contribution of ribosome-associated non-coding RNAs (rancRNAs) to translation regulation, however, remains largely unexplored in human cells. Here, we identified the human Y3 (hY3) RNA as a rancRNA that inhibits protein synthesis and attenuates cellular metabolism. hY3 function was particularly critical under nutrient deprivation, where it promoted adaptive stress responses. In this context, depletion of hY3 disrupted the delicate balance between survival and apoptosis by reducing the expression of pro-survival factors and impairing the activation of the integrated stress response (ISR). Loss of hY3 reduced starvation-dependent phosphorylation of eukaryotic translation initiation factor 2α, thereby attenuating ISR signalling, which results in non-physiologically elevated global translation rates during nutrient deprivation. Together, our findings establish hY3 as a ribosome-bound regulator of translation and stress responses, positioning it as a determinant of cell fate under metabolic stress.
    DOI:  https://doi.org/10.1093/nar/gkag832
  2. Bioinformatics. 2026 Aug 01. pii: btag431. [Epub ahead of print]42(Supplement_2):
    Pocket-PROTACs: an interpretable pocket-aware deep learning framework for predicting PROTAC-induced protein degradation.
    Kai Chen, Zhijian Huang, Yinbo Wang, Siyuan Shen, Jinmiao Song, Lei Deng.
       MOTIVATION: Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation by recruiting an E3 ubiquitin ligase to a protein of interest (POI) and forming a ternary complex. Despite their therapeutic promise, rational PROTAC design remains challenging, as degradation efficacy depends on subtle and highly structure-dependent interactions among the POI, the E3 ligase, and the bifunctional molecule.
    RESULTS: We propose Pocket-PROTACs, a pocket-aware attention-based framework for predicting PROTAC-induced protein degradation from a triplet of POI, E3 ligase, and PROTAC. Pocket-PROTACs encodes protein sequences using a pre-trained protein language model and represents PROTACs with a geometry-aware graph neural network over an ensemble of three-dimensional conformers. Both POI-PROTAC and E3 ligase-PROTAC interactions are explicitly modeled through a residue-atom cross-attention mechanism that captures fine-grained interaction patterns. To improve model interpretability, we introduce a pocket-aware module that incorporates structural context to guide residue-level relevance estimation, enabling multi-level attribution analysis. Experiments on two benchmark datasets show that Pocket-PROTACs consistently outperforms fingerprint-based baselines and recent deep learning methods. The learned relevance maps highlight localized interaction patterns on both the POI and the E3 ligase that are qualitatively consistent with known pocket-level features. A case study on kelch domain containing 2 (KLHDC2)-engaging bromodomain and extra-terminal domain (BET) PROTACs further demonstrates that our model accurately predicts degradation behavior and provides biologically meaningful, attention-based interpretations, offering practical support for PROTAC design and experimental investigation.
    AVAILABILITY AND IMPLEMENTATION: Source code and datasets are available at https://github.com/Adochew/Pocket-PROTACs.
    DOI:  https://doi.org/10.1093/bioinformatics/btag431
  3. Trends Cell Biol. 2026 Aug 27. pii: S0962-8924(26)00159-5. [Epub ahead of print]
    Remaking an exit: dynamic regulation of ER exit sites by post-translational modifications.
    Tetsuya Hirata, Michael Boyce.
      Endoplasmic reticulum exit sites (ERES) are dynamic platforms that coordinate not only protein trafficking but also protein quality control and signaling functions. ERES size, composition, architecture, interactions, and activity must be precisely remodeled in response to myriad pathophysiological cues to finely tune cellular homeostasis. However, the molecular mechanisms underlying this regulation remain incompletely understood. Coat protein complex II (COPII) mediates many ERES functions, and its subunits and client cargos are subject to spatiotemporal regulation by post-translational modifications (PTMs) that modulate ERES assembly, cargo selection, and inter-organelle communication. In this article, we review recent advances in understanding how PTMs control the organization and functional versatility of ERES and the COPII system.
    Keywords:  COPII; ER exit site; ER-phagy; post-translational modifications; protein trafficking; signaling
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.003
  4. Curr Biol. 2026 Aug 24. pii: S0960-9822(26)00997-8. [Epub ahead of print]
    BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.
    Jingru Wang, Dongchen Li, Yazhou Liu, Tiantian Zhou, Lin Deng, Wei-Ke Ji.
      Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes for cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer protein 2 (BLTP2; KIAA0100) is indispensable for ILV/exosome formation and that secretory carrier membrane protein 3 (SCAMP3) recruits BLTP2 to ER-MVB membrane contact sites (MCSs) in a Rab5-dependent manner. Our results indicate that this recruitment is hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion of BLTP2 was found to impede ILV/exosome formation and selectively reduce the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP), and of the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored by supplementation with exosomes from wild-type cells. Our findings suggest that BLTP2 transfers the BMP/lysobisphosphatidic acid (LBPA) precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs.
    Keywords:  ER; LBPA/BMP; MVB; bridge-like lipid transfer protein; exosome; membrane contact sites
    DOI:  https://doi.org/10.1016/j.cub.2026.07.066
  5. Nat Commun. 2026 Jul 22. pii: 8948. [Epub ahead of print]17(1):
    Lipid-manager autophagy proteins ATG2 and ATG9 regulate extracellular vesicle secretion via amphisome biogenesis and cell lipidome modulation.
    Asmita Singh, Dylan J Johnson, Jeffrey Kuhn, Katina L Johnson, Jason G Williams, Ricardo Vancini, Deloris Sutton, Kedar Sharma, Jadranka Loncarek, Mario J Borgnia, Carlos M Guardia.
      Autophagy intersects with endocytic trafficking to regulate extracellular vesicle (EV) biogenesis, but how upstream lipid-handling autophagy proteins influence this crosstalk is unclear. Here we show that the autophagy lipid-supply proteins ATG9A and ATG2A/B restrain small EV (sEV) secretion by promoting amphisome formation and controlling cellular lipid composition. Deletion of ATG9A or ATG2A/B in cells, which abolishes autophagosome biogenesis, causes a RAB27A-dependent increase in secretion of CD63-enriched, smaller sEVs, and accumulation of intraluminal vesicles within multivesicular endosomes. Under lysosomal inhibition, wild-type cells release LC3- and autophagy cargo receptor-positive sEVs, whereas ATG9A- and ATG2A/B-deficient cells, despite hypersecretion of sEVs, fail to load LC3 or canonical cargo receptors, indicating a block in amphisome-mediated export. Proteomics reveals selective depletion of autophagy receptors and ferritinophagy factors and enrichment of RNA-binding proteins and endosomal trafficking regulators in sEVs from ATG9A- and ATG2A/B-deficient cells. Whole-cell lipidomics uncovers extensive rewiring of the lipidome, with accumulation of ceramides and neutral lipids, altered phospholipid balance, and transcriptional remodeling of lipid metabolic enzymes, while neutral sphingomyelinase inhibition normalizes sEV output. These findings identify ATG9A and ATG2A/B as lipid-dependent gatekeepers that couple autophagosome and amphisome formation, regulating membrane partition between degradative autophagy and exosome-mediated secretion.
    DOI:  https://doi.org/10.1038/s41467-026-75742-x
  6. Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00948-4. [Epub ahead of print]45(9): 117870
    Zinc increases stress granule formation by promoting RNA condensation.
    Luisa Macedo de Vasconcelos, Nina Ripin, Roy Parker.
      During cellular stress, mRNAs are condensed into stress granules through the action of G3BP1 and G3BP2. How intracellular conditions affect RNA-protein condensation in stress granules is still unclear. Herein, we present several observations that cells modulate intracellular zinc concentrations to reduce the direct impact of zinc on RNA condensation. We show that oxidative stress increases the intracellular labile zinc and the expression of zinc-sequestering proteins, metallothioneins. Increased intracellular zinc leads to increased stress granule formation and delays stress granule disassembly without increasing translational repression, while zinc depletion decreases stress granule formation, demonstrating that even endogenous levels of free zinc can affect granules. Mechanistically, we demonstrate how zinc promotes stress granule formation by directly stimulating RNA condensation interactions at 100× lower concentrations than magnesium. Together, these data indicate that zinc modulates RNA condensation and stress granule formation and implies an unappreciated potential role for zinc in modulating intracellular RNA structures and interactions.
    Keywords:  CP: cell biology; CP: molecular biology; RNA condensation; oxidative stress; stress granules; zinc
    DOI:  https://doi.org/10.1016/j.celrep.2026.117870
  7. Med Oncol. 2026 Aug 24. pii: 254. [Epub ahead of print]43(10):
    Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.
    Semahat Celikten, Zafer Yildirim, Sevim Aydemir, Busra Bara, Eda Dogan, Zuhal Eroglu, Vildan Bozok.
      Cisplatin-based chemotherapy remains a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC); however, the emergence of chemoresistance severely limits its clinical efficacy. Endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) have been implicated in cancer cell survival and therapy resistance, highlighting modulation of this signalling as a potential therapeutic strategy. In this study, we investigated whether pharmacological induction of endoplasmic reticulum stress via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition could attenuate cisplatin resistance in NSCLC. Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Notably, thapsigargin pre-treatment significantly reduced cisplatin IC₅₀ values and decreased resistance indices in resistant cells, indicating attenuation of the resistant phenotype. In addition, SERCA inhibition enhanced apoptotic cell death in selected models and markedly suppressed clonogenic survival and migratory capacity across all cell lines examined. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC.
    Keywords:  ATF4; Cisplatin resistance; Endoplasmic reticulum stress; GRP78; Non-small cell lung cancer; PERK signalling; Thapsigargin; XBP1
    DOI:  https://doi.org/10.1007/s12032-026-03369-5
  8. FEBS J. 2026 Aug 29.
    The dual role of Rpt3 in protecting cells from proteotoxic damage.
    Ziting Zhu, Xiao Feng, Boyi Song, Hongzhen Zhu, Chunyi Lv, Qiaoqiao Zheng, Siyu Pan, Zheyu Fan, Zhiwei Huang, Ping Shi.
      Disrupted protein homeostasis is a shared characteristic in ageing, obesity-induced lipotoxicity and neurodegenerative diseases. The accumulation of misfolded or unfolded proteins within the cell triggers endoplasmic reticulum (ER) stress. In response, the unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways are activated. A key mechanism to alleviate intracellular protein aggregation involves ubiquitination of substrates and their subsequent degradation by the proteasome. The ubiquitin-proteasome system (UPS) is indispensable for cellular protein quality control, and its dysfunction contributes to various proteopathies. However, the crosstalk between the proteasome subunit Rpt3 and the Ire1-Hac1 pathway appears to be rarely reported. In Saccharomyces cerevisiae, growth curve and spotting assay demonstrated that overexpression of Rpt3 reduced the sensitivity of ire1Δ or hac1Δ to ER stressors. The growth-promoting effect of Rpt3 is not a common feature of the BASE subunits, as overexpression of Rpt6 failed to rescue the growth inhibition. Deletion of hac1 resulted in stoichiometric imbalance among proteasomal subunits, which may be key for Rpt3-mediated rescue of hac1Δ growth, as deletion of the proteasome transcriptional factor Rpn4 impedes Rpt3 from restoring the growth of hac1Δ from ER stress. Overexpression of Rpt3 enhanced proteasome assembly and activity, reducing intracellular ubiquitin levels in hac1Δ. Moreover, Rpt3 increased the protein level of Hac1, and its alleviation of proteotoxic stress was dependent on the collaboration of ubiquitinating enzymes and chaperones. Western blot and proteasome activity assay in human cells confirmed the cross-species conservation of Rpt3 function. These results highlight a dual role for Rpt3 in proteostasis: beyond enhancing proteasomal activity, Rpt3 upregulates Hac1 protein abundance, thereby ensuring proteostasis maintenance.
    Keywords:  Rpt3; endoplasmic reticulum stress; proteasome; proteostasis
    DOI:  https://doi.org/10.1111/febs.70714
  9. HGG Adv. 2026 Aug 27. pii: S2666-2477(26)00106-5. [Epub ahead of print] 100666
    The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression.
    Hans M Dalton, Elizabeth M Brydon, Tiffany S Chan, Katie G Owings, Mandi M L Wild, Naomi J Young, Clement Y Chow.
      The cell must defend against various stressors from internal and external sources that disrupt cell homeostasis. The integrated stress response (ISR) is a highly conserved pathway that helps restore this homeostasis through upregulating the transcription factor, ATF4. Despite its importance to cell health and human disease, ATF4 has several duplications in humans that have not been characterized. Here, we characterize four retroduplications (retrocopies) of ATF4 in humans. Evolutionary analysis demonstrates that these retrocopies are present and intact in many primate species over the past 37 million years, including several independent copies. We also find evidence of non-neutral evolution among primates. Human ATF4 retrocopies show basal transcription in healthy, unstressed cells and can be upregulated by the ISR. When translated in human cells, ATF4 retrocopy proteins are regulated by the proteasome in the same way as the parent ATF4 protein. Remarkably, each retrocopy can also alter the expression of several canonical ATF4 target genes, demonstrating that they can impact ISR-ATF4 stress signaling. Overall, ATF4 retrocopies are conserved, biologically functional, and should be considered in future studies of the ISR and ATF4.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100666
  10. FEBS Lett. 2026 Aug 27.
    Translophagy-A potential link between autophagy impairment and translational errors.
    Mykola V Korolchuk, Gailing Ma, Robin Antrobus, Diego Manni, Marco Trevisan-Herraz, Mustafa Khwaja, Max Brown, Gavin D Richardson, Masaaki Komatsu, Daniel Erskine, Viktor I Korolchuk, Tetsushi Kataura.
      Maintenance of protein homeostasis requires coordination between protein synthesis and degradation, yet whether autophagy directly controls translational machinery remains unclear. Here we explored whether autophagy maintains translational fidelity. Proteomic analysis of ubiquitin-enriched fractions and p62-associated proteins in autophagy-deficient tissue confirmed previous studies identifying ribosomal proteins and RNA-binding factors among candidate autophagy cargo. Pharmacological or genetic impairment of autophagy increased translational errors, particularly during oxidative stress. Components of the translational machinery localised to LC3-positive autophagic structures and accumulated in human brain tissue affected by neurodegeneration. These findings support a hypothesis in which autophagy preserves protein synthesis quality by removing damaged translational machinery. We term this proposed mechanism translophagy, potentially linking autophagy dysfunction, oxidative stress and the aberrant proteins in neurodegenerative disease.
    Keywords:  ageing; aggregation; autophagy; mRNA; neurodegeneration; oxidative stress; ribosome; translation
    DOI:  https://doi.org/10.1002/1873-3468.70448
  11. Sci Adv. 2026 Aug 28. 12(35): eaec8271
    Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations in vitro and in vivo.
    Tianzheng Ye, Azmain Alamgir, Cara M Robertus, Darianna Colina, Connor Monticello, Thomas Connor Donahue, Chandra Bandi, Lauren Hong, Sophia Vincoff, Shrey Goel, Kieu Lam, James Heyes, David Putnam, Christopher A Alabi, Pranam Chatterjee, Matthew P DeLisa.
      Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model-driven algorithm called SaLT&PepPr to computationally design "guide" peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called carboxyl terminus of Hsp70-interacting protein. Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that greatly reduced the abnormally stable pool of free β-catenin in the cytosol and nucleus while preserving the normal membrane-associated subpopulation. This selective knockdown of pathogenic β-catenin suppressed Wnt/β-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated β-catenin levels in livers of BALB/c mice following delivery as a lipid nanoparticle-encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively deplete abnormal proteins in vitro and in vivo and open the door to peptide-programmable biologic modulators of other disease-causing proteins.
    DOI:  https://doi.org/10.1126/sciadv.aec8271
  12. Sci Adv. 2026 Aug 28. 12(35): eaec9028
    Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
    Xiangyi Ding, Sweta Kumari, Ellen F Gregory, Daniel A Starr, G W Gant Luxton.
      Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defective nuclear mechanics and transcriptional regulation, yet these mechanisms cannot explain how lamina defects propagate across the cell to produce the complex pathology of laminopathies. Here, we reveal an emerging pathway linking nuclear lamina dysfunction to cytoplasmic reorganization. Using Caenorhabditis elegans EDMD models, we show that disease-linked lamin variants reduce cytoplasmic mesoscale crowding, increase molecular diffusivity, and disrupt nuclear positioning and endoplasmic reticulum architecture, which mirror phenotypes caused by ribosome depletion. Lamin dysfunction also lowers nucleolar fibrillarin levels and ribosome abundance, revealing a nucleolar-ribosomal axis that transmits nuclear defects to the cytoplasm. Loss of the redundant LEM-domain proteins emr-1 and lem-2 phenocopied lamin mutants, indicating that cytoplasmic disorganization is a shared hallmark of EDMD. These findings connect nuclear architecture to whole-cell biophysics and suggest therapeutic strategies aimed at restoring ribosome function.
    DOI:  https://doi.org/10.1126/sciadv.aec9028
  13. Nat Commun. 2026 Jul 24. pii: 9037. [Epub ahead of print]17(1):
    DirectContacts2: a wiring diagram of human physical protein interactions.
    Erin R Claussen, Miles D Woodcock-Girard, Samantha N Fischer, Kevin Drew.
      Cellular function is driven by the activity of proteins in stable complexes. Protein complex assembly depends on the direct physical association of component proteins. Advances in macromolecular structure prediction with tools like AlphaFold and RoseTTAFold have greatly improved our ability to model these interactions in silico, but an all-by-all analysis of the human proteome's ~200 M possible pairs remains computationally intractable. A comprehensive cellular map of direct protein interactions will therefore be an invaluable resource to direct screening efforts. Here, we present DirectContacts2, a machine learning model that distinguishes direct from indirect protein interactions using features derived from over 25,000 mass spectrometry experiments. Applied to ~25 million human protein pairs, our model outperforms previous resources in identifying direct physical interactions and enriches for accurate structural models including ~2500 AlphaFold3 models. Our framework enables structural modeling of disease-relevant complexes (e.g. orofacial digital syndrome (OFDS) complex) offering insights into the molecular consequences of pathogenic mutations (OFD1) and broadly, establishes a highly accurate protein wiring diagram of the cell.
    DOI:  https://doi.org/10.1038/s41467-026-75863-3
  14. Angew Chem Int Ed Engl. 2026 Aug 26. e7042721
    Semi-Synthetic LC3-Interacting Degrader for Visualizing Macroautophagic Activity and Targeted Degradation.
    Ke-Ke Zhang, Ji Cheng, Jing-Yi Zhang, Li-Juan Tang, Fenglin Wang, Xia Chu, Jian-Hui Jiang.
      Macroautophagy is central to cellular homeostasis and emerges as a promising avenue for targeted degradation. However, there is still a lack of efficient approaches allowing for visualizing macroautophagic flux and degradation. Here we develop a semi-synthetic LC3-interacting degrader (SLID) that enables fluorogenic imaging of macroautophagic activities and visualization of targeted degradation. SLID is engineered by fusing LC3-interacting regions (LIRs) to a self-labeling tag and an oligomeric motif, with the LIRs for binding to autophagosomes, the oligomeric motif for enhancing the binding, and the self-labeling tag for visualizing autophagosome formation using a pH indicator. SLID is further coupled to an antibody domain through a dimerization-induced proximity system, allowing chemically inducible degradation of target proteins. We show that this SLID platform permits efficient degradation of diverse target proteins such as disease-associated aggregation-prone proteins and phase-separated condensates. SLID also reveals elevated macroautophagic activities in senescent cells, and is repurposed for inducing senescent cell apoptosis via degradation of pro-survival and anti-apoptotic proteins. Our study highlights the great promise of SLID as a versatile tool for studying macroautophagy and targeted protein degradation.
    Keywords:  apoptosis; biosensors; macroautophagy imaging; macroautophagy‐targeted degradation; senescent cells
    DOI:  https://doi.org/10.1002/anie.7042721
  15. Cell Rep. 2026 Aug 27. pii: S2211-1247(26)00980-0. [Epub ahead of print]45(9): 117902
    An in vivo resource of age-regulated C. elegans intestinal secretory-pathway proteins highlights secreted enzymes associated with lifespan regulation.
    Jason W Miklas, Katharina Papsdorf, Eric D Sun, Aleksandra Tsenter, Nicole R Haseley, Brandon Ameglio, Uche N Medoh, Daniel Richard, Frank McCarthy, Karen L Artiles, Andy Hims, Aleksandra Levina, Olivia Y Zhou, Joshua E Elias, Monther Abu-Remaileh, Anne Brunet.
      Secreted proteins are essential to modulate homeostasis in the extracellular space and facilitate communication to distal cells or tissues. Yet, the identity and functional importance of extracellular proteins in aging have been understudied. Here we use proximity labeling followed by quantitative proteomics to systematically characterize proteins along the intestinal secretory pathway in C. elegans, focusing on secreted proteins. We identify intestine-secreted proteins that are modulated with age, and validate the secretion of these proteins in vivo. One of these secreted proteins, ACP7, is well conserved in humans, and its overexpression extends lifespan in a secretion-dependent manner. Interestingly, we find that ACP7 acts as a secreted phosphatase in the extracellular space. Finally, we identify additional proteins along the secretory pathway that regulate lifespan. Our systematic characterization of tissue-specific secreted proteins during aging uncovers conserved proteins that impact lifespan and highlights extracellular enzymes associated with lifespan regulation.
    Keywords:  CP: metabolism; aging; intestine; lifespan; phosphatase; proximity labeling; quantitative proteomics; secreted proteins; secretome; secretory vesicle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117902
  16. ACS Omega. 2026 Aug 25. 11(33): 50389-50405
    Proximal Proteomics Reveals Potential Regulators of Programmed Death-Ligand 1 in Human Cancer.
    Fujin Shi, Danya Liu, Yaxiong Liu, Fan Li, Chris Zhiyi Zhang, Qiuli Li, Qiu-Hong Tian.
      Programmed death-ligand 1 (PD-L1) is a key mediator of tumor immune evasion, but the protein networks governing its post-translational regulation remain incompletely understood. Here, we used PhastID-based proximity labeling to map the PD-L1 proximal proteome and integrated these data with pan-cancer proteomics and immunohistochemical analysis of clinical tumor samples. We found that C-terminal-proximal proteins were enriched in protein degradation, ER-associated quality control, and immune-related pathways, whereas N-terminal-proximal proteins were mainly associated with protein localization and intracellular transport. Integrated analysis identified CAND1, TXN, and FBXO2 as candidate PD-L1 regulators. Knockdown of CAND1, TXN, or FBXO2 reduced PD-L1 protein expression in cancer cells. Mechanistically, CAND1 interacted with PD-L1 and was detected in a complex containing PD-L1 and FBXO22. CAND1 depletion promoted K48-linked ubiquitination and degradation of PD-L1, while deletion of the PD-L1 intracellular domain or mutation of K271 and K281 attenuated PD-L1 ubiquitination. Functionally, CAND1 knockdown enhanced T cell-mediated tumor cell killing, and elevated CAND1 expression was associated with an immunosuppressive tumor microenvironment. Together, our findings define the PD-L1 proximal proteomic landscape and identify CAND1-mediated regulation of PD-L1 stability as a potential mechanism of tumor immune escape.
    DOI:  https://doi.org/10.1021/acsomega.6c06622
  17. Autophagy. 2026 Aug 26.
    Heat shock-induced autophagy has cargo selectivity in Saccharomyces cerevisiae.
    Dimitra Dialynaki, Yuxiang Huang, Daniel J Klionsky.
      Mechanisms aimed at recovering from heat-induced damage are closely associated with the organism's ability to survive extreme temperature exposure. In such a scenario, we show that autophagy, as a cytoprotective mechanism, ensures recovery and viability after induced heat stress in Saccharomyces cerevisiae. Our findings indicate that heat shock triggers the targeted degradation of ubiquitinated protein aggregates, mediated by the macroaggrephagy receptor Cue5. Moreover, heat stress induces the turnover of the aggrephagy receptor Cct2 and the polyglutamine repeats of the HTT (huntingtin) protein (polyQ-HTT). Notably, even though Cct2 and polyQ-HTT degradation is vacuole-dependent, it is mediated autonomously of canonical autophagy pathways. Collectively, this study demonstrates a novel role of autophagy in maintaining protein homeostasis after heat stress in yeast and provides insights into the potential medical applications of heat treatment.
    Keywords:  Aggrephagy; Cct2; Cue5; autophagy; budding yeast; heat stress; polyQ-HTT
    DOI:  https://doi.org/10.1080/15548627.2026.2724473
  18. Nat Commun. 2026 Jul 24. pii: 9041. [Epub ahead of print]17(1):
    Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.
    Xiao-Chen Xie, Yang Guo, Ran Guo, Yong-Ze Li, Shan-Shan Wang, Xiao-You Jiang, Shuang Hao, Ye Zhang, Yu-Han Li, Xi-Yan Liu, Xiao-Xu Wu, Xin-Yue Zhang, Wen-Dong Guo, Yan-Ling Feng, Jia-Bin Li, Chen Liu, Liang Wang, Zhen-Hua Li, Wei-Ping Teng, Zhong-Yan Shan, Liu Cao, Qi-Qiang Guo.
      Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-76047-9
  19. Cell Death Differ. 2026 Aug 26.
    G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.
    Sarayu Ramakrishna, Laura Ryan, Sung Min Son, David C Rubinsztein.
      The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.
    DOI:  https://doi.org/10.1038/s41418-026-01853-z
  20. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2606688123
    RNF213-dependent lytic destruction of Chlamydia-containing vacuoles activates host cell death pathways.
    Mary S Dickinson, Stephen C Walsh, Robert J Bastidas, Raphael H Valdivia, Jörn Coers.
      The cytokine gamma-interferon promotes antimicrobial cell-autonomous immunity by inducing hundreds of interferon-stimulated genes (ISGs). Among these ISGs is the ubiquitin E3 ligase RNF213 which protects host cells from a wide range of intracellular pathogens including the obligate intracellular bacterium Chlamydia. The human pathogen Chlamydia trachomatis normally employs its secreted virulence effector GarD to evade RNF213-mediated killing. However, in the absence of GarD, RNF213 is recruited to the vacuolar compartment in which C. trachomatis replicates, called the inclusion. Once localized to inclusions, RNF213 ubiquitylates unknown substrates associated with the inclusion membrane and eliminates C. trachomatis through mechanisms that are not yet defined. Ubiquitylation of pathogen-containing vacuoles often results in xenophagy, an autophagy-related defense program. Here, we show that although inclusions can be degraded via xenophagy, this pathway is dispensable for RNF213-dependent inhibition of C. trachomatis replication. In addition to xenophagy, we find that RNF213 targeting can lead to antimicrobial inclusion lysis, thereby releasing bacteria into the host cell cytosol and triggering host cell death. Two cell death pathways occur downstream from RNF213-dependent inclusion rupture: a rapid cell death that despite its apoptosis-like morphology occurs independent of the apoptosis effectors caspase-3 and caspase-7 and instead requires the secreted C. trachomatis protease CPAF, and a slow cell death that is independent of CPAF and instead requires the cytosolic proinflammatory pattern-recognition receptors RIG-I or STING. Thus, RNF213-driven lysis of pathogen-containing vacuoles represents a previously unrecognized mechanism by which RNF213 mediates host defense and triggers a host-pathogen battle over cytosolic immune activation.
    Keywords:  Chlamydia; autophagy; cell death; innate immunity; interferon
    DOI:  https://doi.org/10.1073/pnas.2606688123
  21. Chem Sci. 2026 Aug 17.
    Direct phospho-proteoform delivery reveals a degradation-prone monomeric state of 14-3-3.
    Moriah H Mathis, Stanislau Stanisheuski, Ryan A Mehl, Richard B Cooley.
      Site-specific phosphorylation controls protein function, interactions, and cellular fate, but the effects of individual phospho-proteoforms remain difficult to define in cells. Existing methods rely on kinase-mediated phosphorylation, which often generates heterogeneous mixtures that are phosphatase-sensitive, or on phosphomimetic substitutions that frequently fail to reproduce authentic phospho-states. Here we establish direct phospho-proteoform delivery, which combines genetic code expansion-enabled production of proteins containing the nonhydrolyzable phosphoserine analog nhpS in E. coli with electroporation-based delivery of purified proteins into human cells. This strategy creates an experimental framework for testing defined phospho-proteoforms in cells with control over identity, dose, and timing, independent of intracellular kinase, phosphatase, and expression systems. Using this capability, we tested whether phosphorylation-induced monomerization of 14-3-3 proteins is sufficient to alter cellular protein fate, a question that cannot be addressed by conventional methods. Installation of nhpS at the conserved dimer interface created a proteasome-sensitive, degradation-prone state across multiple paralogs. Although cereblon preferentially associated with monomeric 14-3-3, cereblon knockout did not rescue degradation, and monomeric 14-3-3 also engaged the E3 ligase adaptor SKP1. These findings reveal phosphorylation-induced monomerization as a conserved trigger of 14-3-3 proteostatic control and establish direct phospho-proteoform delivery as a general route to connect single phosphorylation events to cellular phenotypes.
    DOI:  https://doi.org/10.1039/d6sc04499a
  22. J Biol Chem. 2026 Aug 25. pii: S0021-9258(26)02353-7. [Epub ahead of print] 113481
    The N-terminal Extension of Ribosomal Protein Rps2 Shapes Its Early Fate through Chaperone-Importin Competition and Arginine Methylation.
    Maximilian Mack, Benjamin Pillet, Nicole Holton, Ingrid Zierler, Stephanie Himpich, Phyllis Jessen, Markus C Wahl, Dieter Kressler, Brigitte Pertschy.
      Efficient nuclear import of ribosomal proteins is essential for the timely assembly of ribosomal subunit precursors in the nucleus and progression of ribosome biogenesis. Several ribosomal proteins are escorted to the nucleus by dedicated chaperones, which shield their interaction surfaces and assist their delivery. Here, we characterize the N-terminal extension of the small subunit ribosomal protein Rps2 as a regulatory hub that integrates binding of its dedicated chaperone Tsr4, recognition by its importin Pse1, and arginine methylation. By mapping Pse1's interaction interface on Rps2's N-terminal extension, we identified arginine 11 (R11), a known methylation site, as a critical residue. We demonstrate that Rps2 is already methylated while associated with Tsr4, indicating that methylation occurs at an early stage of the Rps2 assembly path prior to nuclear import. We further show that the chaperone Tsr4 and the importin Pse1 compete for binding to the Rps2 N-terminal extension. While Tsr4 binds this region with higher affinity than Pse1, Pse1 also contacts additional regions within full-length Rps2. Arginine methylation of Rps2 modestly reduces Pse1 binding to the Rps2 N-terminal extension, while having little effect on Tsr4 binding, suggesting that this modification can influence importin recognition without disrupting chaperone association. Finally, we find that Rps2 methylation increases at low temperature and that loss of Hmt1-mediated methylation exacerbates translational fidelity defects in an rps2 mutant background. Together, our findings reveal how a ribosomal protein N-terminal extension coordinates sequential interactions and post-translational modification events that shape the early fate of Rps2 and support accurate ribosome function.
    Keywords:  Hmt1; Rps2; Saccharomyces cerevisiae; Tsr4; nuclear transport; post‐translational modification (PTM); protein arginine methylation; protein methylation; protein‐protein interaction; ribosome assembly
    DOI:  https://doi.org/10.1016/j.jbc.2026.113481
  23. EMBO Rep. 2026 Aug 22.
    The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.
    Yingying Guo, Jianfei Zheng, Lei Liu, Shulin Li, Min Zhang, Liang Ge.
      The endoplasmic reticulum-Golgi intermediate compartment (ERGIC) is a dynamic membrane system at the ER-Golgi interface, traditionally viewed as a transient station for COPII- and COPI-dependent trafficking. Emerging evidence redefines the ERGIC as a stress-responsive regulatory hub that integrates membrane trafficking with cellular adaptation. In addition to coordinating bidirectional transport and cargo sorting, the ERGIC actively participates in protein quality control during ER stress and remodels trafficking flux under perturbations. It serves as a platform linking secretory pathways to stress signaling, contributing to autophagosome biogenesis, facilitating unconventional protein secretion under stress conditions, and modulating innate immune responses, including STING activation. The ERGIC is also co-opted by pathogens such as coronaviruses, underscoring its role at the interface of membrane remodeling and host defense. These functions position the ERGIC as a central integrator of trafficking dynamics and stress responses, whose structural plasticity enables rapid adaptation to physiological and pathological challenges.
    DOI:  https://doi.org/10.1038/s44319-026-00908-z
  24. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2606671123
    Cannabinoid tolerance relies on CB1 receptor ubiquitination by NEDD4L.
    Alicia Álvaro-Blázquez, Rui S Rodrigues, Carlos Montero-Fernández, Marta Isasa, Astrid Cannich, Doriane Gisquet, Ignacio Rodríguez-Crespo, Luigi Bellocchio, Giovanni Marsicano, Carlos Costas-Insua, Manuel Guzmán.
      Cannabinoids, the active components of cannabis, exert numerous acute effects in the brain by engaging cannabinoid CB1 receptors (CB1Rs). However, tolerance emerges rapidly after repeated drug exposure, undermining the efficacy of cannabinoid-based therapies and contributing to cannabis-associated adverse effects. Although the processes of CB1R short-term desensitization (i.e., receptor uncoupling and internalization) are well characterized, the mechanisms underlying CB1R long-term tolerance (i.e., downregulation of receptor protein levels) remain elusive. Here, we identify a ubiquitin-dependent pathway that couples CB1R activation to its proteasomal degradation. We show that cannabinoids engage a Gq/11-PLC-PKC signaling cascade that phosphorylates and activates the E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L), promoting its recruitment to CB1R and the ubiquitination of four specific lysine residues. This modification targets the receptor for proteasomal clearance, reducing neuronal CB1R abundance in vitro and in the mouse brain. Using molecular, pharmacological, and circuit-specific rescue approaches, we demonstrate that preventing CB1R ubiquitination stabilizes receptor levels and abolishes behavioral cannabinoid tolerance in mice without impairing acute drug responses. These findings reveal a molecular mechanism that controls CB1R stability and identify NEDD4L-mediated ubiquitination as a central driver of cannabinoid tolerance.
    Keywords:  CB1 receptor; cannabinoid; drug tolerance; protein ubiquitination; synaptic transmission
    DOI:  https://doi.org/10.1073/pnas.2606671123
  25. Plant Physiol. 2026 Aug 25. pii: kiag612. [Epub ahead of print]
    Ubiquitination-driven proteostasis remodeling underlies oxidative stress and actin degradation in citrus Huanglongbing.
    Min Li, Hongkun Qin, Yundan Hu, Bingqian Qin, Zirui Fan, Mingzhuo Li, Yaping Mao, Fajin Liao, Zhigang Ouyang, Huan Chen, Shuo Duan.
      Citrus huanglongbing, caused by Candidatus Liberibacter asiaticus (CLas), is associated with severe metabolic disruption, chronic immune activation, and progressive decline of citrus trees, but the post-translational mechanisms underlying these responses remain poorly understood. Here, we combined ubiquitinated peptide immunoaffinity enrichment with 4D label-free quantitative proteomics to profile protein abundance and protein ubiquitination in infected sweet orange leaves. Infection caused extensive proteome remodeling and a strong global increase in protein ubiquitination. Integrated analysis revealed a predominant group of proteins with reduced abundance and increased ubiquitination, pointing to ubiquitination-associated depletion of proteins involved in chloroplast function, redox homeostasis, and primary metabolism. The degradation machinery itself was also remodeled, including widespread ubiquitination of proteasome subunits and increased proteasome-dependent bulk protein turnover. Physiological and biochemical analyses showed that infection suppressed the hydrogen peroxide-scavenging system, with reduced abundance and increased ubiquitination of catalase, accompanied by elevated hydrogen peroxide accumulation. We also identified actin as a major downstream target of CLas-induced proteostasis remodeling. Actin proteins underwent enhanced ubiquitination and degradation in infected tissues, accompanied by actin filament disruption, and CsACT7 showed 26S proteasome-dependent degradation. Seven CLas-upregulated ubiquitination sites acted cooperatively to promote CsACT7 degradation, as simultaneous substitution of all seven lysines with alanine strongly stabilized CsACT7 and reduced CLas accumulation in citrus hairy roots. Together, these findings establish ubiquitination-dependent proteome remodeling as a central feature of the citrus response to CLas infection and link ubiquitination-mediated post-translational regulation to redox imbalance, cytoskeletal disruption, and disease susceptibility.
    Keywords:   Candidatus Liberibacter asiaticus; Huanglongbing; actin; antioxidant; citrus greening disease; ubiquitin-proteasome system; ubiquitination
    DOI:  https://doi.org/10.1093/plphys/kiag612
  26. Nat Cell Biol. 2026 Aug 25.
    The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
    Xin Gao, Michael Lanz, Rosslyn Grosely, Jonas Cremer, Joseph Puglisi, Jan M Skotheim.
      Cell growth underlies nearly all eukaryotic physiology, yet its quantitative principles remain unclear. Here, using single-molecule ribosome tracking, spike-in RNA sequencing and quantitative proteomics across 15 nutrient-limited conditions in budding yeast, we define how growth is controlled in the budding yeast Saccharomyces cerevisiae. Ribosome concentration scales linearly with growth rate, while peptide elongation speed remains constant at approximately nine amino acids per second. While elongation is not a regulatory lever, total mRNA concentration increases proportionally with ribosomes to accelerate growth. A simple kinetic model of mRNA-ribosome binding accurately predicts the fraction of active ribosomes, growth rate and responses to transcriptional or size perturbations. Consistent with this model, transient inhibition of mRNA degradation boosts growth by elevating mRNA concentration. These results reveal that eukaryotic cells accelerate proliferation primarily by proportionally scaling mRNA and ribosome abundance, establishing a quantitative framework for understanding eukaryotic biosynthesis.
    DOI:  https://doi.org/10.1038/s41556-026-02045-0
  27. New Phytol. 2026 Aug 27.
    Dual localization of PDI5 couples endoplasmic reticulum proteostasis to meristem organization and meiotic fidelity in Arabidopsis.
    Mohammad Aslam, Beenish Fakher, Bello Hassan Jakada, Yuan Qin, Hanyang Cai.
      Plant growth and reproduction require coordinated control of hormone-dependent tissue patterning and faithful meiotic chromosome segregation, yet whether upstream proteostasis contributes to both processes remains unclear. Here, we show that Arabidopsis PROTEIN DISULFIDE ISOMERASE 5 (PDI5) contributes to auxin-associated developmental patterning and meiotic fidelity. Native-promoter reporter constructs corresponding to two annotated PDI5 transcript isoforms show distinct subcellular enrichment, with one displaying an endoplasmic reticulum (ER)-associated distribution and the other showing nuclear enrichment. Disruption of PDI5 alters bulk glycoprotein staining and glycoside and trafficking-associated transcriptional programs, reduces the abundance of PIN-FORMED 2-green fluorescent protein (PIN2-GFP), alters its brefeldin A-sensitive intracellular accumulation, and is associated with perturbed auxin-response patterning and disorganized root meristems. In reproductive tissues, the pdi5 mutant shows abnormal germline-associated cell-fate restriction, impaired meiotic chromosome behavior, reduced chiasma formation and decreased fertility. Proteomic and interaction analyses identify the cohesin subunit SISTER-CHROMATID COHESION PROTEIN 3 (SCC3) as a PDI5-associated protein, and disruption of a conserved SCC3 N809-centered motif reduces its detectable association with PDI5. In a PDI5 promoter-driven conditional complementation assay, SCC3^N809E fails to support fertility rescue. These findings support a model in which PDI5-dependent proteostasis contributes to auxin-associated developmental patterning and meiotic chromosome fidelity, potentially through compartmentally distributed PDI5 functions.
    Keywords:  Arabidopsis thaliana; ER proteostasis; N glycosylation; PDI5; meiosis
    DOI:  https://doi.org/10.1111/nph.71522
  28. Dev Cell. 2026 Aug 28. pii: S1534-5807(26)00290-X. [Epub ahead of print]
    Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
    Matej Durik, Mona Karout, Daniel Sampaio Gonçalves, Tania Knauer-Meyer, Coralie Spiegelhalter, Nadia Messaddeq, Marco Seehawer, Pauline Stephan, Dmitry V Bulavin, Yann Herault, Lars Zender, William M Keyes.
      Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here, we identify that senescent cells dispose of large fragments through cell-to-cell adhesion, which we term "senescent-cell adhesion fragments" (SCAFs). Found in many senescent states, including human and mouse cells, and mouse tissues, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreases SCAF formation but induces senescent-cell death, due to an inability to shed damaged mitochondria. Live imaging and proteomics show that SCAFs ultimately rupture, releasing a complex proteome, including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Immunostaining also reveals amyloid-like material in senescent cells that can be externalized through fragmentation. Altogether, these findings identify a feature that facilitates senescent cell survival but also externally deposits damaged intracellular contents, with implications for cancer and neurodegeneration.
    Keywords:  DAMPs; aging; amyloid; cancer; cell-cell adhesion; debris; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2026.08.002
  29. Angew Chem Int Ed Engl. 2026 Aug 27. e3312795
    Harnessing the E3 Ligase KLHL12 for Tumor-Selective Protein Degradation.
    Shicheng Xu, Xian Zhang, Shunbo Hu, Xinyi Wang, Yuxin Ge, Ziquan Zhao, Tianbao Zhu, Nan Wang, Limin Du, Qidong You, Xiaoke Guo, Zhengyu Jiang.
      Proteolysis-targeting chimeras (PROTACs) are currently constrained by a reliance on ubiquitously expressed E3 ligases, which compromises tumor selectivity and raises toxicity risks. Here, we identified KLHL12 as a potentially tumor-selective E3 ligase and reported the development of the first-in-class KLHL12-recruiting PROTACs. Guided by a structure-based macrocyclization strategy, we obtained a high‑affinity cyclic peptide, cp4, as a KLHL12‑binding ligand and constructed novel PROTACs against oncogenic BRD4 and EGFR. The optimal compound k12bp-1 achieved tumor-selective BRD4(L) degradation in A549 cells, significantly inhibiting cell proliferation and driving cell apoptosis while sparing normal cells. It demonstrated robust in vivo antitumor efficacy in A549 xenograft mouse models without observable systemic toxicity. Collectively, this work established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
    Keywords:  KLHL12; protein degradation; proteolysis‐targeting chimeras; tumor‐selective
    DOI:  https://doi.org/10.1002/anie.3312795
  30. Sci Adv. 2026 Aug 28. 12(35): eaea7513
    Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation.
    Yali Xu, Ting Su, Hricha Mishra, Naoshi Dohmae, Takehiro Suzuki, Yuriko Sakamaki, Haruyo Aoyagi, Hideki Aizaki, Hajime Nishimura, Erina Furuhata, Yuqing Gong, Qi Cheng, Beiyuan Zhang, Chenzhe He, Kaori Yanaka, Yutaka Furutani, Hideki Tatsukawa, Harukazu Suzuki, Wenkui Yu, Xian-Yang Qin.
      Sepsis-associated liver dysfunction is a life-threatening condition with a high mortality rate and no mechanism-based therapy. In this study, we identify the cross-linking enzyme transglutaminase 2 (TG2) as a driver of liver inflammation by activating macrophages in a mouse model of sepsis. Pharmacological inhibition of TG2 improves survival and reduces multiorgan inflammation, with the liver as a primary therapeutic target. Mechanistically, TG2 activity was up-regulated in macrophages, where it cross-linked vimentin to promote oligomerization and intermediate filament remodeling. Genetic ablation of TG2 or vimentin suppressed macrophage cytokine production and attenuated lipopolysaccharide-induced inflammation. Notably, vimentin-deficient macrophages exhibited enhanced proteasome recruitment to detergent-insoluble protein aggregates, accelerating the degradation of proinflammatory mediators such as Traf6, thereby dampening nuclear factor κB signaling. Proteomic profiling revealed a previously unrecognized Rab27a-positive vesicle trafficking pathway for inflammatory aggregate clearance. Together, these findings define a TG2-vimentin axis that controls macrophage activation through proteostasis regulation, linking cytoskeletal remodeling to inflammatory signaling.
    DOI:  https://doi.org/10.1126/sciadv.aea7513
  31. iScience. 2026 Sep 18. 29(9): 117203
    Subtype-specific secretion of extracellular vesicles by LRRK2 and Rab GTPases under lysosomal stress.
    Maria Sakurai, Tomoki Kuwahara, Shoichi Suenaga, Sho Takatori, Taisuke Tomita, Tammy Shalit, Elizabeth Tengstrand, Frank Hsieh, Takeshi Iwatsubo.
      LRRK2, the Parkinson's disease-associated kinase, phosphorylates a subset of Rab GTPases and regulates membrane dynamics. We previously reported that lysosomal stress activates LRRK2 and thereby induces the exocytic secretion of lysosomal contents, but the detailed secretion mechanism remained unclear. Here we found that, under lysosomal stress, endolysosomal luminal and membrane components were secreted with extracellular vesicles (EVs) via LRRK2. Bis(monoacylglycerol)phosphate, an endolysosomal lipid and a urinary marker of LRRK2 activity, was similarly secreted via LRRK2, whereas CD9-positive EVs were not involved. Further dissection of the secreted EVs revealed that Alix-positive EVs were secreted via Rab8a as well as the ESCRT component VPS4, whereas LAMP1/cathepsin B-positive EVs were secreted via Rab10/Rab35, and SNARE proteins syntaxin 2 and VAMP8 regulated the secretion of both EV subtypes. These findings suggest a distinctive stress-induced secretory mechanism whereby LRRK2 facilitates the secretion of multiple EV subtypes by controlling Rab GTPases involved in each pathway.
    Keywords:  LRRK2; Parkinson’s disease; extracellular vesicles; lysosomal stress; rab
    DOI:  https://doi.org/10.1016/j.isci.2026.117203
  32. Science. 2026 Aug 27. 393(6814): eady4523
    Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology.
    Belinda Wang, Rasika Vartak, Kelsey M Hennick, Yefim Zaltsman, Zun Zar Chi Naing, Benjamin J Polacco, Ali Bashir, Manon Eckhardt, Mehdi Bouhaddou, Jiewei Xu, Nawei Sun, Micaela C Lasser, Yuan Zhou, Justin McKetney, Keelan Z Guiley, Pawel Gniewek, Una Chan, Naufa Amirani, Owen Griffiths, Nishant Chadha, Reshmi Tognatta, Merve Cakir, Martin Gordon, Prachi Khare, Sam Drake, Vanessa Drury, David F Burke, Silvano Gonzalez, Sahar Alkhairy, Reuben Thomas, Stephanie Lam, Montana Morris, Ethel Bader, Mélanie Dos Santos, Anastassia V Komarova, Maxwell Bennett, Craig Ennis, Octavio Castillo, Yvonne Lim, Robert Martin, Meghan Seyler, Tierney Baum, Rebecca Krasnoff, George Wang, Sagnik Middya, Sheng Wang, Presley Pham, Juan Arbelaez, Dexter Pratt, Sofia Bali, Shivali Chag, Julia A Kaye, Nadir Mahmood, Lee Spraggon, Thomas Rolland, Shawn Hervey-Jumper, James S Fraser, Thomas Bourgeron, Steven Finkbeiner, Caroline Demeret, Danielle L Swaney, Sourav Bandyopadhyay, Trey Ideker, Pedro Beltrao, Helen Rankin Willsey, Ruth Hüttenhain, Kirsten Obernier, Tomasz J Nowakowski, Matthew W State, A Jeremy Willsey, Nevan J Krogan.
      Systematic mapping of protein-protein interaction (PPI) networks and determining how causal mutations rewire them in autism spectrum disorder (ASD) provide a powerful framework for uncovering disease mechanisms and therapeutic opportunities. Using affinity purification-mass spectrometry, we systematically mapped PPIs for 100 high-confidence ASD genes, uncovering more than 1800 interactions. By assessing the impact of pathogenic missense mutations, leveraging AlphaFold, and validating key findings in human-derived model systems, we identified marked convergence onto shared protein complexes in the wild-type state and convergent PPI rewiring driven by independent mutations. For example, distinct patient-derived variants in FOXP1 disrupt its interactions with FOXP4, leading to changes in cortical neurogenesis and neural activity in brain organoids. Overall, these findings link genetic variation to protein networks and convergent neurodevelopmental dysfunction in ASD.
    DOI:  https://doi.org/10.1126/science.ady4523
  33. Nat Commun. 2026 Aug 28. pii: 9144. [Epub ahead of print]17(1):
    A programmable lipid-triggered allosteric site modulates LC3 LIR receptor binding activity.
    Deepanshi Gahlot, Jesu Castin, Shruti Mathur, Debajyoti Das, Ajit Kumar, Akanksha Arun, Chandrima Gain, Mridul Sharma, Ravi Kant Pal, Niyati Jain, Bichitra K Biswal, Rajat Singh, Lipi Thukral.
      Membrane recruitment is a fundamental regulator of protein function. However, the allosteric mechanisms by which lipid binding controls protein activity remain poorly understood. In autophagy, the ubiquitin-like protein LC3 is lipid-anchored to autophagosomes, where it is essential for receptor recruitment and vesicle formation. While LC3-receptor interactions are structurally well defined, how membrane engagement governs LC3 functional dynamics has remained enigmatic. Here, we uncover that membrane binding triggers a major conformational transition in LC3, exposing functional pockets that are occluded in its cytosolic form. We demonstrate that this shift is mediated by dynamic coupling between the allosteric site (α3-loop5-β3-loop6) and the functional binding pockets. To conclusively test this mechanism, we utilised an ensemble-based protein design strategy guided by molecular dynamics to engineer the allosteric site. From a series of mutants, two variants emerged that stabilized LC3 conformation in either active or inactive state on the membrane. X-ray crystal structures of mutant LC3, biophysical assays, super-resolution microscopy, and TEM confirmed that the activated allosteric site mutant facilitates receptor binding and cargo capture. In contrast, the inactive variant is functionally inert on the membrane. Our work identifies a fundamental lipid-triggered allosteric site in LC3 that is critical for autophagy regulation and broader implications of membrane-dependent reprogrammable protein activities.
    DOI:  https://doi.org/10.1038/s41467-026-76697-9
  34. Mol Biol Cell. 2026 Aug 26. mbcE26080357T
    Sequential restriction of SNARE-mediated fusion by the COPII inner coat and SNARE chaperones.
    E J Mackey, T Takenaka, E A Miller, A J Merz.
      SNARE-mediated fusion requires assembly of four SNARE domains (R, Qa, Qb, and Qc) distributed across two membranes, with an SM (Sec1/Munc-18 family) chaperone catalyzing this assembly. We investigated topological requirements for the four SNAREs that mediate ER-Golgi fusion using in vitro assays. In the presence of the cognate SM Sly1, we find that the R SNARE must be in trans to the Qa and Qb SNAREs. The Qc SNARE functions on either membrane but is most active in cis to Qa and Qb. These results prompted us to look upstream, at COPII-SNARE interactions. The assembled COPII coat is known to block fusion. We discovered that of five COPII core subunits, the Sar1 GTPase and Sec23/Sec24 subunits were necessary and sufficient to prevent fusion for prolonged periods, and that Sar1 was dispensable for inhibition over short periods. When Sec24- interactions with R and Qc SNAREs were disrupted, inhibition was relieved, indicating that SNARE sequestration COPII on the nascent carrier prevents fusion. These observations help to explain how appropriate fusion events are facilitated while inappropriate events are deterred.
    DOI:  https://doi.org/10.1091/mbc.E26-08-0357-T
  35. JCI Insight. 2026 Aug 25. pii: e203285. [Epub ahead of print]
    Heat-shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss.
    Jintao Yu, Miguel A Ramirez, Yi-Zhi Wang, Seby Edassery, Maxwell Shramuk, SangEun Yeom, Casey Jiaxi Li, Yuvraj Joshi, Mary Ann Cheatham, Mark A Rutherford, Leah J Welty, Jeffrey N Savas.
      Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in spiral ganglion neurons as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.
    Keywords:  Aging; Chaperones; Neuroscience; Otology; Synapses; Transcriptomics
    DOI:  https://doi.org/10.1172/jci.insight.203285
  36. ACS Chem Biol. 2026 Aug 21. 21(8): 1906-1916
    Tau-Targeted PROTACs Degrade Pathology-Associated Tau and Improve Memory in Alzheimer's Disease Models.
    Tian Zhao, Tian-Yang Wang, Hao-Sen Wang, Yeh-Jun Lim, Zhi-Jun Zhang, Xin-Rong Duan, Liang Li, Yan-Mei Li.
      Tau aggregation and hyperphosphorylation are key pathological features of Alzheimer's disease (AD). Because Tau is intrinsically disordered, conventional small-molecule inhibitors have achieved limited success. Proteolysis-targeting chimeras (PROTACs) enable the targeted proteasomal degradation of previously considered undruggable proteins. We designed Tau-targeted PROTAC candidates using methylene blue (MB) as a recognition moiety for aggregation-prone motifs within the microtubule-binding region and varied the linker lengths and E3 ligase recruitment ligands to optimize degradation efficiency. Cell-based screening revealed that MB-2-VHL1 and MB-2-VHL2 are active degraders. In vivo studies confirmed a reduction in total Tau levels and degradation of phosphorylated Tau (p-Tau). In 3xTg-AD mice, subcutaneous administration of MB-2-VHL2 was associated with reduced hippocampal Tau and p-Tau levels and improved recognition memory and spatial learning. MB-2-VHL2 was also detectable in both serum and brain tissue by LC-MS/MS after subcutaneous administration and did not cause detectable histological or biochemical toxicity. These results indicate that MB-2-VHL2 can reduce both total Tau and p-Tau levels in vivo. Although the reduction in p-Tau appeared more pronounced under our experimental conditions, whether MB-2-VHL2 preferentially targets pathological Tau remains to be determined. Overall, these findings support further optimization and preclinical evaluation of Tau-targeted PROTACs as a potential therapeutic strategy for AD.
    DOI:  https://doi.org/10.1021/acschembio.6c00096
  37. J Biol Chem. 2026 Aug 26. pii: S0021-9258(26)02370-7. [Epub ahead of print] 113498
    Endolysosomal inhibition uncouples tau uptake from intracellular seeding.
    Dana A Dodd, Michael S LaCroix, Clarissa Valdez, Ayde Mendoza-Oliva, Joshua D Beaver, Anthony R Vega, Ashwani Kumar, Chao Xing, Charles L White, Marc I Diamond.
      Neurodegenerative tauopathies, including Alzheimer's disease, appear to be driven by propagation of tau assemblies, which must access the cytoplasm to recruit monomer and self-replicate, a process termed "seeding." The prevailing model holds that tau seeds enter cells via macropinocytosis and reach the cytosol through lysosomal rupture or micro-perforation. Our findings revise this model by revealing that endocytosis is not required for seeding. Using genome-scale CRISPR screening, we identified multiple v-ATPase components whose loss reduced tau uptake (measured by flow cytometry) yet paradoxically increased seeding (measured by FRET biosensors). Acute v-ATPase inhibition with bafilomycin A1 produced the same effect in v2L tau biosensors and iPSC-derived neurons. Among regulators of endosome maturation, dominant-negative Rab5a decreased internalization while enhancing cytoplasmic templating. Cholesterol depletion produced identical results. Strikingly, transient hypothermia eliminated virtually all detectable tau uptake and dramatically increased seeding, without affecting subsequent tau monomer or aggregate degradation. We conclude that efficient endolysosomal trafficking does not appear to be required for cytoplasmic seeding under the conditions studied here. Across diverse perturbations, reduced endolysosomal flux consistently enhanced tau seeding, consistent with prior work indicating that most internalized aggregates are routed toward degradation rather than amplification. To seed effectively, tau must cross the plasma or vesicular membranes into the cytoplasm. We have found that proper endolysosomal trafficking suppresses cytoplasmic tau seeding, as all perturbations augmented this process. These findings reframe the role of the endolysosomal system in tau seeding and identify membrane transit rather than macropinocytosis itself as a critical gateway to cytoplasmic tau amplification.
    Keywords:  Alzheimer’s disease; Rab5a; Tauopathy; endocytosis; tau seeding; vacuolar ATPase
    DOI:  https://doi.org/10.1016/j.jbc.2026.113498
  38. Cell Rep. 2026 Aug 18. pii: S2211-1247(26)00934-4. [Epub ahead of print]45(8): 117856
    Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
    Wuyue Zhou, Alice Long, Cameron J Douglas, Dalila Gallegos, James M Burke, David W C MacMillan, Ezgi Hacisuleyman, Ciaran P Seath.
      Tumor suppressor p53 is a transcription factor mutated in ∼50% of cancers. Somatic mutations in the DNA-binding domain abolish tumor suppression and thus lead to a loss-of-function activity, while a small subset of recurrent "hotspot" mutants have been shown to confer gain-of-function activities. Using an intein-based μMap photoproximity labeling approach, we map the interactomes of five hotspot mutants and find that mutant p53 (mut p53) acquires interactions with RNA-binding proteins, shifts toward the cytoplasm, and shows increased proximity to structured RNA and RNA-binding proteins. CLIP (Cross-linking and immunoprecipitation) experiments show that mut p53 possesses an RNA-binding motif and is enriched at 3'UTRs, promoting ribosomal localization and localization at the mitochondrial surface. Using ribosome profiling, we further show that mut p53 alters translation and promotes changes in miRNA processing and mitochondrial function, providing a mechanistic rationale for historically reported but poorly understood phenotypes.
    Keywords:  CLIP-seq; CP: cancer; CP: molecular biology; RNA binding; cancer; gain-of-function; mitochondria; mutant p53; proximity labeling; ribosome profiling; translation; μMap
    DOI:  https://doi.org/10.1016/j.celrep.2026.117856
  39. Sci Adv. 2026 Aug 28. 12(35): eaef5385
    Prefoldin function links meiotic chromosome segregation with cellular remodeling and reveals tubulin sensitivity of the meiotic spindle.
    Naohiro Kuwayama, Benjamin S Styler, Bojana Stekovic, Helen Sakharova, Liana Lareau, Marko Jovanovic, Elçin Ünal, Gloria A Brar.
      Faithful chromosome segregation is essential for producing viable gametes during meiosis, a specialized type of cell division relative to mitosis. Here we identify Gim3, a subunit of the ubiquitously expressed and conserved prefoldin complex, as a critical regulator of meiotic but not mitotic chromosome segregation in budding yeast. Loss of Gim3 causes profound defects in chromosome segregation and gamete viability through reduced tubulin protein levels, which are also associated with reduced spindle length. In mitosis, GIM3 deletion minimally affects spindle length and chromosome segregation, despite similarly reduced tubulin levels in both contexts, highlighting an intriguing difference between the sensitivity of meiotic and mitotic spindles to tubulin abundance. Beyond chromosome segregation defects, gim3∆ cells exhibit aberrant meiotic cellular remodeling, including defects in exclusion of age-associated protein aggregates from newly forming gametes. Independently induced meiotic chromosome missegregation similarly disturbs cellular remodeling, pointing to a fundamental coupling between these aspects of gamete production. Together, our findings identify Gim3 as a key factor required for maintaining meiotic chromosome segregation integrity, and reveal an exciting and previously unrecognized link between chromosome segregation and meiotic cellular remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef5385
  40. Sci Adv. 2026 Aug 28. 12(35): eaec4519
    Sorting of lysosomal enzyme and autophagy are regulated by the GGA1-induced TGN lipid scrambling.
    Kohta Takahashi, Nario Tomishige, Mitsuhiro Abe, Gašper Šolinc, James Rae, Toshiyuki Yamaji, Frédéric Przybilla, Ludovic Richert, Nicolas Humbert, Takefumi Uemura, Thomas Wollert, Satoshi Waguri, Kentaro Hanada, Yasushi Sako, Gregor Anderluh, Robert G Parton, Yves Mély, Catherine Tomasetto, Fabien Alpy, Toshihide Kobayashi.
      The physiological role of lipid asymmetry in intracellular membranes remains poorly understood. Here, we show that sphingomyelin (SM), typically confined to the lumen of the trans-Golgi network (TGN), is exposed on its cytoplasmic surface by the action of the Golgi-associated protein, Golgi-associated gamma-adaptin ear-containing adenosine 5'-diphosphate-ribosylation factor-binding protein 1 (GGA1). This exposure is driven by the GGA1 GAT domain, which induces lipid scrambling in a manner dependent on membrane curvature and cholesterol. SM exposure coincides with the exit of mannose 6-phosphate receptors from the TGN, a process essential for lysosomal enzyme trafficking. Furthermore, SM is transferred to autophagic membranes, where it facilitates autophagosome-lysosome fusion. These findings reveal a previously unrecognized role for lipid remodeling in membrane trafficking and autophagy.
    DOI:  https://doi.org/10.1126/sciadv.aec4519
  41. Nat Commun. 2026 Jul 23. pii: 8969. [Epub ahead of print]17(1):
    Multi-subunit collaboration enables Smc5/6 to function as a composite SUMO E3 complex.
    Xiaoyu Xue, Jiayi Fan, Shibai Li, Sofya Ignatyeva, Patricia Gallegos-Elias, Heather McEntire-Benitez, Xinji Zhu, Tanu Rani Kar, John Epps, Lillian Eliaz, Kiana Holland, Andrea Romero, Xiaolan Zhao.
      The SUMO E3 enzymes control the efficiency and specificity of protein SUMOylation, providing regulatory means for many cellular processes. While most SUMO E3s fulfill their roles as single proteins, the conserved Nse2 E3 is an obligatory subunit of the genome-protecting complex Smc5/6. How the Smc5/6 complex functions in SUMOylation and the roles of its non-SUMO E3 subunits in this process remain to be elucidated. Here we examine the budding yeast Smc5/6 in SUMOylation reactions and in cellular SUMOylation assays. Biochemical data show that DNA stimulates Smc5/6's E3 activity by fostering enzyme and substrate proximity. Mutational analyses reveal that four non-SUMO E3 subunits utilize their DNA-binding abilities to support this stimulation. Moreover, ATP binding by SMC subunits favors SUMOylation by enhancing Smc5/6 association with DNA and chromatin and by enabling conformational changes. Our findings thus provide evidence for a specialized DNA- and ATP-stimulated composite SUMO E3 complex that uses inter-subunit collaboration to achieve efficient SUMOylation in genome regulation.
    DOI:  https://doi.org/10.1038/s41467-026-75592-7
  42. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103052
    ESCRT-I complex enhances therapeutic efficacy of ASO drugs by regulating endosomal escape and glucose homeostasis.
    Le Tra Giang Nguyen, Sherouk M Tawfik, Jing Jin, Andrea Durwin, Beshoy Armanios, Xiao-Bo Zhong.
      Antisense oligonucleotide (ASO) therapeutics silence gene expression through RNase H-mediated mRNA degradation or steric blockade, yet their clinical efficacy is limited by inefficient intracellular trafficking, with <1% of internalized ASOs escaping endosomes to access target RNA. A deeper understanding of the cellular mechanisms governing ASO trafficking and activity is therefore critical. Here, we identify the endosomal sorting complex required for transport-I (ESCRT-I) as a previously unrecognized regulator of ASO pharmacological activity. Using human hepatocyte-derived cell models and FDA-approved ASO drugs inotersen and mipomersen, we demonstrate that suppression of specific ESCRT-I subunits, VPS23 and VPS28, markedly enhances ASO-mediated target silencing, whereas depletion of other subunits has minimal effect. Mechanistically, VPS23 functions as a central ESCRT-I component linking endosomal trafficking to intracellular glucose homeostasis. Loss of VPS23 reduces expression of the glucose transporter GLUT2, lowers intracellular glucose levels, and possibly enables ASO endosomal escape without altering cellular uptake or RNase H1-dependent activity. VPS23 suppression disrupts endosomal morphology, decreases ASO retention in late endosomes, and enhances cytosolic availability of ASOs. Notably, this regulatory effect extends beyond ASOs to small interfering RNA (siRNA) therapeutics, indicating a broader role for ESCRT-I in RNA drug biology. Together, these findings uncover a metabolic-endosomal axis controlling nucleic acid drug efficacy and provide new mechanistic insight into intracellular determinants of RNA-based therapeutics.
    Keywords:  ASO; ESCRT-1 complex; MT: oligonucleotides: therapies and applications; endosomal escape; glucose
    DOI:  https://doi.org/10.1016/j.omtn.2026.103052
  43. EMBO Mol Med. 2026 Aug 22.
    IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.
    Dimitrios Doultsinos, Ingrid Tomljanovic, Eleftherios Pilalis, Sophia M Abusamra, Mohammed Alshalalfa, Romuald Parmentier, Vidhula Ahire, Imogen E Bridges, Sandy Figiel, Joanna Hester, Damien Leach, Ashwin Nandakumar, Rensheng Wan, Yanis Zekri, Jichang Zhang, Charlotte L Bevan, Edward O'Neill, Alastair D Lamb, Valentine Macauley, Jean Phillipe Theurillat, Alfonso Urbanucci, R Jeffrey Karnes, Daniel E Spratt, Elai Davicioni, David Quigley, Wilbert Zwart, Clementine Le Magnen, Aristotelis Chatziioannou, Ian G Mills.
      Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. To improve treatment outcomes for patients at high risk of metastasis, PCa is in need of better risk stratification at diagnosis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and acquired treatment resistance has not been defined. We use pre-clinical models of stress response to describe the impact of IRE1 activity loss on multiple PCa stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club-like phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution and develop an IRE1 activity signature (IRE1sig1.0) reflecting both tumoral and micro-environmental stress responses. IRE1sig1.0 correlates with tumoral identity, and prognosticates localised and metastatic disease independently from AR activity. Using IRE1sig1.0 as a tool may inform ARSI suitability and guide IRE1 modulation as a novel combination therapeutic in prostate cancer.
    DOI:  https://doi.org/10.1038/s44321-026-00490-w
  44. Mitochondrion. 2026 Aug 22. pii: S1567-7249(26)00095-4. [Epub ahead of print]91 102205
    Loss of mitochondrial co-chaperone GRPEL2 protects mice from age- and diet-induced obesity.
    Yang Yang, Nirajan Neupane, Jouni Kvist, Jonna Saarimäki-Vire, Matthias Schewe, Kalle Luopajärvi, Pooja Manjunath, Svetlana Konovalova, Rubén Torregrosa-Muñumer, Veijo Kinnunen, Pekka Katajisto, Timo Otonkoski, Eija Pirinen, Jayasimman Rajendran, Henna Tyynismaa.
      Mitochondrial protein homeostasis intersects with metabolic control, but the in vivo roles of specific mitochondrial co-chaperones remain unclear. The chaperone mtHSP70 plays a key role in import and folding of nuclear-encoded proteins targeted to mitochondrial matrix. Its protein folding cycle is regulated by the GrpE-like nucleotide exchange factor GRPEL1. Vertebrates also have a GRPEL2 paralog, postulated as the stress-sensitive counterpart, but its physiological relevance is not known. We show here that GRPEL2 is not essential for viability in mice, and its absence does not induce proteotoxic stress responses in stark contrast to GRPEL1. However, we find that GRPEL2 has a role in regulating body weight homeostasis. GRPEL2 knockout mice are protected from age- and diet-induced weight gain and maintain a better metabolic health and insulin sensitivity. Transcriptional profiling revealed minimal changes in liver and skeletal muscle, whereas white adipose tissue from Grpel2-deficient mice lacked the obesity-associated remodeling seen in controls. We propose that GRPEL2 fine-tunes metabolic setpoints without broadly perturbing mitochondrial protein import, thereby maintaining adipose tissue health during nutritional excess. These findings show that subtle alterations in mitochondrial chaperone systems reshape systemic metabolism and could suggest strategies to mitigate obesity and insulin resistance through targeted modulation of mitochondrial proteostasis.
    Keywords:  Adipose tissue; Body weight homeostasis; Grpel2; Mitochondrial protein import; Nucleotide exchange factor; mtHSP70
    DOI:  https://doi.org/10.1016/j.mito.2026.102205
  45. Cancer Lett. 2026 Aug 25. pii: S0304-3835(26)00560-4. [Epub ahead of print]659 218796
    Regulation of ubiquitination and degradation of the gap junction channel protein Connexin43 involves the concerted action of multiple members of the NEDD4 family of E3 ubiquitin ligases.
    Max Zachrisson Totland, Nikoline Lander Rasmussen, Vilde Cecilie Wivestad Elster, Karen Irene Arnesen, Dina Glømmi Bergmann, Ida Bergill, Jakob Mørkved Stenersen, Mathias Larsen, Joachim Jordal Moe, Sebastian Basing, Vigdis Sørensen, Trond Aasen, Edward Leithe.
      Intercellular communication via gap junctions is often lost during cancer development, which may contribute to increased tumor growth and affect how cancer cells respond to radio- and chemotherapy. Gap junction channels comprise transmembrane proteins belonging to the connexin family, of which connexin43 (Cx43) is the most ubiquitously expressed in humans. SMAD ubiquitination regulatory factor 2 (SMURF2), a member of the neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) family of E3 ubiquitin ligases, often accumulates in the cytoplasm in cancer cells, where it may display oncogenic properties. Here, we demonstrate that SMURF2 interacts with Cx43 and promotes its ubiquitination in HeLa cells, which is associated with loss of Cx43-based gap junctions and reduced levels of Cx43. Moreover, SMURF2 was found to cooperate with two other NEDD4 family members, NEDD4 and ITCH, to regulate Cx43 ubiquitination and degradation. Simultaneous depletion of these three E3 ubiquitin ligases significantly reduced the Cx43 ubiquitination and degradation rate compared with their single depletion. Their combined knockdown was also found to reduce the ubiquitination and degradation of Cx43 following exposure to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). Collectively, these data identify SMURF2 as a negative regulator of gap junctional intercellular communication in cancer cells by inducing the loss of Cx43-based gap junctions. The study also establishes that Cx43 ubiquitination and degradation are controlled by the concurrent participation of multiple E3 ubiquitin ligases, both under basal conditions and in response to TPA exposure.
    DOI:  https://doi.org/10.1016/j.canlet.2026.218796
  46. Curr Biol. 2026 Aug 24. pii: S0960-9822(26)01004-3. [Epub ahead of print]
    The proteasome promotes cytokinetic abscission by relieving an Aurora B-dependent inhibition of ESCRT-III dynamics.
    Rayane Dibsy, Tamara Advedissian, Clotilde Custot, Buzz Baum, Arnaud Echard.
      Cytokinesis finalizes cell division by physically separating the daughter cells. After furrow ingression, the intercellular bridge (ICB) connecting the dividing cells is cut via microtubule severing, followed by membrane scission, which requires dynamic ESCRT-III polymers. Proteasomal degradation is crucial for mitotic exit and the early steps of cytokinesis, but whether it plays a role in abscission is unknown. Here, we found that inhibiting the proteasome after furrow ingression in human cells led to increased Aurora B levels at the ICB and delayed both microtubule cutting and membrane scission. Overexpression of Aurora B phenocopied these cytokinetic defects, whereas inhibiting Aurora B activity fully rescued the defects caused by proteasome inhibition. Mechanistically, proteasome inhibition increased the levels of active Aurora B, enhanced the phosphorylation of its substrate CHMP4C, and reduced the amount of the ESCRT-III remodeling ATPase VPS4 at the ICB. Consequently, this led to a reduction in the dynamics of the ESCRT-III polymer at the ICB. Remarkably, proteasome inhibition did not delay abscission in cells expressing a mutant of CHMP4C that cannot be phosphorylated by Aurora B, thus demonstrating that the function of the proteasome in abscission is to degrade Aurora B and thereby limit CHMP4C phosphorylation. Our findings reveal a key role of the proteasome in the final step of cell division by decreasing Aurora B levels and activity to enable ESCRT-III function in abscission.
    Keywords:  Aurora B; ESCRT; cell division; cytokinesis; membrane scission; microtubule; mitosis; polymer; proteasome
    DOI:  https://doi.org/10.1016/j.cub.2026.07.073
  47. Genetics. 2026 Aug 22. pii: iyag220. [Epub ahead of print]
    Ribosome heterogeneity provides a translational barrier against protein misfolding disease in Saccharomyces cerevisiae.
    Min Suk Jang, Sia Han, Eunsil Choi, Jihwan Hwang, Moonil Son.
      The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor Sup35p (eRF3). Among 79 ribosomal proteins in Saccharomyces cerevisiae, through a genetic screen for novel anti-prion factors, we identified RPL24B, a 60S ribosomal subunit protein, as a key determinant of prion generation. Our findings revealed that the functional distinction between the ribosomal paralogs RPL24A and RPL24B is the primary driver of ribosomal heterogeneity-based anti-prion generation. Heterogeneity establishes a critical genetic checkpoint that strictly regulates the emergence and heritable diversity of prions and their variants. We demonstrate that deleting RPL24B (rpl24bΔ) significantly increased the frequency of [PSI+] generation compared to the wild-type strain. Crucially, the resulting [PSI+] prions in the rpl24bΔ mutants exhibited distinct heritable diversity, characterized by high thermostability and exceptionally high propagon numbers. This anti-prion activity is uniquely specific to the RPL24B paralog, because deletion of its highly homologous counterpart, RPL24A, does not reproduce the effects observed in rpl24bΔ. Mechanistically, we identified valine 138 (V138) in Rpl24b as the major molecular determinant of its anti-prion generation activity. Loss of Rpl24b perturbs the cellular protein quality control landscape, leading to high accumulation of misfolded protein aggregates. This work suggests that RPL24B functions as a specialized retainer of genetic robustness, providing a translational barrier against protein misfolding diseases by filtering out robust amyloid variants.
    Keywords:  Ribosomal protein; [PSI+]; [URE3]; prion; yeast
    DOI:  https://doi.org/10.1093/genetics/iyag220
  48. PLoS Biol. 2026 Aug 25. 24(8): e3003971
    IP3R2-mediated inter-organelle calcium signaling suppresses melanosome degradation.
    Suman Saurav, Anuradha Jadon, Rajender K Motiani.
      Organelle turnover is fundamental to cellular homeostasis and regulates both physiological processes and pathological outcomes. Skin pigmentation is determined by the balance between melanosome biogenesis and degradation. However, the mechanisms governing melanosome degradation, i.e., melanophagy remain largely unappreciated. Here, we reveal Inositol 1,4,5-trisphosphate receptor 2 (IP3R2) as a selective suppressor of melanophagy. To enable real-time monitoring of melanophagy, we developed and characterized two novel ratiometric live-cell imaging probes. Using a multi-pronged strategy combining live-cell imaging with the probes, biochemical studies, ultrastructural analyses, molecular approaches, and calcium imaging, we demonstrate that IP3R2 suppresses melanophagy. Importantly, in vivo studies in zebrafish model and meta-analysis of human skin microarrays substantiate the physiological relevance of IP3R2 in pigmentation. Mechanistically, IP3R2 depletion impairs mitochondrial Ca2+ uptake, elevates the ADP/ATP ratio and initiates melanophagy. Concurrently, IP3R2 loss enhances ER-lysosome contacts, increases lysosomal Ca2+ levels via TMEM165, and activates TRPML1 and nuclear translocation of TFEB. This in turn transcriptionally induces melanophagy receptor and E3 ligase. Collectively, IP3R2 acts as a critical determinant of melanophagy and a potential therapeutic target for pigmentary disorders and skin malignancies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003971
  49. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2601318123
    Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells.
    Jing Wang, Zegui Ni, Xinxin Zhang, Linling He, Xinyue Zhang, Xu Cheng, Haimo Wang, Guoying Sun, Zhenwei Lu, Chengxu Liu, Hongjie Qian, Youli Lu, Gangyi Liu, Jingying Jia, Jian Ye, Linzhang Huang, Haobin Ye, Rong Li, Wufan Tao, Peng Li, Tong-Jin Zhao, Xingrong Du.
      Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.
    Keywords:  CORVET/HOPS; T cells; amino acid; integrated stress response; metabolism
    DOI:  https://doi.org/10.1073/pnas.2601318123
  50. Cell Death Differ. 2026 Aug 27.
    TRIM32-mediated ubiquitination of STING promotes glycolysis and tumor progression.
    Huaxin Zhou, Zhengyao Guan, Zhaoqing Yin, Biaofeng Shan, Jun Wu, Kangping Lu, Jiazheng Li, Hao Zhang, Jianyun Wang, Chongzhong Liu, Zhangshuo Yang, Xiangyu Zhai.
      The Warburg effect, a hallmark of metabolic reprogramming, drives tumor progression, but its upstream regulation remains unclear. Using hepatocellular carcinoma (HCC) as a model, we identify TRIM32, an E3 ubiquitin ligase, as a potent activator of glycolysis that promotes malignancy. TRIM32 is upregulated in HCC tissues and cell lines, correlating with aggressive features and poor prognosis. Gain- and loss-of-function studies show that TRIM32 enhances proliferation, invasion, and migration in vitro and accelerates tumor growth and lung metastasis in xenografts. Mechanistically, TRIM32 mediates K48- and K63-linked polyubiquitination of STING, accelerating its degradation and relieving glycolytic suppression. Reduced STING elevates HK2 and promotes its mitochondrial localization, sustaining glycolysis and bioenergetics. TRIM32 knockdown decreases tumor burden, metastasis, and glycolytic activity, while hepatocyte-targeted STING knockdown rescues tumorigenesis in liver-specific TRIM32 knockout mice. These findings define a TRIM32-STING-HK2 axis that links ubiquitin-mediated suppression of innate immune signaling to glycolytic activation. Although validated in HCC, this mechanism likely applies broadly across solid tumors and nominates TRIM32 as a therapeutic target to reprogram tumor metabolism and limit malignancy.
    DOI:  https://doi.org/10.1038/s41418-026-01855-x
  51. Cell Rep. 2026 Aug 22. pii: S2211-1247(26)00965-4. [Epub ahead of print]45(9): 117887
    16S ribosomal RNA modification drives transcript-specific translation efficiency.
    Zachory M Park, Christina R Savage, Amanda R Decker-Farrell, Chin-Hsien Tai, Tapan K Maity, Weiming Yang, Lisa M Jenkins, Kumaran S Ramamurthi.
      Bacterial ribosomal RNAs (rRNAs) are decorated with conserved nucleotide modifications, but the functionality of these modifications is often underexplored. MraW (RsmH) is a 16S rRNA methyltransferase. Here, we report that deletion of mraW corrects a late-stage sporulation defect in Bacillus subtilis by bypassing a sporulation checkpoint. Ribosomes purified from ΔmraW cells display a ∼2-fold decrease in translation efficiency; in vivo, ΔmraW cells produced decreased levels of the sporulation checkpoint protein CmpA. Reduced production of CmpA is mediated by mRNA sequences that form a stem-loop which occludes early cmpA codons. Proteomic analysis revealed that MraW mediates production of multiple proteins, some of whose mRNA form similar structures as the cmpA transcript. We propose that MraW modification of 16S rRNA enhances translation efficiency in general, and that specific transcripts have evolved structural features that fine-tune protein levels. This type of control may be prevalent in bacteria which exhibit uncoupled transcription and translation.
    Keywords:  30S subunit; CP: microbiology; CP: molecular biology; RsmI; SpoIVA; SpoVM; elongation; initiation; stationary phase
    DOI:  https://doi.org/10.1016/j.celrep.2026.117887
  52. Bioinformatics. 2026 Aug 01. pii: btag448. [Epub ahead of print]42(Supplement_2):
    Stoic: fast and accurate protein stoichiometry prediction.
    Daniil Litvinov, Lorenzo Pantolini, Peter Škrinjar, Gerardo Tauriello, Caitlyn L McCafferty, Benjamin D Engel, Torsten Schwede, Janani Durairaj.
       MOTIVATION: Protein complexes are central to cellular function, but experimental determination of their structures remains challenging. Structure prediction methods require prior knowledge of stoichiometry-the number of copies of each protein entity within a complex. Current approaches rely on computationally expensive brute-force methods that run structure prediction on multiple stoichiometry combinations, often with limited accuracy.
    RESULTS: We introduce Stoic, a method that uses protein language model embeddings to predict protein complex stoichiometry. Our approach learns to identify interface residues that participate in protein-protein interactions, rather than relying on global sequence features. By integrating these interface-aware embeddings into a graph neural network, Stoic achieves fast and accurate stoichiometry prediction for both homomeric and heteromeric targets.
    AVAILABILITY: Source code for inference and training along with web versions are available in the repository at https://github.com/PickyBinders/stoic.
    DOI:  https://doi.org/10.1093/bioinformatics/btag448
  53. Autoimmun Rev. 2026 Aug 26. pii: S1568-9972(26)00182-5. [Epub ahead of print]25(12): 104168
    The integrated stress response in immune thrombocytopenia: from cellular stress to hematopoietic adaptation.
    Xin Zhou, Yang Jiang, Shan Xu, Ningning Shan.
      Immune thrombocytopenia (ITP) is an autoimmune hematologic disorder characterized by immune-mediated platelet destruction and impaired platelet production. In addition to these core abnormalities, ITP is associated with persistent inflammation, metabolic disturbance, oxidative injury, and altered proteostasis in immune cells, megakaryocytes, platelets, and the bone marrow microenvironment. In this narrative review, we examine whether the integrated stress response (ISR) could provide a mechanistic link between these stress phenotypes and cell-specific responses in ITP. Evidence for the involvement of the four canonical eIF2α kinases is uneven and varies substantially by cell type and experimental setting. We therefore propose a cell-specific hematopoietic response model in which sustained stress inputs interact with the distinct response capacities of immune and hematopoietic cell populations. From a therapeutic perspective, we discuss current ITP treatments in terms of their established immunological or hematopoietic actions and distinguish these primary effects from secondary changes in cellular stress that may follow disease control. We also refer to some experimental methods to confirm the participation of ISR. By emphasizing these differences, the review intends to promote future mechanistic research and the assessment of possible therapeutic strategies related to stress.
    Keywords:  Endoplasmic reticulum stress; Immune regulation; Immune thrombocytopenia; Integrated stress response; Megakaryopoiesis
    DOI:  https://doi.org/10.1016/j.autrev.2026.104168
  54. Nat Commun. 2026 Jul 22. pii: 8940. [Epub ahead of print]17(1):
    Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy.
    Janne Van Hauwenhuyse, Felien Reniers, Leentje Persoons, Sam Noppen, Casey E Wing, Ashley B Niesman, Ho Yee Joyce Fung, Els Vanstreels, Maarten Jacquemyn, Eline Boel, Ann Vankerckhoven, Yani Berckmans, Bert Kwanten, An Coosemans, Guy Van den Mooter, Yuh Min Chook, Wim Dehaen, Dirk Daelemans.
      Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition to Cys528 in the nuclear export signal binding groove of XPO1. Here, we describe a novel XPO1 inhibitor, FR-027, that targets Cys528 through nucleophilic aromatic substitution. In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Structural analysis of the XPO1-FR-027 complex reveals covalent modification of Cys528 and a closed-groove conformation that prevents degradation. FR-027 demonstrates potent on-target activity across multiple cancer cell types and delays disease progression while extending overall survival in xenograft and syngeneic models, including intracranial tumors. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs.
    DOI:  https://doi.org/10.1038/s41467-026-75741-y
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