bims-proteo Biomed News
on Proteostasis
Issue of 2026–05–24
fifty-six papers selected by
Eric Chevet, INSERM
  1. The Golgi vesicle tether p115/USO1 can bind directly to the ER exit site organiser Sec16A.
  2. Protein Age Bias in Target Degradation by PROTACs.
  3. In situ cryo-ET defines the ultrastructure of ER exit sites in human cells.
  4. Intrinsic bias of the genetic code shapes the folding and stability landscapes of microproteins.
  5. Hsp90: A Means to an End.
  6. Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
  7. OptoRibo-seq for spatiotemporally resolved mapping of the local protein translatome.
  8. ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.
  9. Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.
  10. Interpretable deep learning framework for mapping E3-substrate binding interfaces.
  11. Minute-scale control of ubiquitin-mediated degradation reveals dynamics of bacterial secreted effector-functions.
  12. Identification of a conserved receptor for degrading ribosomes through autophagy.
  13. HCMV-pUS2 Disrupts cGAS-STING Signaling through LMAN2L Degradation.
  14. RanBP2-dependent SUMOylation of G3BP2 inhibits formation, and promotes disassembly, of stress granules.
  15. High-resolution mapping of CCR4-NOT recruitment elements reveals transcriptome-wide drivers of mRNA decay.
  16. Unexpected ribosome turnover during prolonged translation inhibition.
  17. De novo design of a macrocycle-induced dimerization system for cellular control.
  18. Chaperone-mediated autophagy is required for regulatory T cell function.
  19. SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
  20. Diverse stresses differentially regulate rRNA biogenesis and mRNA translation.
  21. In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging.
  22. Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis.
  23. The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
  24. The Shape of Things to Come: α-Helical Membrane Protein Folding on the Ribosome.
  25. A functional map of the human intrinsically disordered proteome.
  26. Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
  27. Alphaviral non-structural protein-host RBP co-condensation as a mechanism to sustain virus replication.
  28. Light-based modulation of astrocytic calcium for regulation of organelle dynamics and morphogenesis.
  29. Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.
  30. A Scalable, Direct-to-Biology Platform for Accelerated Discovery of Cereblon-Based Molecular Glue Degraders.
  31. Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.
  32. Intermolecular β-sheet Formation Guides the Interaction between Ubiquitin-like Modifier FAT10 and Adapter Protein NUB1L.
  33. Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
  34. ANYI: The ANnotated Yeast Interactome.
  35. De novo design of miniproteins targeting GPCRs.
  36. A mechanism for substrate quality control in outer membrane protein assembly.
  37. Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
  38. ProteomeLM: A proteome-scale language model enables accurate and rapid prediction of protein-protein interactions and gene essentiality across taxa.
  39. Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.
  40. 20S proteasome-regulated proteostasis in ELVAs is critical for oocyte-to-embryo transition and female fertility.
  41. The Pseudomonas aeruginosa ribonuclease Ribocin cleaves eukaryotic ribosomes at helix 69 to inhibit host translation.
  42. DGAT: a dual-graph attention network for inferring spatial protein landscapes from transcriptomics.
  43. Nitric oxide drives proteomic diversity through alternative splicing.
  44. Diverse mechanisms of translation arrest by a Clostridia ribosome stalling peptide CliM.
  45. Light-controlled disruption of cancer cell dormancy via photoswitchable stress hormone receptor degraders.
  46. The proteomics and phosphoproteomics landscape of melanoma under T cell attack.
  47. Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.
  48. The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
  49. In silico design and binding mechanism of UBR1 E3 ligase recruiters.
  50. Ribosomal RNA processing undergoes surveillance by the mRNA guard protein Npl3.
  51. Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.
  52. Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation.
  53. MARCHF6 orchestrates hepatic lipid homeostasis by targeting SREBP1 for ER-associated degradation.
  54. Ribonuclease DIS3 delays aging and senescence by generating tRNA halves.
  55. VCP modulation ameliorates pathological features in C9orf72 models.
  56. Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
  1. J Cell Sci. 2026 May 22. pii: jcs.264894. [Epub ahead of print]
    The Golgi vesicle tether p115/USO1 can bind directly to the ER exit site organiser Sec16A.
    Igor Yakunin, Alison K Gillingham, Conceição Pereira, David C Gershlick, Sean Munro.
      Newly made secretory and membrane proteins exit the endoplasmic reticulum (ER) in COPII vesicles that form at specialised ER exit sites. These exit sites are typically near to the early Golgi compartments that receive these vesicles. A key player in the delivery of vesicles to the early Golgi is p115 (USO1), a homodimer with a folded head domain and a coiled-coil tail that is anchored to Golgi membranes. p115 has been shown to capture vesicles and to bind to SNARE proteins to promote membrane fusion. Here we report that the head domain of human p115 can bind directly to Sec16A, a large scaffolding protein that organises ER sites and promotes COPII vesicle formation. Structural prediction and deletion mapping define the region of interaction to a conserved motif in the unstructured N-terminal region of Sec16A, and mutations in p115 that block motif binding reduce the efficiency of secretion. This interaction could potentially allow a subset of p115 molecules to reach across from the early Golgi to ER exit sites to contribute to the large-scale organisation of the early secretory pathway.
    Keywords:  COPII vesicles; ER exit site; Golgi; Membrane traffic
    DOI:  https://doi.org/10.1242/jcs.264894
  2. bioRxiv. 2026 May 05. pii: 2026.05.01.722262. [Epub ahead of print]
    Protein Age Bias in Target Degradation by PROTACs.
    Bingbing X Li, Xiangshu Xiao.
      Targeted protein degradation (TPD) by PROteolysis TArgeting Chimeras (PROTACs) has emerged as a powerful chemical biology and therapeutic modality, yet many degraders exhibit incomplete target clearance and characteristic rebound kinetics despite continuous exposure. The mechanistic basis for this behavior remains poorly understood. Here we uncover protein age as a previously unrecognized determinant of PROTAC efficacy. Using CG □SLENP, a chemical genetics strategy that selectively labels newly synthesized and pre □existing proteins within the same living cell, we directly resolve PROTAC□induced degradation of distinct intracellular protein populations. Applying this approach to the bromodomain protein BRD4, we show that two mechanistically and structurally distinct PROTACs, dBET6 and MZ□1, preferentially degrade pre □existing BRD4, while newly synthesized BRD4 is degraded substantially more slowly and incompletely. This age□dependent degradation bias is observed in live□cell imaging, across compound concentrations and time scales, and for both reporter and endogenous BRD4. These findings reveal that PROTAC□mediated degradation is governed not only by target engagement and ternary complex formation, but also by the dynamic balance between protein synthesis and degradation. By identifying temporal proteostasis as a critical parameter in TPD, this work provides a mechanistic framework for incomplete degradation and rebound kinetics and establishes protein maturation state as an important consideration for degrader design and evaluation.
    DOI:  https://doi.org/10.64898/2026.05.01.722262
  3. Nat Cell Biol. 2026 May 20.
    In situ cryo-ET defines the ultrastructure of ER exit sites in human cells.
    Katie W Downes, Julia R Flood, Andrea Nans, Sander E Van der Verren, Anjon Audhya, Giulia Zanetti.
      Trafficking of secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus comprises the first, essential steps towards the appropriate localization of 30% of eukaryotic proteins. Coat protein complexes COPII and COPI are involved in the forward and retrograde transport of cargo and cargo receptors between the ER and the Golgi, respectively. Although COPII forms coated vesicles in vitro, the biogenesis, morphology and organization of transport carriers in mammalian cells is subject to debate. Here we use in situ cryo-electron tomography and super-resolution fluorescence microscopy to reveal the molecular architecture of ER exit sites in human cells that were not perturbed with drugs, temperature blocks or overexpression systems. We visualize ribosome-exclusion zones enriched with COPII- and COPI-coated vesicles and thus resolve the debate regarding the existence of COPII-coated vesicles. COPII vesicles derive from ER membranes, whereas COPI vesicles originate from vesicular-tubular clusters that constitute the ER-Golgi intermediate compartment (ERGIC). We quantify coated vesicle morphology and positioning with respect to other ER exit site components, providing a molecular description of the organization of the mammalian early secretory pathway.
    DOI:  https://doi.org/10.1038/s41556-026-01964-2
  4. Mol Cell. 2026 May 19. pii: S1097-2765(26)00275-3. [Epub ahead of print]
    Intrinsic bias of the genetic code shapes the folding and stability landscapes of microproteins.
    Yabo Guo, Ti Qin, Jiancheng Luo, Qiannan Pan, Runguo Shu, Ruiyang Guo, Jiajia Qian, Chenyang Xu, Jiawei Wang, Ziyi Wang, Nanxiang Zheng, Hao Li, Xiaogang Guo, Xiongwen Cao, Yong Wang, Shan Zhang.
      Thousands of non-canonical open reading frames (ORFs) in the human transcriptome are translated into microproteins, many with ribosome occupancy comparable to canonical proteins. Intriguingly, most microproteins fail to accumulate as stable proteins; instead, their derived peptides are widely presented by human leukocyte antigen class I (HLA-I) molecules and show emerging immunomodulatory roles. To understand the underlying biology, we explored the folding and stability landscape of a large microprotein cohort, revealing a fundamental rule that connects the genetic code, protein folding, and stability. Structural modeling and parallel profiling revealed that most microproteins are intrinsically disordered and rapidly degraded. Mechanistically, the high GC content of microprotein-coding sequences, which facilitates non-canonical translation, enriches for residues encoded by multiple GC-rich codons (primarily glycine, arginine, alanine, and proline), thereby promoting structural disorder and terminal-residue motif-mediated, Cullin-RING E3 ubiquitin ligase (CRL)-dependent proteasomal degradation. Together, our findings establish a concise, quantitative rule by which high GC content constrains protein evolvability, revealing how surveillance machinery differentially targets microproteins versus canonical proteins.
    Keywords:  GC content; genetic code; lncORF; microprotein; non-canonical translation; protein stability; protein structure; uORF
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.021
  5. Cell Stress Chaperones. 2026 May 20. pii: S1355-8145(26)00046-5. [Epub ahead of print] 100190
    Hsp90: A Means to an End.
    Katie M Whalen, Brian C Freeman.
      The Hsp90 molecular chaperone is a key component of the protein homeostasis (proteostasis) system. Hsp90 likely serves as a gatekeeper in a cell's protein quality control decision tree since this chaperone is linked to nascent polypeptide folding, client maturation, metastable protein maintenance, and polypeptide degradation. Interestingly, how a client protein is directed through the decision process is unclear. Minimally, modifications to the amino-terminal ATP-binding domain of Hsp90 can favor client degradation. As this includes a common class of Hsp90 inhibitors that trigger the breakdown of clinically relevant factors, a better understanding of Hsp90's role in quality control is merited. Here, we explore how Hsp90 links to both polypeptide biogenesis and triage, the events that regulate the decision route, and how Hsp90's connections to proteolysis pathways are being exploited for the development of new therapeutics.
    Keywords:  Hsp90; molecular chaperone; proteolysis; proteostasis
    DOI:  https://doi.org/10.1016/j.cstres.2026.100190
  6. bioRxiv. 2026 May 07. pii: 2026.05.03.720925. [Epub ahead of print]
    Stress-Responsive Protein IFRD1 Protects Assembled Ribosomes via a Ribosome-Salvaging Mechanism.
    Charles J Cho, Molly K Crowder, Amala K Rougeau, Thanh Nguyen, Steven J Bark, Sammy Lee, Jeffrey W Brown, Jason C Mills.
      The ability of epithelial cells to cope with injury and undergo regeneration depends on tightly coordinated cellular responses. IFRD1 is a stress-responsive protein that is evolutionarily conserved and required for the cellular regeneration program paligenosis; however, how IFRD1 works in paligenosis is not known. Here we demonstrate that IFRD1 is primarily a cytosolic ribosome-binding protein, specifically binding 80S monosomes that are not actively engaged in translation. Using multiple in vivo and in vitro injury models, including cerulein-induced pancreatitis in mice and tunicamycin-induced ER stress in cell culture, we demonstrate that IFRD1 acts as a ribosome-salvaging factor, preventing ribosomes from degradation. In the absence of IFRD1 during ER stress, non-translating 80S ribosomes were unstable and prone to disassembly and selective degradation. The resulting accumulation of degraded ribosomal subunits overwhelmed cellular autophagic machinery, as evidenced by accumulation of the autophagy-tagging protein p62, even though overall autophagic flux remained unaffected. Ultimately, cells lacking IFRD1 showed reduced mTORC1 activity followed by increased cell death, consistent with patterns observed in cells lacking IFRD1 during paligenosis. Thus, we detail a previously unrecognized cellular function for IFRD1 in stabilizing and preserving the mature ribosome pool during metabolic and translational transitions such as paligenosis.
    DOI:  https://doi.org/10.64898/2026.05.03.720925
  7. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2519235123
    OptoRibo-seq for spatiotemporally resolved mapping of the local protein translatome.
    Ruixuan Wang, Ruixiang Wang, Wentao Wang, Yanjun Liu, Fu Zheng, Huixin Luo, Peng R Chen, Peng Zou.
      Localized protein translation occurs in numerous subcellular compartments and regulates diverse biological processes by rapidly changing protein compositions in response to subcellular needs. Existing assays for subcellular local translation either require physical isolation, which is prone to contamination and loss of material, or imaging-based readout, which is often hampered with low throughput. In this study, we report the development of the optoRibo-seq method that features photoactivatable enzyme-mediated proximity labeling of ribosomes in genetically specified subcellular locations. We demonstrate the spatial specificity of optoRibo-seq at the endoplasmic reticulum (ER) membrane, with a temporal resolution of 1 min. In cells undergoing chemically induced ER stress, optoRibo-seq allowed mapping of the dynamic changes in the ER-proximal translatome, identifying transcripts involved in protein folding and targeting. Our strategy provides a general platform for spatiotemporally resolved profiling of subcellular protein translation.
    Keywords:  ER stress; biotin ligase; genetic codon expansion; proximity labeling; ribosome profiling
    DOI:  https://doi.org/10.1073/pnas.2519235123
  8. bioRxiv. 2026 May 08. pii: 2026.05.07.723621. [Epub ahead of print]
    ASPL-driven subunit exchange remodels VCP/p97 hexamers and is impaired by a multisystem proteinopathy mutation.
    Jingxuan Tang, Laxmikanta Khamari, Benjamin Dodd, Guoming Gao, Liuhan Dai, Stephanie L Moon, Nils G Walter.
      Valosin-containing protein (VCP/p97) is an essential homohexameric AAA+ ATPase that powers ubiquitin-dependent protein quality control by extraction and unfolding of clients for proteasomal degradation. Heterozygous, autosomal-dominant VCP missense mutants are associated with multisystem proteinopathy (MSP) through unclear molecular mechanisms. We developed a single-molecule pull-down assay to quantify VCP hexamer assembly and subunit exchange dynamics directly in human cell lysate. We show the common MSP-associated VCP variant R155H co-assembles with wild-type subunits to form heterohexamers. Wild-type VCP complexes readily undergo subunit exchange in cell lysates, but this exchange is markedly reduced for purified complexes in buffer. We identify the VCP-interactor ASPL as a selective mediator of monomer exchange that efficiently remodels wild-type, but only modestly exchanges R155H variants within multimers. Single-molecule kinetics analyses reveal ∼2-fold faster ASPL association with, and ∼4-fold slower dissociation from, wild-type VCP than R155H-VCP. We propose that ASPL-driven monomer exchange remodels VCP molecular machines to sustain proteostasis. The failure of ASPL-driven exchange of MSP variant monomers would be predicted to stabilize mutant VCP in assemblies, revealing a potentially targetable defect.
    DOI:  https://doi.org/10.64898/2026.05.07.723621
  9. Angew Chem Int Ed Engl. 2026 May 19. e1777033
    Reengineering Protease Inhibitors to Disrupt Hsp70 Chaperone Function.
    Aweon Richards, Ascensión Ariza-Mateos, Antara Ghosh, Max Kim, Sterling Sandler, Isabelle Yardumian, Gideon Yawson, Jeremy Baryza, Alexander Serganov, Tania J Lupoli.
      The heat shock protein 70 (Hsp70) family consists of ATP-driven molecular chaperones essential for maintaining protein homeostasis (proteostasis) across all cell types, however, modulation of chaperone activity by small molecules remains challenging. In bacteria, a major Hsp70 called DnaK represents a putative antibacterial target, as it plays essential roles in growth, antibiotic resistance, and stress response. While Hsp70 inhibitors are in development as potential cancer and neurodegenerative disease treatments in humans, we lack generalizable methods to target Hsp70s across species. Here, we address how peptidomimetic scaffolds designed to inhibit proteases, exemplified by the drug telaprevir, interact with two different bacterial DnaKs to disrupt chaperone function. We perform extensive structure-function studies of telaprevir analogs against DnaK to inform the design of synthetic unnatural peptide sequences with a range of inhibitory potencies. X-ray crystallography analysis of telaprevir and several synthetic peptidomimetics reveal interactions with DnaK's substrate binding domain via ligand side chain recognition reminiscent of that observed in protease active sites, but in two orientations. These co-complexes inspire the synthesis of shorter peptidomimetics capable of allosterically inhibiting DnaK's ATPase activity. Overall, this work demonstrates that chemical scaffolds devised for protease inhibition may be modified to disrupt Hsp70 chaperone activities.
    Keywords:  DnaK; allosteric inhibition; molecular chaperones; peptidomimetics; proteotoxic stress
    DOI:  https://doi.org/10.1002/anie.1777033
  10. Nat Commun. 2026 May 20.
    Interpretable deep learning framework for mapping E3-substrate binding interfaces.
    Dianke Li, Yuting Zhang, Yuan Liu, Zihao Zhang, Yingjie Qu, Jiajun Li, Linyang Jiang, Lihong Diao, Ziding Zhang, Lingqiang Zhang, Chun-Ping Cui, Dong Li.
      E3 ubiquitin ligases recognize substrates through specific interfaces. Accurate delineation of these interfaces is essential, as mutations disrupting them impair protein ubiquitination and drive cancer progression. However, available E3-substrate interface data are sparse and systematic prediction methods remain lacking. Here, we propose MetaESI, a deep learning framework that simultaneously predicts E3-substrate interactions and leverages its interpretable architecture to infer binding interfaces de novo. With a two-stage meta-learning strategy, MetaESI generalizes across diverse E3s and achieves state-of-the-art performance in both interaction and interface prediction. We applied MetaESI at the proteome scale to generate MetaESI-Atlas, which comprises 68,056 annotated interactions across eight species. Integrating multi-omics data, we identified mutations at MetaESI-predicted interfaces that disrupt E3-substrate binding, and experimentally validated representative examples including JunB Q244E and SPOP F102C as oncogenic drivers. By combining interpretable AI with mechanistic insight, MetaESI establishes a methodological paradigm for interpretable model design and a foundational resource for precision oncology and targeted protein degradation.
    DOI:  https://doi.org/10.1038/s41467-026-73143-8
  11. Nat Commun. 2026 05 18. pii: 4420. [Epub ahead of print]17(1):
    Minute-scale control of ubiquitin-mediated degradation reveals dynamics of bacterial secreted effector-functions.
    Haolin Zhang, Yongxia Guo, Bikash Adhikari, Nevenka Dudvarski-Stankovic, Elmar Wolf, Thomas Rudel.
      Precise temporal control of protein abundance is essential for dissecting dynamic cellular processes. While degron-based systems enable rapid protein depletion in eukaryotic cells, comparable tools are lacking for bacterial effectors delivered into host cells during infection. Here, we establish AIDE (Auxin-Inducible Degradation of Effectors), a host-directed degradation platform that harnesses the ubiquitin-proteasome system to selectively eliminate secreted bacterial proteins, including membrane-integrated effectors. By integrating a minimal auxin-inducible degron (AID) tag into effector genes, AIDE enables rapid, reversible, and spatially confined degradation while preserving native expression and secretion. We apply AIDE to Chlamydia trachomatis and show, that the membrane-integrated deubiquitinase Cdu1 suppresses autophagy early and later promotes developmental transitions, whereas the integral membrane fusogen IncA remains continuously required to maintain homotypic inclusion fusion. This AIDE platform provides minute-scale, spatiotemporal control over bacterial effector activity and offers a broadly applicable framework for dissecting virulence mechanisms and host-pathogen interactions across diverse secretion-dependent pathogens.
    DOI:  https://doi.org/10.1038/s41467-026-73213-x
  12. Autophagy. 2026 Jun;22(6): 1149-1150
    Identification of a conserved receptor for degrading ribosomes through autophagy.
    Chhabi K Govind, Daniel J Klionsky.
      Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria.Abbreviations: AIM: Atg8-family interacting motif; ATG: autophagy related; LIR: LC3-interacting region; NUFIP1: nuclear FMR1 interacting protein 1.
    Keywords:  Autophagy; Rpl12A; ribophagy; ribosomes; starvation
    DOI:  https://doi.org/10.1080/15548627.2026.2624242
  13. PLoS Pathog. 2026 May;22(5): e1014246
    HCMV-pUS2 Disrupts cGAS-STING Signaling through LMAN2L Degradation.
    Yue-Peng Zhou, Yong-Xuan Yao, Jin-Peng Wu, Yu-Ting Pan, Wen-Bo Zeng, Jin-Yan Sun, Yue Zhao, Han Cheng, Min-Hua Luo, Bo Yang.
      Human cytomegalovirus (HCMV) has evolved diverse strategies for immune evasion. In this study, we identified HCMV-pUS2 as an indirect antagonist of the cGAS-STING pathway by promoting the degradation of lectin mannose-binding 2-like protein (LMAN2L), an unrecognized host factor involved in STING pathway. First, we discovered that HCMV, but not other DNA viruses such as HSV-1 and VACV, induces proteasomal degradation of LMAN2L during the immediate-early stage of infection. We then demonstrated that HCMV-pUS2 mediates LMAN2L degradation by recruiting the host E3 ubiquitin ligase RNF139 and E2 ubiquitin-conjugating enzyme UBE2G2, directing LMAN2L to the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. LMAN2L knockout diminishes HCMV-induced expression of type I interferons and interferon-stimulated genes. Furthermore, LMAN2L co-localizes and interacts with STING. Though it does not affect STING dimerization or TBK1 recruitment, it is essential for STING translocation from the ER to the Golgi. Our findings uncover LMAN2L as a novel host regulator of the STING pathway and identify pUS2-mediated ERAD as a previously unrecognized viral immune evasion strategy.
    DOI:  https://doi.org/10.1371/journal.ppat.1014246
  14. Mol Biol Cell. 2026 May 20. mbcE25030135
    RanBP2-dependent SUMOylation of G3BP2 inhibits formation, and promotes disassembly, of stress granules.
    Yifan E Wang, Javid Guliyev, Sean S J Ihn, Gaelen Moore, Fermisk Saleh, Hyun O Lee, Alexander F Palazzo.
      Stress granules and processing bodies (P-bodies) are dynamic cytoplasmic ribonucleoprotein (RNP) condensates that coordinate translation inhibition, mRNA storage, and decay during cellular stress. Emerging evidence suggests that SUMOylation contributes to the regulation of these RNP granules in human cells, though the underlying mechanisms remain largely unexplored. Here, we identify RanBP2-dependent SUMOylation as a key regulator of stress granule and P-body dynamics. Cells that lack RanBP2-mediated SUMOylation show enhanced stress granule assembly and delayed disassembly in response to oxidative stress. We further demonstrate that G3BP2, a core component of stress granules, is SUMOylated in a RanBP2-dependent manner at lysine 281, and that this modification limits spontaneous stress granule formation and promotes efficient disassembly. In addition, the loss of RanBP2-mediated SUMOylation reduces P-body abundance and promotes the merging of a subset of P-bodies with stress granules during stress. Together, our findings suggest that SUMOylation may regulate RNP granules by increasing G3BP solubility, thereby limiting stress granule formation, and by maintaining the balance and segregation of stress granules and P-bodies.
    DOI:  https://doi.org/10.1091/mbc.E25-03-0135
  15. Cell Rep. 2026 May 18. pii: S2211-1247(26)00426-2. [Epub ahead of print]45(5): 117348
    High-resolution mapping of CCR4-NOT recruitment elements reveals transcriptome-wide drivers of mRNA decay.
    Zijun Luo, Aldo Hernandez-Corchado, William R Brothers, Zahra Aryanpour, Zia Z Zhao, Justin Zhao, Lindsay Clarke, Connor CampbellSmith, Gene W Yeo, Hamed S Najafabadi, Marc R Fabian.
      The CCR4-NOT complex is a central regulator of gene expression, orchestrating mRNA turnover through interactions with RNA-binding proteins (RBPs) and the microRNA (miRNA)-induced silencing complex. However, identifying which RBP- and miRNA-associated RNA elements recruit CCR4-NOT remains challenging, due in part to the multiple modes by which the complex can be recruited. To address this, we developed TRACER (targeted RNA association with CCR4-NOT and element recovery), a high-throughput method for transcriptome-wide identification of RNA elements that recruit the CCR4-NOT to target RNAs. TRACER analysis in human epithelial cells uncovers thousands of CCR4-NOT-associated elements, including many that map to known and/or predicted RBP and miRNA target sites. We show that TRACER-identified elements drive mRNA repression and decay, and disrupting elements via gene editing or antisense oligonucleotides can relieve repression, boosting target gene expression. This positions TRACER as a powerful discovery platform for identifying regulatory RNA elements that can be targeted to control gene expression.
    Keywords:  CCR4-NOT complex; CP: molecular biology; RNA regulatory elements; RNA-binding proteins; RNA-protein interactions; mRNA decay; microRNA-mediated repression
    DOI:  https://doi.org/10.1016/j.celrep.2026.117348
  16. bioRxiv. 2026 May 13. pii: 2026.05.06.723260. [Epub ahead of print]
    Unexpected ribosome turnover during prolonged translation inhibition.
    Paul J Russell, Caleb A Clark, Mia Ashriem, Michael G Kearse.
      Eukaryotes use several distinct quality control pathways to resolve aberrant ribosomes and mRNAs. For example, the no-go decay mRNA pathway is stimulated after ribosome collisions caused by stalled ribosomes translating damaged or truncated mRNAs. Separate decay pathways for non-functional 40S and 60S subunits containing rRNA mutations affecting decoding and peptidyl transferase activity, respectively, have also been elucidated. To our knowledge, whether eukaryotes have evolved a quality control pathway to sense and process globally stalled ribosomes is unclear; however, such a pathway would be advantageous to eukaryotes during exposure to natural elongation inhibitors such as ricin and diphtheria toxin. Here, we test how prolonged robust inhibition of elongation using a high dose of cycloheximide (CHX) affects ribosome turnover. Despite no decrease in cell viability and that mammalian ribosomes have been classically characterized of having a half-life of 3-5 days, a single 24 hr high dose of CHX resulted in drastically shortened half-lives (<24 hr) of 28S and 18S rRNA in A549 cells. A ~2-fold reduction in nearly all ribosome species was observed by polysome analysis in HeLa and A549 cells after prolonged CHX treatment. Depletion of ribosomes was also evident when assessing ribosomal proteins from both the 40S and 60S subunits by Western blot. Literature supports that ribosomes can be degraded by autophagy and the ubiquitin (Ub)-proteasome system. Upon testing inhibitors of both pathways, only proteasome inhibitors (i.e., MG132 and bortezomib) rescued both rRNA and ribosomal protein levels. Proteasome inhibitors also rescued ribosome levels in polysome profiling experiments. Remarkably, rRNA levels were not rescued during CHX treatment when co-treated with the Ub activating enzyme E1 inhibitor, TAK243. Polysome analysis also showed that the high prolonged dose of CHX did not cause robust accumulation of collided ribosomes compared to control treatments. Proteasome-dependent turnover of rRNA was also observed with high doses of other elongation inhibitors, namely anisomycin, homoharringtonine, and lactimidomycin. The recognition capabilities of the pathway were further expanded as we observed that 80S ribosomes not trapped on the mRNA were also targeted for degradation by the proteasome. Together, our findings define the framework of a regulatory pathway in mammalian cells that degrades both ribosomal subunits in response to prolonged periods of robust elongation inhibition.
    DOI:  https://doi.org/10.64898/2026.05.06.723260
  17. Nat Commun. 2026 May 18.
    De novo design of a macrocycle-induced dimerization system for cellular control.
    Stephanie Hanna, Patrick J Salveson, Basile Wicky, Madison A Kennedy, Derrick R Hicks, Carolina Moller, Suna Cheng, Xinting Li, Mohamad Abedi, Brian Coventry, Meerit Y Said, Asim K Bera, Alex Kang, Barry L Stoddard, David Baker.
      Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo-designed ligand and protein pair. Here, we describe the design of a C2 symmetric membrane-permeable macrocyclic peptide and a cognate protein homodimer which binds the macrocycle through a large interface with both chains. The designed homodimer binds the macrocycle with a KD of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrate conditional control over both a reporter gene expression and luciferase reconstitution.
    DOI:  https://doi.org/10.1038/s41467-026-71345-8
  18. Nat Commun. 2026 May 22.
    Chaperone-mediated autophagy is required for regulatory T cell function.
    Ranee Harrison, Floralba Gjergjova, Sandra Pelka, Adrian Macho-Gonzalez, Bhakti Chavda, Kristen Lindenau, Aiara Gazteluiturri Garcia, Rabia R Khawaja, Jennifer T Aguilan, Simone Sidoli, Susmita Kaushik, Yair Botbol, Ana Maria Cuervo, Fernando Macian.
      Chaperone-mediated autophagy (CMA) is a selective form of protein degradation in lysosomes that declines with age. Besides protein quality control, CMA also regulates several cellular processes through timely proteome remodeling. We previously demonstrated the importance of CMA in the activation of helper T cells. In this work, we analyzed the role of CMA in the generation and function of regulatory T cells (Tregs), a specialized type of T cells that suppress immune responses. We found that the basal CMA activity of Tregs further increases upon their activation. Using a Treg-specific CMA-deficient mouse model, we show that CMA is crucial for maintenance of peripheral tolerance by Tregs. Mice with CMA-defective Tregs display signs of chronic inflammation, which results in reduced survival as they age. We demonstrate that CMA-deficient Tregs have reduced suppressive activity in vivo using an experimental model of inflammatory bowel disease and a second model of tumor-induced immune response. Comparative quantitative proteomic analysis enabled us to identify the subproteome degraded by CMA and, consequently, the cellular pathways modulated by this type of autophagy to sustain Treg homeostasis and function. Collectively, our findings uncover a previously unknown role for CMA in regulating Treg function.
    DOI:  https://doi.org/10.1038/s41467-026-73417-1
  19. EMBO Rep. 2026 May 18.
    SIRT2 mediates integrated stress response by deacetylating and stabilizing 4E-BP1 to suppress translation.
    Yanlin Zi, Jiaqi Zhao, Miao Wang, Dan Hou, Richard A Cerione, Hening Lin.
      The ability to adapt to nutrient stress, such as amino acid limitation, is crucial for cell survival. The mTORC1 complex and integrated stress response (ISR) are two mechanisms that sense the availability of amino acids and regulate protein synthesis. Here, we reveal a new SIRT2-mediated pathway, downstream of the ISR, that is activated under amino acids limitation to suppress global translation. Under amino acid deprivation, SIRT2 protein level is upregulated translationally by its upstream open reading frame (uORF). SIRT2 in turn suppresses translation, which helps cells to survive amino acid limitation. We identify eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), which binds to eIF4E and inhibits translation, as a substrate of SIRT2. SIRT2 deacetylates 4E-BP1 at lysine 69 and stabilizes 4E-BP1 by protecting it from proteasomal degradation, leading to suppression of global translation. Our study uncovers a role for SIRT2 in regulating translation and identifies a new regulatory mechanism of 4E-BP1 in cells.
    DOI:  https://doi.org/10.1038/s44319-026-00803-7
  20. Nucleic Acids Res. 2026 May 05. pii: gkag499. [Epub ahead of print]54(9):
    Diverse stresses differentially regulate rRNA biogenesis and mRNA translation.
    Anne Aldrich, Rachael Thomas, Michael Blower, Shawn M Lyons.
      Ribosome synthesis is one of the most energy-intensive processes in a growing cell, consuming >60% of cellular energy reserves. As such, ribosome biogenesis is highly sensitive to stress to prevent costly expenditures under adverse conditions. Moreover, successful assembly requires precise stoichiometric balance between ribosomal proteins and ribosomal RNAs (rRNA). Here, we define novel regulatory mechanisms of ribosome biogenesis under stress that reveal previously unrecognized aspects of rRNA maturation. We demonstrate that early pre-rRNA processing is particularly sensitive to stress induced by environmentally relevant heavy metals. Surprisingly, our analysis shows that 5' and 3' end processing can be uncoupled in human cells, with 3' end cleavage occurring independently of 5' end processing. We further show that classical inducers of endoplasmic reticulum stress suppress ribosomal protein synthesis without inhibiting rRNA transcription, leading to an imbalance between these essential components of ribosome assembly. This imbalance may exacerbate cellular stress and compromise proteostasis. Together, our findings uncover stress-specific checkpoints in ribosome biogenesis that link environmental exposures to disrupted nucleolar function and highlight new layers of regulation in human rRNA maturation.
    DOI:  https://doi.org/10.1093/nar/gkag499
  21. Mol Cell. 2026 May 22. pii: S1097-2765(26)00271-6. [Epub ahead of print]
    In vivo single-cell ribosome profiling reveals cell-type-specific translational programs during aging.
    Clara Duré, Umesh Ghoshdastider, Ramona Weber, Ameya Khandekar, Fabiola Valdivia-Francia, Peter F Renz, Federica Sella, Katie Hyams, David Taborsky, Merve Yigit, Mark Ormiston, Homare Yamahachi, Mitchell Levesque, Stephanie J Ellis, Ataman Sendoel.
      Somatic stem cells are characterized by their low overall protein-synthesis rates, a feature implicated in driving their stemness. However, how aging reshapes the translational landscape of stem cells remains poorly understood. Here, we present an in vivo single-cell ribosome profiling strategy to monitor tissue-wide translational landscapes of the epidermis during aging. By implementing ribosomal elongation-inhibited cell isolation and switching to RNase I, we expand the applicability of single-cell ribosome profiling to in vivo systems and facilitate the evaluation of triplet periodicity, a hallmark of high-quality data. Leveraging this strategy, we document the in vivo translational landscapes of the major epidermal cell types, outline cell-type-specific translational efficiencies, and identify a pronounced translational reprogramming of AP-1 subunits specifically in aged epidermal stem cells. Our study illustrates the power of in vivo single-cell ribosome profiling to map cell-type-specific translational programs and offers a scalable strategy for tissue-wide interrogation of translational landscapes.
    Keywords:  AP-1; aging; epidermis; mRNA translation; ribosome profiling; single-cell biology; translational control
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.017
  22. J Cell Biol. 2026 Jul 06. pii: e202509040. [Epub ahead of print]225(7):
    Arl8b inactivates the Rab11a recycling pathway to promote LAMP1 sorting and lysosome biogenesis.
    Priya Chouhan, Yogita Phogat, Kshitiz Walia, Saikat Debnath, Sandeep Choubey, Medha Gupta, Amit Tuli, Mahak Sharma.
      The small GTP-binding protein Arl8b is established as a regulator of lysosome positioning and fusion, yet its role in lysosome biogenesis remains unclear. Here, we investigate the role of Arl8b in the trafficking of newly synthesized LAMP1 to lysosomes using the Retention Using Selective Hook (RUSH) assay. We find that Arl8b localizes to post-endocytic LAMP1-containing vesicles prior to fusion with acidic lysosomes. Arl8b depletion leads to Rab11a-dependent recycling of LAMP1 to the plasma membrane, impairing its lysosomal delivery. Mechanistically, Arl8b recruits the Rab11a GAP, TBC1D9B, to LAMP1-positive membranes, and TBC1D9B depletion similarly disrupts LAMP1 sorting. Notably, TBC1D9B knockdown also impairs the retrieval of cation-independent mannose-6-phosphate receptor (CI-M6PR) from Rab11a- and Rab14-positive endosomes to the trans-Golgi network, impairing pro-cathepsin trafficking and cargo degradation. These findings reveal that Arl8b-mediated recruitment of Rab GAP TBC1D9B is crucial for inactivation of the Rab11a recycling pathway, leading to efficient sorting of lysosomal cargo to their functional location.
    DOI:  https://doi.org/10.1083/jcb.202509040
  23. Protein Sci. 2026 Jun;35(6): e70622
    The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
    Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.
      Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.
    Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system
    DOI:  https://doi.org/10.1002/pro.70622
  24. Chem Rev. 2026 May 18.
    The Shape of Things to Come: α-Helical Membrane Protein Folding on the Ribosome.
    Edward Lambden, Benjamin Russell Lewis, Zadie L R Baker, Marvin V Dilworth, Erin C Johnston, Juan Palacios-Ortega, Kaylee Patel, Colin P Pilkington, Heather E Findlay, Paula J Booth, Grant A Pellowe.
      Understanding how membrane proteins insert into and fold within cell membranes is critical for explaining the molecular basis of many diseases. It also underpins advances in biotechnology, including the development of therapies for protein misfolding disorders and improved methods for producing membrane proteins at high yield. In cells, nearly all α-helical membrane proteins are synthesized and inserted cotranslationally, folding sequentially as they emerge from the ribosome. This process occurs under spatial constraints imposed by the translational machinery and in membranes with complex physicochemical properties. These processes are vastly different from classical in vitro refolding studies of full-length purified proteins, highlighting a critical need to alter our experimental approach to understand de novo membrane protein folding. The mechanisms driving membrane protein folding remain elusive, largely due to the limited availability of approaches that can probe these processes both in real-time and in their native context. Here, we discuss recent progress in uncovering how membrane proteins fold during synthesis and insertion, and highlight how established and emerging biophysical and structural tools are beginning to resolve cotranslational events with greater mechanistic detail than has been previously possible. Together, these advances are reshaping our understanding of membrane protein biogenesis far beyond traditional refolding models.
    DOI:  https://doi.org/10.1021/acs.chemrev.6c00236
  25. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2604562123
    A functional map of the human intrinsically disordered proteome.
    Iva Pritišanac, T Reid Alderson, Đesika Kolarić, Taraneh Zarin, Shuting Xie, Alex Lu, Aqsa Alam, Abdullah Maqsood, Ji-Young Youn, Julie D Forman-Kay, Alan M Moses.
      Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy the established structure-function paradigm. Because IDRs often have limited positional sequence conservation, the functional classification of IDRs using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features of IDRs enable clustering of the human disordered proteome (IDRome) into a map with strong functional enrichments. We quantify how conserved IDR features correlate with functional terms and, for a subset of terms, provide proteome-wide predictions of annotations for IDRs. Further, we show that conserved features of IDRs can predict protein localization to different biomolecular condensates and underlie elevated intracluster connectivity in condensate-associated IDRs, as well as enrich for short-linear motif-binding domains among interaction partners. We highlight patterns of conservation in disordered proteins with unknown function and in clusters enriched for proteins encoded by disease-risk genes. Our map of the human IDR-ome should be a valuable resource that aids in the discovery of new IDR biology.
    Keywords:  biomolecular condensates; interaction networks; intrinsically disordered proteins; molecular features; protein functional prediction
    DOI:  https://doi.org/10.1073/pnas.2604562123
  26. Mol Cell Biochem. 2026 May 21.
    Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
    Ângela Oliveira, Liliana M Almeida, Jorge M A Oliveira, Brígida R Pinho.
      Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.
    Keywords:  Aggregation; Huntingtin; Huntington’s disease; Integrated stress response; Metabolism; Mitochondrial pyruvate carrier
    DOI:  https://doi.org/10.1007/s11010-026-05573-3
  27. Mol Cell. 2026 May 21. pii: S1097-2765(26)00276-5. [Epub ahead of print]
    Alphaviral non-structural protein-host RBP co-condensation as a mechanism to sustain virus replication.
    Yi Liu, Zhiying Yao, Yun Zhang, Zhenshuo Zhu, Ziqiu Wang, Qi Chen, Zemin Yang, Yexuan He, Xiaoxin Chen, Le Tian, Jiang Du, Jinjun Wu, Hong Joo Kim, Jing Huang, Yongdeng Zhang, Weirui Ma, Wenchun Fan, J Paul Taylor, Peiguo Yang.
      It has long been recognized that the intracellular replication of alphaviruses critically relies on several key host RNA-binding proteins (RBPs), including G3BP1/2 and FXR1/FXR2/FMR1. But how these RBPs modulate alphaviral replication, and whether it would be possible to target them for antiviral treatment, is less explored. Here, using Semliki Forest virus (SFV) as a model, we report that SFV non-structural protein 3 (nsP3) exploits G3BP to drive its condensation and transforms antiviral stress granules into proviral nsP3-G3BP co-condensates. The gel-like co-condensates enrich and protect viral genomic RNAs from host RNase degradation and promote viral translation and replication. nsP3-RBP co-condensation is widespread among alphaviruses, and condensate disruption is a plausible antiviral approach. Thus, these findings uncover a general anti-alphavirus strategy based on the conserved reliance of virus-host protein co-condensation.
    Keywords:  antiviral; biomolecular condensates; phase separation; stress granule; virus-host interaction
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.022
  28. J Cell Biol. 2026 Jul 06. pii: e202506032. [Epub ahead of print]225(7):
    Light-based modulation of astrocytic calcium for regulation of organelle dynamics and morphogenesis.
    Lan Yang, Mikael Björklund, Cong Yi, Shue Chen, Zhi Hong.
      Astrocytes are essential for neuronal homeostasis, and synaptic modulation and development. While astrocytes exhibit distinct Ca2+ signaling patterns, decoding their physiological roles remains challenging because conventional approaches generate nonphysiological, spatially imprecise Ca2+ surges that obscure endogenous signals. Here, we developed a tunable light-based tool to modulate astrocytic Ca2+ activity, mimicking localized spikes and global waves elicited by graded glutamate through endogenous mGluR-Gq-IP3R signaling. IP3R triple knockout abolished light-evoked Ca2+ elevations, indicating elevated Ca2+ requires ER-IP3Rs. Using this modulation platform, we found that local Ca2+ spikes enhance organelle entry into astrocytic processes, whereas global Ca2+ waves arrest organelle movement. FKBP-FRB motor recruitment assays showed that global Ca2+ elevations acutely suppress motor-driven transport when cargo adaptors are bypassed. Combining our method with astrocyte process outgrowth analysis showed that Ca2+-dependent distal organelle accumulation promotes process elongation. Together, this light-based strategy provides a versatile platform for eliciting endogenous-like astrocytic Ca2+ patterns and reveals how distinct Ca2+ patterns differentially control organelle dynamics and astrocytic structural remodeling.
    DOI:  https://doi.org/10.1083/jcb.202506032
  29. bioRxiv. 2026 May 05. pii: 2026.05.01.722286. [Epub ahead of print]
    Npl4 decodes polyubiquitin length and gates D1-D2 coupling in human VCP/p97.
    Laxmikanta Khamari, Jingxuan Tang, Stephanie L Moon, Nils G Walter.
      VCP/p97 binds the Npl4 - Ufd1 heterodimer adaptor to extract polyubiquitinated substrates for proteasomal degradation, but how it decodes K48-linked chain length and how D1-coupled events license downstream D2 power strokes remain unclear. Here we introduce smUbiRAD, or single-molecule ubiquitin recognition and dynamics, and identify a sharp chain-length threshold: Npl4 binds transiently to short chains but switches to long-lived, multivalent engagement on tetra- and penta-ubiquitin. Ufd1 and p97 further stabilize these complexes mainly by suppressing Npl4 dissociation without affecting initial encounter. In fully assembled p97-Ufd1-Npl4-substrate complexes, D1 ATP hydrolysis-rather than D2-drives rapid Npl4 exchange. These results support a model in which D1-powered conformational changes promote cofactor Npl4, but not Ufd1, turnover and gate iterative coupling to downstream D2-driven substrate processing. Finally, we show that multisystem proteinopathy variants R155H and A232E bias p97 toward a high-affinity resting state and accelerate Npl4 exchange, implicating hyperactive cofactor cycling as a disease-linked dysregulation.
    DOI:  https://doi.org/10.64898/2026.05.01.722286
  30. Angew Chem Int Ed Engl. 2026 May 18. e3518516
    A Scalable, Direct-to-Biology Platform for Accelerated Discovery of Cereblon-Based Molecular Glue Degraders.
    Jia-Yu Wang, Guang-Liang Yin, Yijia Chi, Yuan-Peng Feng, Chu-Cheng Zhou, Hui-Jun Nie, Zhi-Gao Zhang, Shuting Meng, Yang Chen, Zhi-Peng Zhou, Jia-Yu Zhang, An Xu, Ye-Kai Xu, Linhui Zhai, Minjia Tan, Dongxin Zhao, Xiao-Hua Chen.
      Molecular glue degraders (MGDs) offer transformative potential for expanding the druggable proteome; however, their discovery is severely impeded by mechanistic complexities that hinder rational design and synthetic bottlenecks that restrict the scale and diversity of E3 ligase-centric compound libraries. Here, we introduce a general framework that transforms MGD discovery from a serendipity-driven endeavor into a systematic, scalable pipeline by integrating modular, in situ library assembly with direct-to-biology phenotypic screening. Powered by biocompatible primary amine-based photoclick chemistry, this platform enables the efficient, purification-free generation of over 1000 structurally diverse cereblon (CRBN)-centric molecules within days directly in multi-well plates, facilitating a seamless transition from chemical synthesis to biological evaluation. Applying this strategy, we rapidly identified novel CRBN-based MGDs that potently and selectively degrade GSPT1 or CK1α, as well as a multi-target degrader of GSPT1/2 and stearoyl-CoA desaturase (SCD). Crucially, our integrated validation highlights targeted CK1α degradation as a promising therapeutic strategy for prostate cancer. By leveraging the abundance and structural diversity of primary amines, this scalable platform expands the accessible chemical space, circumventing the complexities of de novo rational design. Ultimately, this work provides a streamlined engine for harnessing diverse E3 ligases, accelerating the development of next-generation MGDs to tackle intractable diseases.
    Keywords:  direct‐to‐biology phenotypic screening; modular assembly; molecular glue degrader; photoclick chemistry; targeted protein degradation
    DOI:  https://doi.org/10.1002/anie.3518516
  31. Autophagy. 2026 May 18.
    Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.
    Yu B Ko, Minjeong Ko, Marius Ueffing, Hye Jin Kang, Ho Jeong Kwon.
      Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for degradation. VCP overexpression supports cancer cell survival and correlates with poor prognosis, promoting the development of VCP inhibitors as anti-cancer agents. However, the molecular basis for cancer-selective vulnerability of VCP inhibition remains unclear. Here, we demonstrate that allosteric VCP inhibition triggers cell- type specific macroautophagy/autophagy through dynamic reorganization of organelle contact sites. In human umbilical vein endothelial cells (HUVECs), VCP inhibition induces adaptive autophagy through coordinated reorganization of plasma membrane (PM)-ER-mitochondria contacts. Controlled opening of the mitochondrial permeability transition pore (mPTP) releases calcium into the cytosol, activating AMP-activated protein kinase (AMPK) and TFEB pathways, collectively enhancing autophagic flux and sustaining endothelial survival. Critically, calcium-activated kinase inhibitor or calcium chelators blocked VCP inhibitor-induced autophagy in HUVECs, confirming calcium signaling as the central mediator of adaptive autophagy. In contrast, HCT116 colon cancer cells fail to maintain calcium homeostasis under VCP inhibition, leading to mitochondrial calcium overload, defective autophagy, and cell death. Together, our findings identify organelle contact reorganization and calcium homeostasis as key determinants of cell fate under conditions of proteotoxic stress, revealing how VCP inhibition selectively suppresses tumor progression while preserving vascular integrity that could enhance drug delivery and reduce tumor hypoxia.
    Keywords:  Autophagy; VCP/p97 inhibition; calcium signaling; cancer selectivity; organelle contact reorganization; proteostatic stress
    DOI:  https://doi.org/10.1080/15548627.2026.2677184
  32. J Am Chem Soc. 2026 May 20.
    Intermolecular β-sheet Formation Guides the Interaction between Ubiquitin-like Modifier FAT10 and Adapter Protein NUB1L.
    Charlotte Weiss, Sarah Overall, Nicola Catone, Alexander B Barnes, Annette Aichem, Guinevere Mathies.
      Under inflammatory conditions, the ubiquitin-like modifier FAT10 targets proteins for rapid and irreversible degradation by the 26S proteasome. FAT10 is degraded along with its substrates and in this process, the loose folding of FAT10 and adapter protein NUB1L have long been suspected to play crucial roles. We report here the investigation of the N-domain of FAT10 and its interaction with NUB1L by magic-angle spinning (MAS) NMR spectroscopy. A stretch of residues that is intrinsically disordered when the N-domain of FAT10 is in its ubiquitin-like β-grasp fold, becomes part of a regularly structured loop and an intermolecular β-sheet upon binding to NUB1L. The rest of the N-domain is now disordered, with exception of a series of anchor residues and the N-terminus. We propose that, in preparation of degradation by the proteasome, NUB1L stabilizes N-FAT10 in an unfolded state, acting as a holdase. The ability of FAT10 to interact in folded as well as unfolded form is essential for its role in inflammation-linked proteostasis.
    DOI:  https://doi.org/10.1021/jacs.6c05291
  33. Mol Cancer. 2026 May 21.
    Increased mRNA translation delays tumour initiation and exposes a therapeutic vulnerability in lung cancer.
    Luis Pardo, Madeleine Moore, Ruhi Deshmukh, Ian Powley, Joseph A Waldron, Bjorn Kruspig, Lynn McGarry, Lobsang Dolma, America V Campos, Colin Wood, Holly Leslie, Mark Hughes, Emanuel Jeldes, June Munro, Louise Mitchell, Leah Officer-Jones, Rachel Baird, Hugo Coquelet, Nigel B Jamieson, David Sumpton, Douglas Strathdee, John le Quesne, Martin Bushell, Daniel J Murphy, Jim C Norman.
       BACKGROUND: Although inhibitors of mRNA translation are being evaluated as anti-cancer agents, the dynamics of protein synthesis throughout tumour progression are still poorly understood. Here we assess how alterations in mRNA translation during early tumorigenesis affect tumour development in KRAS-driven lung adenocarcinoma (LuAd).
    METHODS: We deployed autochthonous mouse models of LuAd driven by oncogenic KRASG12D combined with moderate overexpression of MYC and simultaneously manipulated mRNA translation by deleting the mRNA helicases eIF4A1 and eIF4A2 or by administering pharmacological inhibitors of protein synthesis, such as rapamycin. This permits synchronous assessment of LuAd initiation and progression in vivo and is amenable to parallel ex vivo culture of tumour-derived cells for detailed analysis of protein synthesis (using ribosome footprinting) and metabolic landscapes. These approaches also allowed us to perform multiplex imaging and spatial transcriptomics to characterise tumour formation in altered mRNA translation conditions and to compare results obtained in mice against the Lattice-A cohort of non-small cell lung cancer (NSCLC) patients.
    RESULTS: Deletion of the mRNA-translation repressor, eIF4A2 in KRAS-driven LuAd leads to a dysregulated protein synthesis landscape characterised by a strongly upregulated secretome, enlarged secretory compartments, increased oxidative metabolism and acquisition of senescence-like characteristics. Paradoxically, this overdriven secretory protein synthesis landscape delays tumorigenesis and leads to the appearance of clusters of non-proliferative, p21-positive KRASG12D-expressing cells in the lung. Consistently, reduction of mRNA translation with rapamycin in Eif4a2-deleted tumours suppresses senescence and restores tumorigenesis. Importantly, some Eif4a2 knockout cells overcome senescence to form tumours that exhibit enhanced MAP-kinase signalling and, in contrast to eIF4A2+/+ lesions, these were eradicated by administration of a MEK inhibitor. Consistently, MAP-kinase signalling was significantly increased in human NSCLC expressing low levels of eIF4A2.
    CONCLUSIONS: Our study highlights that restraint of mRNA translation by eIF4A2 is critical in the early-stages of KRAS-driven LuAd to allow bypass of oncogene-induced senescence and tumour progression. Importantly, because tumours with dysregulated mRNA translation rely heavily on MAP-kinase signalling they are exquisitely sensitive to MEK inhibition, and this indicates the possibility that low expression of eIF4A2 could be used to identify potential responders to MEK inhibitors in clinical trials.
    Keywords:  KRAS; Lung adenocarcinoma; Metabolism; Oncogene-induced senescence; Rapamycin; Trametinib; eIF4A; mRNA translation
    DOI:  https://doi.org/10.1186/s12943-026-02680-z
  34. bioRxiv. 2026 May 05. pii: 2026.04.30.721908. [Epub ahead of print]
    ANYI: The ANnotated Yeast Interactome.
    Daniel A Nissley, Muskan Goel, Xavier Castellanos-Girouard, Charles P Kuntz, Yiqing Wang, M Shahid Mukhtar, Adrian Serohijos, Jonathan P Schlebach.
      Although several existing protein-protein interaction (PPI) databases provide yeast PPI data, none unify large-scale network topology information with detailed biophysical, proteostasis, and regulatory annotations in a single protein-centric framework. To address this gap, we developed the ANnotated Yeast Interactome (ANYI), an open, integrated resource that combines experimental yeast PPIs with sixteen feature annotation types, including protein abundance, half-life, disorder content, post-translational modifications, conformational stability, chaperone interactions, sequence, and structure. ANYI integrates 3,927 proteins with 155 annotation features, forming a unified matrix that enables systematic cross-layer analyses. Available via GitHub and Docker Hub with an interactive network browser for broad accessibility, ANYI provides both experienced and beginner computational scientists with tools to investigate the yeast interactome. For example, users can directly test whether highly connected hub proteins exhibit distinct stability, disorder, or proteostasis signatures relative to peripheral nodes.
    AVAILABILITY AND IMPLEMENTATION: The code used to assemble ANYI is available on GitHub at https://github.com/NCEMS/energetic-origins-of-PPI-connectivity and the database itself and interactive browser tool are available on Docker Hub as dannissleypsu/anyi-browser:v1.0.2.
    DOI:  https://doi.org/10.64898/2026.04.30.721908
  35. Nature. 2026 May 21.
    De novo design of miniproteins targeting GPCRs.
    Edin Muratspahić, David Feldman, David E Kim, Xiangli Qu, Ana-Maria Bratovianu, Paula Rivera-Sánchez, Jan Hendrik Voss, Emil P T Hertz, Mads Jeppesen, Federica Dimitri, Kensuke Sakamoto, Amrita Nallathambi, Pia Peceli, Jianjun Cao, Brian P Cary, Matthew J Belousoff, Peter Keov, Phuc N H Trinh, Qingchao Chen, Yue Ren, Justyn Fine, Sudha Mishra, Annu Dalal, Shachie Sinha, Ramanuj Banerjee, Manisankar Ganguly, Karthik Varappalayam Karuppusamy, Isaac Sappington, Thomas Schlichthaerle, Jason Z Zhang, Arvind Pillai, Brian Coventry, Ljubica Mihaljević, Magnus Bauer, Susana Vázquez Torres, Amir Motmaen, Gyu Rie Lee, Long Tran, Xinru Wang, Inna Goreshnik, Dionne K Vafeados, Justin E Svendsen, Parisa Hosseinzadeh, Nicolai Lindegaard, Matthäus Brandt, Yann Waltenspühl, Kristine Deibler, Lukas Deweid, Anja Bennett, Jendrik Schöppe, Tiantang Dong, Xiaoli Yan, Luke Oostdyk, William Cao, Lakshmi Anantharaman, Johan J Weisser, Jesper Frank Bastlund, Christoffer Bundgaard, Ayodeji A Asuni, Justin G English, Lance Stewart, Lauren Halloran, Jamie B Spangler, André Lieber, Arun K Shukla, Patrick M Sexton, Bryan L Roth, Brian E Krumm, Denise Wootten, Christopher G Tate, Christoffer Norn, David Baker.
      G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development1,2, but the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic3-6. Here we describe computational de novo design methods and a high-throughput "receptor diversion" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity. We design miniprotein agonists that activate receptors involved in itch and pain, as well as antagonists that inhibit receptors implicated in cancer, metabolic disorders such as diabetes and obesity, and migraine. Cryo-electron microscopy (cryo-EM) structures of five receptor-bound designs are close to the computational design models. A designed chemokine receptor antagonist mobilizes hematopoietic stem and progenitor cells in vivo at a level comparable to a clinically used drug, with fewer adverse effects.
    DOI:  https://doi.org/10.1038/s41586-026-10656-8
  36. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2536912123
    A mechanism for substrate quality control in outer membrane protein assembly.
    Ashton N Combs, Anna Konovalova, Thomas J Silhavy.
      The assembly of β-barrel proteins into the outer membrane (OM) of Gram-negative bacteria is catalyzed by the β-barrel assembly machine (Bam) complex, which consists of two essential proteins, the BamA β-barrel and the lipoprotein BamD, and three nonessential lipoproteins BamBCE. While it is well established that BamD serves an essential role in regulating the activity of BamA, the physiological reasons underpinning the need for BamD-mediated regulation of β-barrel assembly are unclear. Here, we demonstrate that BamD-mediated regulation of BamA functions as a mechanism of substrate quality control that ensures the efficient assembly of β-barrel proteins into the OM. Through the use of substrate C-terminal fragments and multiple alleles of bamA and bamD that prevent effective regulation of BamA by BamD, we show that BamD activity is necessary to prevent the accumulation of defective β-barrel substrates on BamA. Notably, these bamAD alleles all confer resistance to the Bam complex inhibitor MRL-494 in a manner that correlates with the degree to which BamD activity is bypassed, suggesting that MRL-494 inhibits β-barrel assembly by disrupting BamD-mediated conformational changes in BamA. We further show that BamD activity functions to prevent the uptake of toxic small molecules across the OM through a mechanism that functionally overlaps with that of the substrate quality control protein Skp. Collectively, these results not only establish that BamD, like Skp, functions to ensure proper quality control of β-barrel substrates but also demonstrate the importance of substrate quality control functions in maintaining the integrity of the OM permeability barrier.
    Keywords:  Bam complex; gram-negative bacteria; outer membrane proteins; protein folding; protein quality control
    DOI:  https://doi.org/10.1073/pnas.2536912123
  37. Nat Metab. 2026 May 18.
    Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
    Annamaria Regina, Francesca Solagna, Malkon Sanchez Estrada, Maaike M E Jacobs, Daniel Martinez-Martinez, Theodoros Georgomanolis, Irma Alibashikj, Sara Gjurgji, Claire Pearson, Dehui Chang, Chrysanthi Moschandrea, Ana Sagrera Aparisi, Elena Crespo, Jessica Buechel, Farina Schneider, Lea Trojahn, Paulina Pfelzer, Milica Popovic, Elena Potenza, Agnieszka M Kabat, Carien Niessen, Borko Amulic, Niloufar Safinia, Sara Cogliati, David E Sanin, Matteo Villa, Edward J Pearce, Christian Frezza, Erika L Pearce, Filipe Cabreiro, Fiona Powrie, Mauro Corrado.
      Loss of host-microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (Treg) cells to preserve gut-immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired Treg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs Treg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut-immune homeostasis and dictates outcome in pathobiont infections.
    DOI:  https://doi.org/10.1038/s42255-026-01533-9
  38. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2524201123
    ProteomeLM: A proteome-scale language model enables accurate and rapid prediction of protein-protein interactions and gene essentiality across taxa.
    Cyril Malbranke, Gionata Paolo Zalaffi, Anne-Florence Bitbol.
      Language models trained on biological sequences are advancing inference tasks from the scale of single proteins to that of genomic neighborhoods. Here, we introduce ProteomeLM, a transformer-based language model that uniquely operates on entire proteomes from species spanning the tree of life. ProteomeLM is trained to reconstruct masked protein embeddings using the whole proteomic context, yielding contextualized protein representations that reflect proteome-scale functional constraints. Notably, ProteomeLM's attention coefficients encode protein-protein interactions (PPI), despite being trained without interaction labels. Furthermore, it enables interactome-wide PPI screening that is substantially more accurate, and orders of magnitude faster, than amino acid coevolution-based methods. We further develop ProteomeLM-PPI, a supervised model that combines ProteomeLM embeddings and attention coefficients to achieve state-of-the-art PPI prediction across benchmarks and species. Finally, we introduce ProteomeLM-Ess, a supervised gene essentiality predictor that generalizes across diverse taxa. Our results demonstrate the potential of proteome-scale language models for addressing function and interactions at the organism level.
    Keywords:  biological language models; coevolution; gene essentiality; protein sequences; protein–protein interactions
    DOI:  https://doi.org/10.1073/pnas.2524201123
  39. EMBO J. 2026 May 20.
    Atg18 interaction positions Atg2 for efficient lipid transfer into phagophore elongation.
    Sabrina Chumpen Ramirez, Dmitry Shvarev, Prado Vargas Duarte, Yara Ahmed, Jana Milach, Emma Lang, Stefan Kuchenbuch, Stefano Vanni, Fulvio Reggiori, Arne Moeller, Christian Ungermann.
      During macroautophagy, the de novo formation of the autophagosome at a membrane contact site (MCS) with the endoplasmic reticulum requires directional lipid flux for the growth of the initial phagophore before its sealing into an autophagosome and subsequent fusion with the lysosome/vacuole. It remains unclear, however, how the formation of this specialized MCS and the directionality of the lipid flux are controlled. Here, we present the structure of the key lipid transfer protein Atg2 from yeast solved together with its Atg18 binding partner, a phosphatidylinositol-3-phosphate (PtdIns3P) effector, using cryo-electron microscopy. We reveal a new interface in Atg2 that, together with PtdIns3P, is required for Atg18 recruitment and lipid transfer activity. Furthermore, we visualize lipid densities along the internal hydrophobic cavity of Atg2, providing structural evidence that Atg2 cavity is filled with lipids throughout the entire length, even when Atg2 is cytosolic. Finally, molecular dynamics simulations show that the complex generates membrane curvature, efficiently positioning the lipid channel of Atg2 towards the membrane to promote lipid transfer into the elongating phagophore.
    DOI:  https://doi.org/10.1038/s44318-026-00802-3
  40. EMBO J. 2026 May 21.
    20S proteasome-regulated proteostasis in ELVAs is critical for oocyte-to-embryo transition and female fertility.
    Yan Rong, Yingyan Chen, Huiwen Cao, Chengkan Liu, Haomang Xu, Xiaomei Tong, Anxuan Fang, Leilei Ai, Yucong Zhu, Yingyi Zhang, Peipei Ren, Xiaoxuan Li, Yufan Gao, Xiaolin Tian, Lugeng He, Songying Zhang, Chao Yu.
      Programmed degradation of maternal proteins is essential for the oocyte-to-embryo transition (OET). While pharmacological inhibition studies have established the importance of proteasomes in ovarian reserve maintenance, oocyte maturation and fertilization, the physiological impact of intrinsic proteasome insufficiency and underlying molecular mechanisms remain poorly understood. In mice, endolysosomal vesicular assemblies (ELVAs), specialized membraneless compartments composed of proteasomes, endolysosomes and autophagosomes, facilitate protein degradation during oocyte maturation and early embryogenesis. In this study, we generated mice with oocyte-specific deletion of the proteasomal core subunit Psma7, to investigate the physiological function of the 20S proteasome and its roles in ELVAs-mediated protein degradation. PSMA7-deficiency destabilized 20S proteasomes and disrupted translocation of ELVAs, leading to pronounced accumulation of ubiquitinated proteins in oocytes and zygotes. Consequently, maternal Psma7 deletion resulted in female infertility, manifested by impaired oocyte maturation and developmental arrest at one- to two-cell stage. Furthermore, we observed reduced proteasome abundance and dysfunction of ELVAs in aged oocytes, providing a mechanistic explanation for the decline in developmental competence associated with oocyte aging. Taken together, our findings elucidate the critical function of proteasome-regulated proteostasis within ELVAs in maintaining oocyte quality during OET and reproductive aging.
    DOI:  https://doi.org/10.1038/s44318-026-00813-0
  41. PLoS Biol. 2026 May;24(5): e3003790
    The Pseudomonas aeruginosa ribonuclease Ribocin cleaves eukaryotic ribosomes at helix 69 to inhibit host translation.
    Alejandro Vasquez-Rifo, Denis Susorov, Emily H Sholi, Gabriel Demo, Yasaman Jami, Jihui Sha, James A Wohlschlegel, Andrei Korostelev, Victor Ambros.
      Pseudomonas aeruginosa employs host translation inhibition as a virulence-enhancing strategy. We previously showed that the bacterium induces cleavage of Caenorhabditis elegans large ribosomal RNA at helix 69 (H69), part of a central intersubunit bridge and the ribosomal decoding center. In this study, we demonstrate that a previously uncharacterized ribonuclease, Ribocin, is necessary and sufficient for H69 cleavage. Recombinant Ribocin cuts H69 in worm and mammalian ribosomes, indicating that H69 cleavage by P. aeruginosa is phylogenetically conserved. In worms, mammalian cells, and rabbit reticulocyte lysates, H69 cleavage results in translation inhibition. Furthermore, Ribocin contributes to bacterial virulence toward C. elegans, triggers a major host response to translation inhibition, and operates in parallel with Exotoxin A-mediated translation inhibition. These findings unveil the first known nuclease that cleaves eukaryotic ribosomes at H69 and expand the understanding of host translation-inhibition by establishing targeted rRNA cleavage as a mechanism of host attack.
    DOI:  https://doi.org/10.1371/journal.pbio.3003790
  42. Nat Commun. 2026 May 21.
    DGAT: a dual-graph attention network for inferring spatial protein landscapes from transcriptomics.
    Haoyu Wang, Brittany Cody, Manuel Saavedra, Lanuza A P Faccioli, Rodrigo M Florentino, Alejandro Soto-Gutierrez, Hatice Ulku Osmanbeyoglu.
      Spatial transcriptomics (ST) technologies provide genome-wide transcriptomic profiles in tissue context but lack direct protein-level measurements, which are critical for interpreting cellular function and microenvironmental organization. To bridge this gap, we develop DGAT (Dual-Graph Attention Network), a deep learning framework that imputes spatial protein expression from ST data by learning RNA-protein relationships from spatial transcriptomic and proteomic datasets. The model constructs heterogeneous graphs integrating transcriptomic, proteomic, and spatial information, encoded using graph attention networks. Task-specific decoders reconstruct mRNA and predict protein abundance from a shared latent representation. Benchmarking across public and in-house datasets demonstrates that DGAT outperforms existing methods in protein imputation accuracy. Applied to ST datasets lacking protein measurements, the framework reveals spatially distinct cell states, immune phenotypes, and tissue architectures not evident from transcriptomics alone. Here, we show that this framework accurately reconstructs spatial protein landscapes, reveals biologically meaningful tissue organization, and enables protein-level interpretation from transcriptomics-only spatial data.
    DOI:  https://doi.org/10.1038/s41467-026-73114-z
  43. Mol Cell. 2026 May 21. pii: S1097-2765(26)00278-9. [Epub ahead of print]
    Nitric oxide drives proteomic diversity through alternative splicing.
    Joseph C Schindler, Puneet Seth, Alfred Hausladen, E Ricky Chan, Jun Yang, Jun Qin, Zhaoxia Qian, Divya Seth, Kathleen Lundberg, Joseph M Luna, Richard T Premont, Jonathan S Stamler.
      Redox signaling by nitric oxide (NO) is estimated to control a large part of the global proteome via S-nitrosylation (SNO-modification). Here, we report that RNA-binding proteins (RBPs) represent the most significantly enriched class of S-nitrosylation targets, with broad coverage of spliceosomal factors. We demonstrate that NO regulates alternative splicing (AS) and that S-nitrosylation of PTBP1, a central regulator of AS, can massively shift and contextually alter gene expression while further enriching the transcriptome for SNO sites. PTBP1 S-nitrosylation changes RNA-binding domain conformation, RNA motif recognition, protein-RNA and protein-protein interactions, and intracellular trafficking to impact pathways for viral infection and neurodegeneration. Levels of SNO-PTBP1 are reduced in mouse and human Alzheimer's disease brains and correlate with adverse clinical outcomes. Overall, SNO-RBPs are characterized by conservation across diverse lineages and SNO sites and provide a blueprint for redox regulation of both transcriptome and proteome in physiology and disease.
    Keywords:  CLIP-seq; PTBP1; RNA-binding proteins; S-nitrosylation; alternative splicing; gasotransmitter; nitric oxide; redox signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.024
  44. Nat Commun. 2026 05 18. pii: 4202. [Epub ahead of print]17(1):
    Diverse mechanisms of translation arrest by a Clostridia ribosome stalling peptide CliM.
    Mayu Yoshida, Felix Gersteuer, Ole Berendes, Keigo Fujiwara, Haaris A Safdari, Helge Paternoga, Hiraku Takada, Nozomu Obana, Helmut Grubmüller, Lars V Bock, Daniel N Wilson, Shinobu Chiba.
      Ribosome arrest peptides undergo programmed translational stalling in response to changes in the cellular environment to feedback-regulate gene expression. CliM, an arrest peptide in Clostridia, is encoded upstream of the YidC membrane protein insertase gene, but its function and mechanism remain unclear. Here we show that CliM monitors YidC activity to maintain adequate cellular YidC capacity. Interestingly, Clostridium kluyveri CliM induces elongation arrest at multiple sense codons, whereas Clostridioides difficile CliM causes termination arrest. Cryo-EM-based structural and mutational analyses demonstrate that C. difficile CliM adopts multiple α-helices within the nascent polypeptide exit tunnel, where it forms extensive arrest-essential interactions with the ribosome. The residue immediately N-terminal to the stalling site contributes to arrest by sterically interfering with full accommodation of the release factor or aminoacyl-tRNA in the A-site. Molecular dynamics simulations suggest that membrane insertion of CliM induces sequential unwinding of these α-helical structures and relocation of the penultimate residue, thereby triggering arrest release. These findings provide a unified mechanistic framework that explains the distinct arrest behaviors of CliM homologs.
    DOI:  https://doi.org/10.1038/s41467-026-72673-5
  45. Proc Natl Acad Sci U S A. 2026 May 26. 123(21): e2528760123
    Light-controlled disruption of cancer cell dormancy via photoswitchable stress hormone receptor degraders.
    Karina M Freitag, Robin Scheuplein, Chiara Orlacchio, Viola Ansuinelli, Tommaso Fava, Vincent Fischer, Bohan Zhang, Miriam Kretschmer, Mahshid Gazorpak, Erick M Carreira, Katharina Gapp.
      Cancer cell dormancy is a key contributor to therapy resistance and disease relapse. The glucocorticoid receptor (GR), a major mediator of stress hormone signaling, has emerged as a central regulator of dormancy in non-lymphoid solid tumors, particularly lung cancer. However, systemic GR inhibition or degradation using conventional Proteolysis Targeting Chimeras (PROTACs) risks widespread on-target toxicity due to their constitutive activity. We hypothesized that integrating photoswitchable elements into PROTACs, termed photoPROTACs, would enable wavelength-specific, spatiotemporally precise modulation of GR degradation and dormancy-associated signaling pathways. Here, we synthesized a diverse series of photoPROTACs incorporating photoswitchable arylazotriazole or arylazopyrazole scaffolds, including previously unreported (OEt)2- and (NMe2)2-substituted photoswitches. Arylazopyrazole-based GR photoPROTACs bearing Me2- and (OEt)2 substituents exhibited near-quantitative photoisomerization (95% Z-isomer; 89 to 92% E-isomer), no photobleaching, and thermal half-lives in the range of 3 to 12.2 d in dimethyl sulfoxide (DMSO). Among them, KH-5-306 and KH-5-309 induced potent, specific, and reversible GR degradation in their thermodynamically stable E-isomeric form at low nanomolar concentrations, with markedly reduced activity in the Z-isomeric state. Transcriptomic profiling showed that E-KH-5-309 disrupts GR-driven dormancy-associated gene expression programs in a non-small cell lung cancer (NSCLC) model, while the Z-isomer remains functionally inert. Our findings establish a framework for the rational design of photoswitchable PROTACs beyond GR and demonstrate their potential to achieve spatiotemporal control of stress hormone receptor signaling, enabling mechanistic insights into GR function and the targeted disruption of cancer cell dormancy.
    Keywords:  PROTAC; cancer cell dormancy; photopharmacology; stress hormone signaling
    DOI:  https://doi.org/10.1073/pnas.2528760123
  46. Cell Rep Med. 2026 May 21. pii: S2666-3791(26)00246-6. [Epub ahead of print] 102829
    The proteomics and phosphoproteomics landscape of melanoma under T cell attack.
    Giulia Franciosa, Agnete W P Jensen, Ana Martinez-Val, Ilaria Piga, Marco Donia, Jesper V Olsen.
      Understanding how tumor cells interact with tumor-infiltrating lymphocytes (TILs) is crucial for improving immunotherapy, yet protein-level changes remain largely unexplored. To address this, we profile the early responses of patient-derived melanoma cells co-cultured with matched autologous TILs. To distinguish tumor from TIL proteomes without physical sorting, we apply stable isotope labeling by amino acids in cell culture (SILAC) coupled with Orbitrap Astral data-independent acquisition (DIA) mass spectrometry (MS). This approach enables cell type-specific profiling of protein phosphorylation and degradation, alongside bulk analysis of the early newly synthesized proteome during active immune attack. Our analyses resolve interferon-γ-dependent changes in melanoma cells, identify the cytotoxic and regulatory T cell molecule (CRTAM) as a selective marker of reactive TILs, and reveal rapid tumor-intrinsic activation of DNA damage response-associated kinases, exposing potential therapeutic vulnerabilities. Overall, this framework provides a powerful resource for dissecting tumor-immune interactions to guide biomarker discovery and advance immunotherapy.
    Keywords:  CRTAM; DNA-PK; TILs; cancer; cell signaling; immunotherapy; mass spectrometry; melanoma; phosphoproteomics; proteomics
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102829
  47. Cell Rep. 2026 May 21. pii: S2211-1247(26)00442-0. [Epub ahead of print]45(6): 117364
    Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.
    Michel Fricke, Anna Mechel, Lennart Evers, Björn Twellsieck, Jessica M Grein, Maria-Sol Cima-Omori, Mohammed Al-Azzani, Tiago F Outeiro, Markus Zweckstetter, Erika L F Holzbaur, C Alexander Boecker.
      Parkinson disease (PD)-associated mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. Here, we show that knockout of the LRRK2-counteracting RAB phosphatase PPM1H causes a gene-dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in PD pathophysiology. Defective autophagosome transport and impaired aSyn degradation correlate with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that is dependent on LRRK2 kinase activity. These findings mechanistically link LRRK2-mediated RAB hyperphosphorylation to defective autophagosomal degradation and enhanced aggregation of aSyn, positioning the LRRK2-RAB axis as a key driver of PD pathophysiology.
    Keywords:  CP: Cell biology; CP: Neuroscience; LRRK2; PPM1H; RAB GTPases; alpha-synuclein; autophagy; axonal transport
    DOI:  https://doi.org/10.1016/j.celrep.2026.117364
  48. Cardiovasc Toxicol. 2026 May 20. pii: 53. [Epub ahead of print]26(6):
    The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
    Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh.
      Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPRmt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPRmt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPRmt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPRmt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPRmt signaling, and suggest that activation of the UPRmt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.
    Keywords:  ATF5; CHOP; Cardiomyocytes; Cardiotoxicity; Doxorubicin; Mitochondria; UPRmt ; eIF2α
    DOI:  https://doi.org/10.1007/s12012-026-10124-9
  49. RSC Adv. 2026 May 18. 16(29): 26659-26668
    In silico design and binding mechanism of UBR1 E3 ligase recruiters.
    Miguel A Maria-Solano, Raudah Lazim, Sun Choi.
      Proteolysis Targeting Chimeric Molecules (PROTACs) represent a promising avenue in drug discovery, as they can induce the targeted degradation of disease-relevant proteins within the cellular machinery. These compounds comprise a ligand tailored to bind the specific targeted protein connected to a recruiter molecule that engages with the E3 ligase. Despite their promise as therapeutic agents, the clinical advancement of these compounds has encountered substantial challenges, primarily due to the limited availability of suitable E3 ligases. Additionally, cell permeability and proteolytic stability, due to their peptide nature, often hinder their application. In this study, we developed a computational framework to model recruiters for the E3 ligase UBR1. This widely expressed protein has recently been demonstrated to be efficient in driving the degradation of oncogenic proteins. Our computational approach leverages a fragment-based peptidomimetics strategy, integrating pharmacophore filtering, docking, and fragment-linking optimization. Finally, we subjected the wild-type peptide and the most promising combined fragments to advanced binding free energy calculations, unveiling insights into their dynamic water-mediated binding mechanisms and their potential as robust E3 ligase UBR1 recruiters. This computational workflow is applicable to model other related PROTACs.
    DOI:  https://doi.org/10.1039/d5ra04908c
  50. Cell Mol Life Sci. 2026 May 19. pii: 209. [Epub ahead of print]83(1):
    Ribosomal RNA processing undergoes surveillance by the mRNA guard protein Npl3.
    Anne-Sophie Lindemann, Fei Yu, Yawen Duan, Ivo Coban, Ulla-Maria Schneider, Jan-Philipp Lamping, Ali Khreiss, Katherine E Bohnsack, Heike Krebber.
      Ribosome production is an essential, but highly energy-demanding and complex cellular process. High-fidelity ribosome assembly is critical to ensure integrity of the proteome, and during their biogenesis, the pre-ribosomal subunits undergo surveillance so that defective complexes are removed. Currently, knowledge on the mechanisms of pre-ribosome quality control lag behind understanding of other RNA surveillance pathways. Interestingly, a family of "guard proteins" has been shown to monitor mRNA maturation in S. cerevisiae and act as maturation switches by either licensing ongoing biogenesis or, in case assembly defects are detected, recruiting components of the RNA degradation machinery. Here, we reveal association of the mRNA guard protein Npl3 with RNA polymerase I, the ribosomal DNA (rDNA) locus and early pre-ribosomal particles. Consistent with this, our data show that Npl3 is required for recruitment of a subset of ribosome assembly factors to the nascent pre-rRNA transcript, and we demonstrate a role for Npl3 in the turn-over of aberrant precursor ribosomal RNA (pre-rRNA). Aberrant pre-rRNAs polyadenylated by Trf5 are bound by Npl3, which in turn interacts with Air1 to recruit the RNA exosome for degradation. Thus, Npl3 is a multifunctional RNA surveillance factor, recognizing different types of aberrant pre-RNAs and promoting recruitment of the RNA degradation machinery to clear these transcripts.
    Keywords:  23S rRNA; ETS1; RDNA; RNA degradation; RNA exosome; RNA polymerase I; RNA quality control; RRNA maturation; RRNA processing; Ribosome biogenesis; TRAMP complex
    DOI:  https://doi.org/10.1007/s00018-026-06246-6
  51. J Biol Chem. 2026 May 15. pii: S0021-9258(26)02037-5. [Epub ahead of print] 113165
    Starvation-induced HSC70 O-GlcNAcylation activates chaperone-mediated autophagy.
    Ningda Xu, Xiangpeng Wang, Jiyue Zhang, Jianxin Zhao, Sheng Yan, Wen Zhou, Wei Chi, Jing Li.
      O-linked β-N-acetylglucosamine (O-GlcNAc) functions as a nutrition rheostat to mediate cellular signaling pathways. It fluctuates in response to various nutritional factors, for instance, glucose availability. Previous investigations have shown that glucose deprivation upregulates O-GlcNAcylation levels. Meanwhile, starvation also activates autophagy, in particular, chaperone-mediated autophagy (CMA). But it is unknown what signal activates CMA during starvation. In the CMA pathway, heat shock cognate 70 kDa protein (HSC70) recognizes client proteins that bear a KFERQ pentapeptide motif, and delivers them for lysosomal degradation. Herein we show that glucose depletion increases both the affinity between HSC70 and O-GlcNAc transferase (OGT), and HSC70 O-GlcNAcylation levels. We validated that HSC70 is O-GlcNAcylated at T430 according to a previous chemoproteomic screen. We further demonstrate that O-GlcNAcylation attenuates HSC70 stability, but increases its binding with known CMA substrates, such as PKM2. We thus posit that starvation-induced HSC70 O-GlcNAcylation may activate CMA. To test this, we used label-free quantitative mass spectrometry to analyze HSC70-WT and HSC70-T430A interactome, and obtained a proteome-wide potential CMA substrate pool. By studying this dataset, we identified a new CMA substrate, Ataxin-10, a protein involved in a neurologic disorder. We then validated our model by mapping a potential KFERQ motif on Ataxin-10 and showing that HSC70-T430A decreased binding with Ataxin-10. In sum, our work suggests that CMA and O-GlcNAcylation intersect at HSC70, and starvation-induced O-GlcNAcylation of HSC70 is part of the signal that activates CMA during fasting.
    Keywords:  Ataxin-10; HSC70; O-GlcNAc; chaperone-mediated autophagy; starvation
    DOI:  https://doi.org/10.1016/j.jbc.2026.113165
  52. Mol Cell. 2026 May 21. pii: S1097-2765(26)00277-7. [Epub ahead of print]
    Ribo-Tweezer: Rapid removal of ribosomal proteins reveals additional layers of post-transcriptional gene regulation.
    Yuxiang Chen, Ching Pin Cheng, Kitra Cates, Georgi K Marinov, Travis C Lantz, Haojun Yang, Isabelle Liu, Naomi R Genuth, Christina Andronescu, Victoria Hung, Abel Bermudez, Daphna Rothschild, Joseph Georgeson, Sonia Bustos Barocio, Anshul Kundaje, Sharon Pitteri, Davide Ruggero, Maria Barna.
      The ribosome is a ribozyme, but it also acts as a dynamic regulator of gene expression. Although ribosomal protein (RP) composition varies, dissecting the functional contributions of individual RPs beyond their housekeeping roles is challenging because of the lack of tools for manipulation in situ. Here, we developed Ribo-Tweezer, a degron-based system directly tethered to mature ribosomes that enables rapid, reversible, and selective depletion of specific RPs. Using Ribo-Tweezer in mouse embryonic stem cells (mESC), we find a previously uncharacterized role for RACK1 in stem cell fate control via translational regulation of zinc-finger transcriptional networks and long interspersed nuclear element-1 (LINE1) expression. This translation-transcription coupling provides a mechanism by which translation control is further amplified in gene regulation. Distinct translational programs induced by RPLP0 and RPLP1 depletion further demonstrate RP-specific regulatory functions in translation. Together, these findings establish Ribo-Tweezer as a powerful platform that has illuminated selective functions for RPs in gene regulation, which gives biological meaning to ribosome heterogeneity.
    Keywords:  LINE-1; P-stalk; Poly(A/U) leader; RACK1; mESC differentiation; ribosome; ribosome heterogeneity; translation control
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.023
  53. J Hepatol. 2026 May 21. pii: S0168-8278(26)00284-9. [Epub ahead of print]
    MARCHF6 orchestrates hepatic lipid homeostasis by targeting SREBP1 for ER-associated degradation.
    Yanan Xu, Tongpeng Yue, Uyanga Batbold, Assa Magassa, Kun Liu, Liping Jiang, Dechen Liu, Long Nguyen Hoang Do, Xiaolei Liu, Ling Yang, Jun Yu, Sheng Wu, Deyu Fang, Xiaofeng Yang, Hong Wang, Xiaoyu Zhang, Ling Leng, Juncheng Wei.
       BACKGROUND & AIMS: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing global health concern. Increased de novo lipogenesis (DNL), largely mediated by Sterol Regulatory Element-Binding Protein 1 (SREBP1), is a hallmark of MASLD. However, the post-translational mechanisms regulating SREBP1 turnover remain poorly understood. Endoplasmic reticulum-associated degradation (ERAD) pathway ensures protein quality and quantity control, yet its role in hepatic lipid metabolism remains elusive. Here, we investigate the function of the ERAD-specific E3 ubiquitin ligase MARCHF6 in hepatic lipid homeostasis and MASLD pathogenesis.
    METHODS: Liver-specific Marchf6 knockout (Marchf6Alb) mice cell lines and organoids were generated to assess the impact of Marchf6 depletion on hepatic lipid metabolism under normal chow, high-fat diet (HFD), and Western diet (WD) conditions. RNA sequencing, proteomics, biochemical and molecular biological analyses were performed to identify molecular pathways regulated by MARCHF6. Functional studies in primary hepatocytes, human hepatoma cells and organoids were conducted to determine the mechanistic link between MARCHF6 and SREBP1.
    RESULTS: Hepatic MARCHF6 expression was significantly reduced in both MASLD mouse models and human patients. Liver-specific Marchf6 deletion aggravated hepatic lipid accumulation, fibrosis, and inflammation. Transcriptomic and proteomic analyses revealed upregulation of lipogenic genes in Marchf6Alb livers, with a marked increase in SREBP1 protein levels. Mechanistically, MARCHF6 directly interacted with and ubiquitinated SREBP1, targeting it for proteasomal degradation. Loss of MARCHF6 prolonged SREBP1 half-life, driving excessive DNL.
    CONCLUSIONS: MARCHF6-ERAD is a critical regulator of hepatic lipid metabolism, functioning as a sterol binding protein to control SREBP1 turnover. Its downregulation promotes hepatic steatosis and MASLD progression, highlighting MARCHF6 as a potential therapeutic target for MASLD intervention.
    IMPACT AND IMPLICATIONS: This study identifies the ER-resident E3 ubiquitin ligase MARCHF6 as a key regulator of SREBP1 stability, hepatic lipid homeostasis and MASLD progression. We demonstrate that loss of MARCHF6 promotes hepatic steatosis and fibrosis, whereas restoration of MARCHF6 largely reverses these phenotypes, highlighting a reversible and therapeutically targetable pathway. These findings provide new mechanistic insight into lipid dysregulation in MASLD and position the MARCHF6-SREBP1 axis as a promising target for metabolic liver disease intervention.
    Keywords:  ERAD; MARCHF6; lipid biosynthesis and MASLD
    DOI:  https://doi.org/10.1016/j.jhep.2026.04.036
  54. Nat Commun. 2026 May 21.
    Ribonuclease DIS3 delays aging and senescence by generating tRNA halves.
    Seokjun G Ha, Hanseul Lee, Jisoo Park, Donghun Lee, Gee-Yoon Lee, Seokjin Ham, Sujeong Kwon, Sangsoon Park, Sieun S Kim, Yoonji Jung, Jongsun Lee, Jooyeon Sohn, Seon Woo A An, Heehwa G Son, Wooseon Hwang, Hyeong-In Kim, Eunseok Kang, Yoon Ki Kim, Gwangrog Lee, Seung-Jae V Lee.
      Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5'-tRH-Gln and 5'-tRH-Asp, from tRNAs. Among them, 5'-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction. Generation of 5'-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1/NRF transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5'-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.
    DOI:  https://doi.org/10.1038/s41467-026-73295-7
  55. Cell Death Dis. 2026 May 17.
    VCP modulation ameliorates pathological features in C9orf72 models.
    Veronica Ferrari, Barbara Tedesco, Marta Cozzi, Paola Pramaggiore, Maria Cristina Gagliani, Rocio Magdalena, Laura Cornaggia, Elena Casarotto, Marta Chierichetti, Ali Mohamed, Maria Brodnanovà, Carmelo Milioto, Margherita Piccolella, Mariarita Galbiati, Valeria Crippa, Alessandro Provenzani, Katia Cortese, Paola Rusmini, Riccardo Cristofani, Angelo Poletti.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative diseases linked by similar pathological mechanisms, which, in some familial forms, may be associated with the same genetic alterations. Among them, the most common is the C9ORF72 (C9) mutation. The C9 mutation consists in an aberrant expansion of the hexanucleotide repeat (G4C2)n that leads to the production and accumulation of toxic dipeptide repeat proteins (DPRs). Some of these C9-DPRs contribute to neuronal dysfunction and degeneration through different mechanisms. One of these involves alterations in the protein quality control (PQC) system, specifically in the autophagy-lysosomal pathway. Valosin-containing protein (VCP) is a critical component of the PQC system, assisting the degradation of misfolded proteins and damaged organelles and the maintenance of cellular homeostasis. In this study, we investigated the role of VCP in modulating pathological features associated with C9 mutation. Using neuronal cell models, we demonstrated that VCP overexpression significantly reduced C9-DPRs levels. This reduction is mediated by mechanisms involving both the ubiquitin-proteasome system (UPS) and autophagy. Additionally, we also observed that C9-DPRs induce lysosomal damage, which is counteracted by VCP overexpression, as indicated by decreased galectin-3 puncta and restored lysosomal pH. We then pharmacologically activated VCP-mediated clearance through SMER28, increasing the clearance of the most toxic DPR, the polyPR. We also determined that in this model, SMER28 activity is mediated by the UPS and is associated with the mitigation of DPR-induced lysosome damage. Additionally, using motor neurons derived from induced pluripotent stem cells (iPSC-MNs) from C9-ALS mutation carriers, we demonstrated that SMER28 treatment significantly decreased polyGA levels, a marker for C9-DPR accumulation. Moreover, SMER28 rescued C9-MNs commitment to differentiation and the alteration in the expression of autophagy-related genes. Taken together, our findings strongly support VCP as a modulator of C9 pathology and highlight its potential as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-08856-1
  56. Nat Aging. 2026 May;6(5): 987-1006
    Peroxisomes orchestrate metabolic flexibility and longevity via an interorganelle cascade.
    Arpit Sharma, Aditi Prabhakar, Miriam Valera-Alberni, Jamie D Kraft, Abigail E Ellis, Ryan D Sheldon, Meeta Mistry, Pallas Yao, Yanshan Liang, Sheng Hui, William B Mair.
      Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of peroxisomal import via PRX-5 declines over age, causing pathological lipid droplet expansion, dysfunctional mitochondrial bioenergetics and metabolic inflexibility. Although targeted PRX-5 degradation recapitulates metabolic aging, its overexpression preserves lipid dynamics and mitochondrial integrity. Notably, dietary restriction maintains peroxisomal pathways and organelle coordination into late life and peroxisomal function causally underpins dietary restriction-mediated longevity. Our findings highlight peroxisomes as central upstream regulators of a dynamic interorganelle cascade driving metabolic plasticity and highlight peroxisomal maintenance as a key determinant of metabolic flexibility during aging.
    DOI:  https://doi.org/10.1038/s43587-026-01122-1
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