bims-proteo Biomed News
on Proteostasis
Issue of 2026–06–14
fifty-two papers selected by
Eric Chevet, INSERM
  1. Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
  2. The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.
  3. Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
  4. Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.
  5. Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.
  6. Ubiquitin beyond the proteome: lipids, glycans, metabolites, nucleic acids, and an expanding molecular landscape.
  7. Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.
  8. Coordinated regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins.
  9. Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
  10. A UFMylation-COPII axis orchestrates lipid transport in intestinal enterocytes and regulates systemic lipid balance.
  11. STING1 senses mitochondrial damage to promote mitophagy.
  12. The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.
  13. mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
  14. Exploring non-autonomous protein homeostasis driven by glutamatergic neurons.
  15. Distinct Proteasomal Pathways Drive Oncogenic PPM1D Activation.
  16. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  17. Human RNA ligase 1 as a novel regulator of ribosome function and translation under oxidative stress.
  18. Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
  19. The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
  20. Extracellular vesicles participate in proteostasis and heat shock adaptation in Plasmodium falciparum.
  21. Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
  22. Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
  23. Inhibition of the QPCT-PDIA4 axis rescues ΔF508 and N1303K CFTR in cystic fibrosis.
  24. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  25. ER-phagy orchestrates virus-host interactions across kingdoms.
  26. Ribosomal allostery as a potential regulator of bacterial dormancy.
  27. Structural insights into YheS-mediated release of SecM-arrested ribosome.
  28. Nucleoplasmic checkpoint of the 40S ribosomal decoding center maturation.
  29. The autophagy protein ATG-9 promotes aversive learning in Caenorhabditis elegans through trafficking neuropeptide receptors.
  30. SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1.
  31. Cell size-dependent mRNA transcription drives proteome remodeling.
  32. Chaperones shape the conformational landscape of 26S-proteasome-base assembly for allosteric ATPase motor activation.
  33. Exploring the organismal role of UFMylation in development, stress resilience and neurological function in C. elegans.
  34. Multicomponent Stapling of Glucagon-Like Peptide-1 Enables Receptor-Guided PROTAC Delivery.
  35. Dimeric architecture and membrane thinning govern substrate recognition by human signal peptide peptidase.
  36. Protocol for massively parallel RNA assay combined with immunoprecipitation for high-throughput analysis of RNA-protein interactions in cells.
  37. TRAINSPOTTER: profiling nascent protein N-termini indicative of bacterial translation initiation via deformylation-assisted N-terminomics.
  38. Chaperonin recognition of protein dynamics drives drug resistance.
  39. The EF-hand domain of MINDY3 is a ubiquitin and RAD23 UBL-binding domain.
  40. STING dampens the unfolded protein response to enable the presentation of self-antigens on MHC-I during inflammation.
  41. Observing intersubunit dynamics in single yeast ribosomes.
  42. A protective role for APP in nuclear waste clearance via lysosomal exocytosis.
  43. Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling.
  44. Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK.
  45. Bacterial extracellular vesicles promote membrane repair and tolerance to polymyxin B.
  46. Endoplasmic reticulum-resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins.
  47. Discriminator-Guided Inverse Folding for Multi-Property Protein Design.
  48. Transcripts enriched in codons that trigger P-site tRNA-mediated mRNA decay possess stable mRNA.
  49. Opposing roles of deubiquitinases in the regulation of IRF7 transcriptional activity.
  50. Protein language models are accidental taxonomists.
  51. Structural basis for regulation of the proteasome 20S core particle by the Parkinsonism-associated proteins FBXO7 and PI31.
  52. Serum starvation drives ALIX-dependent extracellular vesicle biogenesis and determines tumor progression.
  1. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00404-3. [Epub ahead of print]45(6): 117326
    Human J-domain proteins promote stress granule disassembly and suppress neurodegeneration-linked protein aggregation.
    Giovanni J Mastromarco, Rebecca Earnshaw, Gaelen Moore, X Y Sherwin Xu, Nour H Sadek, Fiona Cui, Natalie Lo, Hyun O Lee.
      Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.
    Keywords:  ALS; CP: molecular biology; CP: neuroscience; FUS; HSP70; J-domain proteins/HSP40; biomolecular condensates; cellular stress response; molecular chaperones; neurodegeneration; protein aggregation; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2026.117326
  2. bioRxiv. 2026 Jun 01. pii: 2026.05.29.728519. [Epub ahead of print]
    The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.
    Constantine Bartolutti, Alena Bishop, Yanzhe Ma, Kelsey Van Dalfsen, Elçin Ünal, Marko Jovanovic, Gloria Ann Brar.
      Stress responses, including the unfolded protein response (UPR), are commonly studied via induction with harsh exogenous stressors, leaving endogenous functions of these pathways less well understood. We found that the endogenous UPR that precedes meiosis in budding yeast is required for gamete production but diverges dramatically from previously defined UPR outputs, with only a few characterized UPR targets induced, and mildly. The role of this UPR can be replaced by increasing ER chaperones, reducing bulk translation, or impairing the machinery for protein translocation into the ER. ER integrity appears compromised in pre-meiotic cells lacking the UPR, as foci of reticulon proteins are seen and correlate strongly with an inability of cells to enter meiosis. These findings indicate that physiological UPR activation supports proteostasis and normal ER structure, preparing cells for meiotic entry by reducing the load of proteins that enter the ER. Overall, our study reveals surprising features of a physiological UPR induction that enables a cell fate decision.
    DOI:  https://doi.org/10.64898/2026.05.29.728519
  3. Sci Adv. 2026 Jun 12. 12(24): eaee9856
    Coupling of cargo to the autophagy receptor is a critical step in ER-phagy.
    Shuliang Chen, Subhrajit Banerjee, Dongmei Liu, Kamal Kumar, Christopher J Obara, Peter Novick, William A Prinz, Susan Ferro-Novick.
      During cell stress, endoplasmic reticulum autophagy (ER-phagy) receptors remodel the ER by sequestering membrane proteins (cargo) into autophagosomes for degradation. The conserved ER-phagy receptor, Atg40, contains a motif that binds to Atg8 and a reticulon homology domain that is needed for vacuolar/lysosomal delivery. Cargo capture, however, requires the Atg40 binding partner Lst1/SEC24C. To address whether lipids regulate cargo capture during ER-phagy, we analyzed autophagy in neutral lipid-deficient cells. Unexpectedly, we found that Atg40 was delivered to the vacuole in autophagosomes without Lst1/SEC24C or cargo in mutant cells. Lipidomic analysis revealed changes in the ratio of phosphatidylethanolamine to phosphatidylcholine in the neutral lipid-deficient cells that are predicted to alter ER membrane bendability. Our findings imply that phospholipids control cargo sequestration by regulating receptor-cargo coupling at autophagic sites.
    DOI:  https://doi.org/10.1126/sciadv.aee9856
  4. Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00615-7. [Epub ahead of print]45(6): 117537
    Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.
    Ruoxi Wang, Tina M Fortier, Xiaofeng Sun, Fei Chai, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective removal of endoplasmic reticulum (ER) is important for cell health. Macroautophagy is the primary mechanism for the removal of the ER, but the ER can be cleared in a macroautophagy-independent manner. However, the physiological relevance and mechanisms underlying macroautophagy-independent ER clearance remain largely unknown. Here we show that ER is cleared by lysosomes in a macroautophagy Atg gene-independent manner during development. This developmentally programmed Atg-independent ER clearance by lysosomes requires the ER protein Vap33 that promotes ER and lysosome contact. Oxysterol-binding protein (Osbp) is known to associate with Vap33, and Osbp lysosomal localization is required for ER clearance in cells lacking macroautophagy. Significantly, the cholesterol transport-associated protein Start1 regulates ER and lysosome contact, macroautophagy-independent ER clearance, and cholesterol transport from ER to the lysosome. These studies reveal that Vap33, Osbp, and Start1 promote ER clearance by lysosomes that is associated with cholesterol trafficking.
    Keywords:  CP: cell biology; Drosophila; ER; ESCRT; Osbp; Start1; Vap33; lysosome
    DOI:  https://doi.org/10.1016/j.celrep.2026.117537
  5. J Cell Sci. 2026 Jun 08. pii: jcs.264795. [Epub ahead of print]
    Split GFP-based fluorescent biosensors detect ER-Golgi membrane contact dynamics.
    Ranran Mao, Jiaqi Zhai, Chunfang Tong, Wenfeng Fu, Dong Li, Jia-Jia Liu.
      In eukaryotic cells, organelles communicate through membrane contact sites-specialized regions where their membranes come into close apposition without fusing. Among these, contacts between the endoplasmic reticulum (ER) and the Golgi apparatus are critical for lipid trafficking and polarized sorting of protein cargoes, yet their regulation and physiological roles remain poorly understood due to limited research tools. Here, we developed genetically encoded biosensors that selectively label ER-Golgi contact sites by building upon split GFP/YFP systems. These fluorescent probes reliably detect ER-Golgi contacts whose formation depends on Golgi-enriched phosphatidylinositol 4-phosphate and the lipid transfer activity of Oxysterol-Binding Protein, and reveal the dynamic remodeling of these structures in live cells. Notably, the biosensors captured alterations in ER-Golgi contacts during cell division and ER stress, as well as their developmental loss in mammalian neurons. We propose these biosensors as powerful tools for investigating ER-Golgi interactions in response to physiological cues or pathological perturbations across diverse cell types.
    Keywords:  Biosensor; Endoplasmic reticulum; Golgi; Membrane contact sites; Split GFP
    DOI:  https://doi.org/10.1242/jcs.264795
  6. Biochem Soc Trans. 2026 Jun 24. 54(6): 745-754
    Ubiquitin beyond the proteome: lipids, glycans, metabolites, nucleic acids, and an expanding molecular landscape.
    Akinori Endo, Yukiko Yoshida.
      Ubiquitination is a versatile post-translational modification process in which the small globular protein ubiquitin is covalently attached to substrate proteins to generate diverse cellular signals. Although originally characterized by its role in proteasome-mediated protein degradation, ubiquitination is now recognized as a central regulator of numerous processes, including signaling, trafficking, and immunity. Canonical ubiquitination is mediated by a cascade of E1 (activating), E2 (conjugating), and E3 (ligase) enzymes that repeatedly conjugate ubiquitin molecules to lysine residues on substrate proteins, leading to the formation of polyubiquitin chains with distinct topologies. The modification is reversed by deubiquitinating enzymes. Notably, components of the ubiquitin system comprise approximately 7% of the human proteome, underscoring its importance in biological regulation. Recent advances have revealed the broad scope of ubiquitination. Ubiquitin was found to conjugate not only to lysine but also to serine, threonine, and cysteine, indicating its unexpected chemical flexibility. Furthermore, ubiquitination can be directed toward other post-translational modifications, particularly glycosylation and ADP-ribosylation, highlighting the extensive crosstalk between modification systems. Strikingly, lipids, sugars, metabolites, nucleic acids, and even synthetic small-molecule compounds have been identified as ubiquitinated substrates. The hypothesis that virtually all classes of molecules are targeted by ubiquitination has become increasingly plausible. Taken together, these findings redefine ubiquitination as a far more general modification process than previously appreciated. In this mini-review, we focus on recent progress in non-proteinaceous ubiquitination research, summarize emerging substrate classes, and discuss key challenges in elucidating the underlying mechanisms and physiological roles of this expanding modification landscape.
    Keywords:  Ubiquitin; Ubiquitin ligases; non-proteinaceous
    DOI:  https://doi.org/10.1042/BST20260081
  7. J Cell Biol. 2026 Aug 03. pii: e202603129. [Epub ahead of print]225(8):
    Procollagen 1 assembles into phase-separated condensates in the endoplasmic reticulum.
    Soumya Bhattacharyya, Jose Wojnacki, Nathalie Brouwers, Vivek Malhotra.
      Procollagen I (PC1) is assembled into a trimer within the lumen of the endoplasmic reticulum (ER). In vitro, collagen trimers form rigid molecules reaching lengths of up to 400 nm, and this conformation is presumed to represent their assembled state in vivo. Here, we demonstrate that endogenous PC1 assembles into biomolecular condensates in the ER of activated human hepatic stellate cells. PC1 condensates form in response to increased collagen synthesis and are part of a multicomponent system enriched in the chaperones Hsp47 and calreticulin, as well as the disulfide isomerases PDIA1 and PDIA6, but notably lacking the unfolded protein sensor BiP. PC1 condensates localize to ER exit sites, a process mediated by TANGO1, and dissipate upon ER stress. We propose that this organization enables the accommodation of large quantities of PC1 in the ER lumen without triggering degradation. Furthermore, we suggest that PC1 within condensates is exported in a manner resembling liquid extrusion rather than as a rigid trimer.
    DOI:  https://doi.org/10.1083/jcb.202603129
  8. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00589-9. [Epub ahead of print]45(6): 117511
    Coordinated regulation of mRNA translation and stability by ZC3H7A and ZC3H7B RNA-binding proteins.
    Patric Harris Snell, Parisa Naeli, Aitor Garzia, Yanyu Chen, Joseph A Waldron, Susanta Chatterjee, Tom McGirr, Aidan Kilmartin, Eman Suleiman Mohammad Almomani, Ian R Kelsall, Reese Jalal Ladak, Jung-Hyun Choi, Jun Luo, Sami A Leino, Naomi Jess, S Ali Shariati, Ximena Soto, Christos G Gkogkas, Nahum Sonenberg, Thomas Tuschl, Sarah Maguire, Seyed Mehdi Jafarnejad.
      mRNA translation and stability are tightly regulated and functionally linked through cis-acting sequence elements and trans-acting factors, including RNA-binding proteins (RBPs). Here, we report that two chordate-specific paralogous RBPs, ZC3H7A and ZC3H7B, preferentially bind the coding region (CDS) and 3' untranslated region (3' UTR) of A/U-rich mRNAs, particularly those with enrichment of A/U at their wobble sites (A/U3 codons). Upon binding to target mRNAs, ZC3H7A/B promote mRNA degradation through recruitment of the CCR4-NOT deadenylase complex. Furthermore, these proteins engage ribosomes lacking elongation factors and repress translation initiation via the GIGYF2/4EHP translation repressor complex. Depletion of ZC3H7A/B or 4EHP impairs the translational repression of A/U3-rich mRNAs. Together, these findings reveal a mechanism in higher eukaryotes that links A/U-rich sequence content within the CDS and 3' UTR to the coordinated post-transcriptional regulation of mRNA stability and translation.
    Keywords:  3′ untranslated region; 4EHP; CP: molecular biology; GIGYF2; ZC3H7A; ZC3H7B; codon content; eIF4E2; mRNA decay; mRNA translation; non-optimal codons
    DOI:  https://doi.org/10.1016/j.celrep.2026.117511
  9. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00598-X. [Epub ahead of print]45(6): 117520
    Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer.
    Ankita Shrivastava, Eric Nels Pederson, Trang Uyen Nguyen, Jacky Chuen, Prathibha Mohan, Shivangi Pande, Ana Ruiz Toribio, Nicolas Lecomte, Jerry Melchor, John C McAuliffe, Paul M Grandgenett, Vinagolu K Rajasekhar, Kaila Nishikawa, Anna Knörlein, Yael David, Ian M Willis, Christine A Iacobuzio-Donahue, Zhengqing Ouyang, Kamini Singh.
      Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in cancer.
    Keywords:  CP: cancer; CP: molecular biology; EEF1A; EIF4A; KRAS inhibitors; Ribosome; mRNA translation; mTOR signaling; mutant KRAS; oncogenic signaling; ribosome profiling; ribosome stalling, pancreatic cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117520
  10. Mol Metab. 2026 Jun 12. pii: S2212-8778(26)00081-5. [Epub ahead of print] 102397
    A UFMylation-COPII axis orchestrates lipid transport in intestinal enterocytes and regulates systemic lipid balance.
    Yaqun Wang, Feng Zhou, Xin Xu, Guangyu Wu, Hong Xu, Honglin Li.
       BACKGROUND: Intestinal lipid absorption and chylomicron secretion are essential for systemic lipid homeostasis, yet the regulatory mechanisms coordinating lipoprotein assembly and ER export remain poorly understood. UFMylation is a newly identified ubiquitin-like modification pathway that plays critical roles in endoplasmic reticulum (ER)-related cellular activities such as protein quality control, ER-associated degradation (ERAD) and ER-phagy. However, its role in intestinal lipid transport and systemic lipid homeostasis is completely unclear.
    METHODS: To elucidate the role of UFMylation in intestinal lipid metabolism, we generated intestinal epithelial cell (IEC)-specific knockout mouse model of Ufbp1, a key component of the UFMylation pathway, and a double knockout model of Ufbp1 and IRE1α, one of the three signaling branches of Unfolded Protein response (UPR). After observing lipid droplet accumulation in the intestinal tissue of Ufbp1 and IRE1α double knockout mice, we further examined lipid metabolism in Ufbp1 knockout mice under high-fat diet. Finally, we used C2BBe1, a subclone of Caco-2 cell, as a cell model to investigate the role of UFMylation in Coat Protein Complex II (COPII)-mediated lipid transport in enterocytes.
    RESULTS: We serendipitously found that the combination of Ufbp1 and IRE1α deficiencies led to dramatic accumulation of lipid droplets in the enterocytes, thereby impairing enterocyte function and causing significant growth retardation. Furthermore, we found that Ufbp1 IEC-specific knockout mice were highly resistant to high-fat diet-induced hyperlipidemia. On the molecular level, we found that the components of the UFMylation pathway interacted with COPII complex and regulates the recruitment of COPII coat to ER-located lipoprotein.
    CONCLUSIONS: Our findings have established that the UFMylation pathway is a novel mediator of enterocyte lipid transport and a key partner of COPII-mediated trafficking.
    Keywords:  COPII vesicle; UFMylation; chylomicron; enterocyte
    DOI:  https://doi.org/10.1016/j.molmet.2026.102397
  11. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  12. Mol Biol Cell. 2026 Jun 11. mbcE25110536
    The ESCRT-0 protein HRS regulates hepatocellular lipid droplet catabolism.
    Mathilda M Willoughby, Ankit Shroff, Bridget E Crossman, Micah B Schott.
      Lipid droplets (LDs) are dynamic organelles that regulate lipid storage and metabolism pathways central to metabolic liver disease. LD turnover occurs in part through lysosomal catabolism (lipophagy), whereby LDs are delivered to lysosomes via two distinct trafficking pathways: autophagosome-dependent macrolipophagy and autophagosome-independent microlipophagy. However, the molecular machinery that regulates these two pathways, especially that of microlipophagy in mammalian cells, is poorly understood. In yeast, microlipophagy has been shown to rely on the endosomal sorting complex required for transport (ESCRT) protein family. Here, we used an ESCRT-specific RNAi library in hepatocytes, which identified the ESCRT-0 protein hepatocyte growth factor receptor substrate (HRS) as a critical regulator of LD homeostasis. HRS depletion leads to significant LD accumulation, driven by impaired LD catabolism rather than increased LD biogenesis. While HRS-deficient cells retain lipolytic activity, LD targeting via RAB5-mediated microlipophagy is reduced, and LD targeting by autophagosomes is increased. Consistent with these findings, HRS knockdown suppressed mTORC1 signaling, enhanced autophagosome formation, and reduced autophagic cargo degradation. Notably, despite unchanged lysosomal abundance, HRS knockdown elevated lysosomal pH, potentially impairing autophagic degradation and promoting LD accumulation. Overall, these findings identify HRS as a key regulator of LD turnover in mammalian cells, modulating lipophagy through lysosomal function.
    DOI:  https://doi.org/10.1091/mbc.E25-11-0536
  13. Cell. 2026 Jun 08. pii: S0092-8674(26)00576-3. [Epub ahead of print]
    mRNA 3' UTRs chaperone intrinsically disordered regions to control protein activity.
    Yang Luo, Yaofeng Zhong, Sudipto Basu, Ming-Chung Wu, Christine Mayr.
      More than 2,700 human mRNA 3' UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs encode proteins strongly enriched for long intrinsically disordered regions (IDRs) with hydrophobic amino acid clusters. For MYC, UTX, and JMJD3, we show that their mRNA 3' UTRs control protein activity. Rather than affecting protein abundance or localization, we find that the KDM6B 3' UTR co-translationally changes the folding of JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA has IDR chaperone activity that prevents interference between hydrophobic clusters in the IDR with folding of the structured domain. 3' UTRs with chaperone activity are multivalent and mesh-like condensate-enriched, indicating the presence of localized folding environments for IDR-containing proteins. We show here that the protein sequence is insufficient for the biogenesis of fully active IDR-containing transcriptional regulators in cells, suggesting that mRNA 3' UTRs control their activity by preventing co-translational misfolding.
    Keywords:  3′ UTR; RNA multivalency; RNA-based chaperone activity; RNA–IDR interaction; chromatin regulator; co-translational; crosslinking mass spectrometry; hydrophobic clusters; intrinsically disordered regions; mesh-like condensates; protein folding; transcription factor
    DOI:  https://doi.org/10.1016/j.cell.2026.05.017
  14. MicroPubl Biol. 2026 ;2026
    Exploring non-autonomous protein homeostasis driven by glutamatergic neurons.
    Adam J Hruby, Aeowynn J Coakley, Evan Dittus, Andrew Bong, Camilla Pearson, Jing Wang, Peter J Mullen, Gilberto Garcia, Ryo Higuchi-Sanabria.
      Neuronal overexpression of xbp-1 s , a regulator of the endoplasmic reticulum unfolded protein response (UPR ER ), induces non-autonomous UPR ER activation in distal tissues of Caenorhabditis elegans . Specific neuronal subtypes, including glutamatergic, octopaminergic, and GABAergic neurons, have been implicated in enhancing intestinal proteostasis. Here, we investigated the mechanisms underlying this effect. Glutamatergic xbp-1 s mediated proteostasis improvement was independent of endogenous xbp-1 but required the transcription factor HLH-30 , potentially via autophagy and ER-associated degradation pathways. In contrast, octopaminergic and GABAergic signaling yielded limited insight. These findings highlight the complexity of neuronal control of organismal proteostasis through non-autonomous UPR ER signaling pathways.
    DOI:  https://doi.org/10.17912/micropub.biology.002119
  15. bioRxiv. 2026 Jun 09. pii: 2026.06.01.729344. [Epub ahead of print]
    Distinct Proteasomal Pathways Drive Oncogenic PPM1D Activation.
    Ni Yan, Deumaya Shrestha, Cameron Schluter, Cyrus Jin, Edward Wang, Carmen Da Silva, Ilaria Gritti, Nikolaos Tsopoulidis, Ruxin Yang, Adam S Sperling, Jonathan M Tsai, Andrew E H Elia, Eric S Fischer, Mikolaj Slabicki, Eugene Oh, Peter G Miller.
      PPM1D is a serine/threonine phosphatase and DNA damage response (DDR) regulator recurrently activated in cancer through amplification or C-terminal truncating mutations that increase its abundance. Here we show that truncating mutations fundamentally rewire PPM1D proteostasis, unmasking an oncogenic function of an alternative protein degradation pathway. While full-length PPM1D undergoes rapid ubiquitin-independent proteasomal degradation via a C-terminal degron, truncating mutations redirect degradation to a slower UBR5-mediated ubiquitin-dependent pathway. The resulting accumulation of PPM1D suppresses DDR signaling and enhances cellular fitness under genotoxic stress, which is further amplified by UBR5 loss. Consistent with selective pressure on this axis, cancers harboring PPM1D truncating mutations are enriched for UBR5 loss-of-function mutations. Together, these findings identify escape from ubiquitin-independent proteasomal degradation as a mechanism of oncogenic adaptation and establish proteostatic routing as a regulatory layer linking protein degradation, DDR signaling, and cancer evolution.
    DOI:  https://doi.org/10.64898/2026.06.01.729344
  16. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  17. Nucleic Acids Res. 2026 Jun 08. pii: gkag528. [Epub ahead of print]54(11):
    Human RNA ligase 1 as a novel regulator of ribosome function and translation under oxidative stress.
    Florian Michael Stumpf, Marissa Glauner, Jasmin Jansen, Virginie Marchand, Yuri Motorin, Florian Stengel, Andreas Marx.
      Human RNA ligase 1 (Rlig1) is a recently identified human 5'-3' RNA ligase required for maintaining 28S ribosomal RNA integrity and promoting cell survival under oxidative stress. Although its enzymatic activity suggests a role in RNA processing and repair, the broader molecular context of Rlig1 remains poorly defined. Here, we identified potential Rlig1-associated proteins by affinity enrichment-mass spectrometry. Subsequent analysis revealed proteins involved in RNA surveillance and processing, including RNA-binding and end-processing enzymes, and indicated strong enrichment of ribosomal proteins. We showed that Rlig1 interacts with 80S ribosomes in vitro. Consistent with this observation, polysome profiling revealed recruitment of Rlig1 to ribosomal fractions under oxidative stress. Functionally, Rlig1-knockout (KO) HEK293 cells exhibited accelerated polysome loss and significantly reduced global protein synthesis compared to wild-type (WT) HEK293 cells during oxidative stress. In addition, we showed that stress-induced RNA fragments containing a 5'-PO4 end accumulated in Rlig1-KO cells. Among these, transfer RNA halves were prominently enriched. Together, our study links Rlig1 to ribosomal complexes and suggests that Rlig1 contributes to preserving RNA integrity and supporting translational capacity during oxidative stress.
    DOI:  https://doi.org/10.1093/nar/gkag528
  18. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00585-1. [Epub ahead of print]45(6): 117507
    Cell-type-specific proximity labeling of organ secretomes reveals energy balance-dependent proteomic remodeling.
    Kaja Plucińska, Charlotte R Wayne, Henry Sanford, Boby Mathew, Nathalie Ropek, Stephanie M Adaniya, Corey Model, Nicolás Gómez-Banoy, Ksenia Morozova, Xiongwen Cao, Jeffrey M Friedman, Ken H Loh, Paul Cohen, Ekaterina V Vinogradova.
      Intercellular communication is critical for maintaining organismal metabolic homeostasis. Here, we develop a method enabling temporally controlled, cell-type-specific labeling of secreted and membrane proteins in key metabolic tissues. The method employs a genetically encoded proximity-labeling strategy by targeting a Cre-dependent TurboID ligase to the endoplasmic reticulum (ER) in ES cell-derived mice. The expression of TurboID in hepatocytes, adipocytes, and B lymphocytes enabled the characterization of cell type-specific ER proteomes at baseline and in response to fasting, inflammation, and dietary obesity, revealing tissue- and perturbation-specific changes and augmenting our understanding of how the proteomes of individual tissues change to regulate systemic energy balance. This comprehensive resource represents an important advance toward understanding both how cell-to-cell communication changes in response to energy balance and how it contributes to these alterations. This method is broadly applicable and provides a means for identifying biomarkers and therapeutic targets across a wide range of tissues.
    Keywords:  CP: metabolism; ER proteomics; TurboID; inflammation; obesity; plasma proteomics; proximity labeling
    DOI:  https://doi.org/10.1016/j.celrep.2026.117507
  19. PLoS Genet. 2026 Jun 10. 22(6): e1012203
    The regulation of Xrp1 expression by uORFs and main ORF sequences and its function in Drosophila disease models.
    Hidetaka Katow, Thao Nguyen, Sarah Hyunsoh Park, Hyung Don Ryoo.
      The Integrated Stress Response (ISR) mediates cellular adaptation to endoplasmic reticulum (ER) stress, amino acid deprivation, and mitochondrial dysfunction. The ISR regulates gene expression in part by preferentially translating the transcription factor ATF4, a process regulated by upstream open reading frames (uORFs) in its 5' leader. In Drosophila, Xrp1 is another transcription factor induced during the ISR, but the precise underlying mechanism remains unclear. Here, we report that Xrp1 induction in response to ER stress is regulated by both its uORFs and the main ORF sequence. Xrp1 has seven splice isoforms, and the two predominant transcripts expressed in eye imaginal discs contain uORFs. Expressing the ER stress-imposing ninaEG69D transgene in this tissue induced Xrp1 expression without significantly changing the Xrp1 splice isoform composition. The uORF-containing 5' leaders, particularly the AUG codon of the second uORF, inhibited DsRed expression when placed upstream of the reporter. Unlike ATF4, the uORF-containing 5' leader alone was insufficient to mediate the main ORF induction, but Xrp1 induction occurred in ninaEG69D-expressing discs when Xrp1's 5' leader and the main ORF sequence were both present. Functionally, Xrp1 was required to maintain the integrity of Drosophila photoreceptors exposed to constant light. In a different disease model, parkin mutants activated Xrp1 target gene expression in specific tissues and Xrp1 loss enhanced the viability of parkin mutant flies during adult eclosion. These results provide molecular and pathological insights into Xrp1 regulation and function in disease models.
    DOI:  https://doi.org/10.1371/journal.pgen.1012203
  20. Emerg Microbes Infect. 2026 Jun 08. 2686468
    Extracellular vesicles participate in proteostasis and heat shock adaptation in Plasmodium falciparum.
    Yunuen Avalos-Padilla, Lucía Román-Álamo, Inés Bouzón-Arnáiz, Elsa M Arce, Diego Muñoz-Torrero, Xavier Fernàndez-Busquets.
      Heat shock is a hallmark of clinical malaria, where Plasmodium falciparum parasites are exposed to recurrent febrile episodes exceeding 40 °C and imposing acute proteotoxic stress. Parasite survival under these conditions relies on efficient proteostasis mechanisms and molecular chaperones, yet how stress resilience is coordinated beyond chaperone responses remains poorly understood.Here, we identify a stress-associated role for extracellular vesicles (EVs) in parasite heat shock adaptation linked to PfVps60-dependent vesicular trafficking, an Endosomal Sorting Complex Required for Transport (ESCRT) protein. Using a PfVps60 knockout (PfVps60KO) line, we show that disruption of ESCRT-dependent vesicular trafficking compromises EV cargo composition during thermal stress. Proteomic profiling revealed that 44.8% of EV-associated proteins from P. falciparum 3D7 overlapped with a previously defined set of aggregation-prone proteins. Loss of PfVps60 impaired EV-mediated export of the chaperones PfHsp70-x and PfHsp110, altered aggregation dynamics and induced the redistribution of protein aggregates near the parasitophorous vacuole, reduced induction of the cytosolic chaperone PfHsp70-1, and resulted in early loss of parasite viability following heat shock. Supplementation of PfVps60KO parasites with EVs derived from heat-stressed 3D7 parasites partially rescued heat shock tolerance in a dose-dependent manner. EVs released shortly after thermal stress were enriched in aggregation-prone proteins and associated with neighboring uninfected erythrocytes, suggesting EV-mediated intercellular communication during febrile episodes. Together, these findings support a role for EV-associated cargo as a previously unexplored component of P. falciparum proteostasis during heat shock adaptation, identifying stress-induced EVs as a potential parasite vulnerability for malaria intervention.
    Keywords:  Plasmodium falciparum; extracellular vesicles; heat shock; protein aggregation; stress response
    DOI:  https://doi.org/10.1080/22221751.2026.2686468
  21. Signal Transduct Target Ther. 2026 Jun 09. pii: 224. [Epub ahead of print]11(1):
    Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.
    Ankush Borlepawar, Marco Neu, Ziqi Ma, Anushka Deshpande, Hannah Bühringer, Parvana Hajieva, Norbert Frey, Ashraf Yusuf Rangrez.
      Cellular protein homeostasis, or proteostasis, underpins the integrity, adaptability, and survival of all cells by balancing protein synthesis, folding, trafficking, and degradation. This multilayered network is sustained by coordinated actions of molecular chaperones, the ubiquitin‒proteasome system, autophagy-lysosomal pathways, and organelle-specific quality control programs. When this equilibrium collapses, misfolded, aggregated, or damaged proteins accumulate, driving organelle dysfunction, maladaptive stress signaling, and disease progression. Disruption of proteostasis is now recognized as a unifying pathological hallmark linking neurodegenerative disorders, cancer, cardiovascular and metabolic diseases, and autoimmune conditions. This is particularly consequential in post-mitotic organs such as the heart and brain, which possess limited regenerative capacity and are exceptionally vulnerable to proteotoxic stress. Rapid advances now reveal proteostasis as a multicomponent, cross-compartmental, and dynamically adaptable system, rather than isolated pathways. We frame this complexity through the concept of proteostasis resilience, defined as the ability of cells and tissues to maintain proteome stability under stress, and use it to unify disease mechanisms with therapeutic opportunity. This review integrates mechanistic insights with translational advances, outlining how dysregulation of chaperones, autophagy-mitophagy, the ubiquitin‒proteasome system, and ER stress pathways drive human diseases, while highlighting emerging therapeutic platforms, from pharmacological chaperones and autophagy modulators to targeted protein degradation technologies, CRISPR screens, spatial biology, and AI-guided drug discovery. Together, this systems-level perspective positions proteostasis resilience as a foundational paradigm for understanding disease vulnerability and designing precision proteostasis-based therapies.
    DOI:  https://doi.org/10.1038/s41392-026-02714-4
  22. bioRxiv. 2026 Jun 02. pii: 2026.05.31.729136. [Epub ahead of print]
    Synphilin-1 mitigates autophagy dysfunction, modulates ubiquitinated protein aggregation, and promotes cell survival during proteotoxic stress.
    Nadine M Lebek, Kenneth G Campellone.
      The decline of cellular proteostasis is a hallmark of aging and key contributor to neurodegenerative diseases. Protein turnover is controlled by the ubiquitin-proteasome and autophagosome-lysosome systems, but how degradation is coordinated when one of these pathways is compromised is not well understood. To study the regulation of proteostasis, we utilized human fibroblasts with targeted knockouts of the cytoskeletal factors WHAMM and JMY, which control multiple steps in autophagy. We found that cells lacking both WHAMM and JMY accumulated numerous intense foci of ubiquitinated proteins when exposed to proteotoxic stress and relied on proteasomes to clear the foci when the stressor was removed. RNA-seq and immunoblotting revealed that WHAMM/JMY knockout cells increased their expression of Synphilin-1, an α-synuclein-interacting protein implicated in Parkinson's Disease. In WHAMM/JMY knockout cells that upregulated endogenous Synphilin-1, and in cell lines engineered to overexpress mCherry-Synphilin-1, ubiquitinated proteins were present in structures containing both Synphilin-1 and proteasomes. RNAi-mediated depletion of Synphilin-1 caused a buildup of ubiquitinated proteins and the ubiquitin-binding adaptor protein SQSTM1/p62, while decreasing cell survival in response to proteotoxic stress. These data suggest that Synphilin-1 plays a pro-survival role in cells with impaired autophagy and functions in the distribution of ubiquitinated cargo during proteasomal degradation.
    DOI:  https://doi.org/10.64898/2026.05.31.729136
  23. Nat Commun. 2026 Jun 09.
    Inhibition of the QPCT-PDIA4 axis rescues ΔF508 and N1303K CFTR in cystic fibrosis.
    Le Sun, Larry Rodriguez, Sandra Pankow, Jolene Diedrich, Ke Qin, Jianan Zhang, Xu Wu, Peng Wu, John R Yates.
      Cystic fibrosis (CF) is a genetic disorder caused by CFTR mutations, most commonly ΔF508, leading to defective ion transport and multisystem pathology. Small-molecule modulators partially restore mutant CFTR function, but therapeutic efficacy remains limited, particularly for N1303K mutation refractory to current treatments. Here, we show that inhibition of the glutaminyl-peptide cyclotransferase (QPCT)-dependent pathway rescues both the surface expression and functional activity of ΔF508 CFTR. Integrated molecular and physiological analyses identify protein disulfide-isomerase A4 (PDIA4) as a key mediator of this process through a pyroglutamate (pGlu)-dependent association with misfolded ΔF508 CFTR. QPCT-dependent pGlu modification promotes the association of PDIA4 with mutant CFTR within the endoplasmic reticulum (ER) quality control machinery, whereas inhibition of QPCT disrupts this interaction, relieving ER retention and enabling a fraction of ΔF508 CFTR to reach the cell surface. Furthermore, inhibition of QPCT also restores the function of the N1303K CFTR mutant, indicating a broader relevance of this pathway in regulating CFTR proteostasis. These findings provide evidence for an ER quality control mechanism governing mutant CFTR fate and suggest potential therapeutic strategies for CFTR mutations that are unresponsive to existing modulators.
    DOI:  https://doi.org/10.1038/s41467-026-74078-w
  24. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  25. Trends Microbiol. 2026 Jun 10. pii: S0966-842X(26)00157-5. [Epub ahead of print]
    ER-phagy orchestrates virus-host interactions across kingdoms.
    Ruiqi Wang, Qianshen Zhang, Yiping Wang, Yongliang Zhang.
      Beyond maintaining endoplasmic reticulum (ER) homeostasis, ER-phagy (or reticulophagy) serves as a conserved antiviral defense across kingdoms. By targeting viral replication organelles and degrading viral components, it restricts infection, while viruses counteract or exploit this pathway. This dynamic interplay shapes infection outcomes and highlights ER-phagy as a promising target for antiviral intervention.
    Keywords:  ER remodeling; ER-phagy; antiviral defense; counterdefense; viral infection
    DOI:  https://doi.org/10.1016/j.tim.2026.05.017
  26. Nat Commun. 2026 Jun 12.
    Ribosomal allostery as a potential regulator of bacterial dormancy.
    Danis Yangaliev, Eun Chae Moon, Gürol M Süel, S Banu Ozkan.
      Ribosomes are central to protein synthesis but also serve as dynamic hubs that integrate cellular stress responses. Here, we investigate how ribosomal protein L11 regulates ribosome conformational dynamics and long-distance coupling. Long-timescale molecular dynamics simulations of wild-type and L11-deleted (ΔL11) ribosomes reveal that L11 functions as a global allosteric regulator coordinating communication between the ribosomal stalk and the peptidyl transferase center. The absence of L11 disrupts long-distance couplings involving RelA and Obg and rigidifies the hibernation-promoting factor site, suggesting altered hibernation dynamics that could affect ribosome persistence under stress. To examine the physiological implications of these computational predictions, we construct a ΔL11 Bacillus subtilis strain and quantify its sporulation behavior. The ΔL11 variant exhibits delayed entry into and exit from dormancy, consistent with a breakdown in stress-adaptive ribosomal regulation. Overall, these results highlight the role of L11 in ribosomal allostery, suggesting how local perturbations propagate through the ribosome to influence global physiological outcomes and bacterial survival under environmental stress.
    DOI:  https://doi.org/10.1038/s41467-026-74199-2
  27. Nat Commun. 2026 Jun 09. pii: 4963. [Epub ahead of print]17(1):
    Structural insights into YheS-mediated release of SecM-arrested ribosome.
    Kaishi Iso, Toma Ikeda, Kohei Yamasaki, Yushin Ando, Fumiya K Sano, Tadaomi Furuta, Hideki Taguchi, Osamu Nureki, Yuhei Chadani, Yuzuru Itoh.
      ATP-binding cassette subfamily F (ABCF) proteins interact with the ribosome to resolve translation defects near the peptidyl transferase center (PTC). In Escherichia coli, four ABCF proteins (EttA, Uup, YbiT, and YheS) selectively promote translation of distinct problematic nascent peptide sequences, but their molecular mechanisms remain unclear. Here, we present a 2.8 Å cryo-EM structure of the ribosome in complex with an ATPase-deficient mutant of YheS and investigate how it releases ribosomes arrested by the SecM nascent chain. YheS binds to the ribosomal E-site via the L1 stalk, and its P-site tRNA-interaction motif (PtIM) extends toward the PTC, displacing the CCA end of the P-site tRNA. Notably, the cryo-EM density corresponding to the SecM nascent chain within the exit tunnel is largely lost upon YheS binding. These observations suggest that YheS relieves peptide sequence-dependent stalling by perturbing nascent chain-tunnel interactions through P-site tRNA relocation. Steered molecular dynamics simulations provide qualitative support for this model. Together, our findings provide mechanistic insight into a mode of arrest release distinct from the translocon-mediated release mechanism.
    DOI:  https://doi.org/10.1038/s41467-026-72863-1
  28. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00623-6. [Epub ahead of print]45(6): 117545
    Nucleoplasmic checkpoint of the 40S ribosomal decoding center maturation.
    Benjamin Lau, Yi Li, Jingyi Zhu, Xianwen Ye, Paulina Fischer, Xiaying Hong, Rui Yuan, Roland Beckmann, Ed Hurt, Jingdong Cheng.
      The decoding center (DC) is a key ribosomal structure for accurate translation, assembled in a multi-step process that starts on nucleolar pre-ribosomes and ends in the cytoplasm. While late cytoplasmic steps and their checkpoint mechanisms are well characterized, the regulation of early nucleoplasmic DC assembly is unclear. Here, we show that the essential assembly factor Rrp12 plays a central coordinating role. Using Chaetomium thermophilum and cryo-electron microscopy analyses of fifteen pre-40S intermediates, we demonstrate that Rrp12 C terminus truncation: (1) inhibits release of the Utp14-Dhr1 pair, (2) displaces Tsr1, (3) promotes premature stabilization of h28, and (4) prevents h44 formation. These defects impair final 18S rRNA processing and prematurely activate the quality control kinase Rio1. Our results reveal a nucleoplasmic checkpoint during DC formation and establish Rrp12 as a critical regulator ensuring accurate assembly and orderly ribosome maturation.
    Keywords:  90S; CP: molecular biology; Chaetomium thermophilum; decoding center; helix28; helix44; pre-40S; premature RNA folding; quality control; ribosome assembly; rrp12
    DOI:  https://doi.org/10.1016/j.celrep.2026.117545
  29. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2531054123
    The autophagy protein ATG-9 promotes aversive learning in Caenorhabditis elegans through trafficking neuropeptide receptors.
    Wai Hou Tam, Yu-Cheng Tang, Hao-Han Shiu, Shang-Heng Tsai, Pei-Shu Jao, Chun-Liang Pan.
      Autophagy is a degradative process that maintains cellular homeostasis. Autophagy biogenesis occurs at synapses, but its impact on synaptic functions is incompletely understood. Here we show that, in Caenorhabditis elegans, synaptic ATG-9, the only transmembrane autophagy protein, contributes to aversive learning under mitochondrial stress. Analysis of the neuronal translatome reveals that autophagy is upregulated by stress in the octopaminergic RIC neuron and it promotes aversive learning. Inactivating autophagy genes, including atg-9, reduces aversive learning. Mitochondrial stress increases synaptic ATG-9 through AP-1- and AP-2-dependent exocytosis and endocytosis, respectively, and reducing synaptic ATG-9 impairs aversive learning. We further identify the FRPR-6 neuropeptide receptor as a substrate of ATG-9 modulation. Both atg-9 and frpr-6 promote aversive learning and RIC activities, and the abundance of FRPR-6 in the RIC neurite depends on atg-9. We postulate that ATG-9-containing synaptic compartments promote neuronal plasticity through modulating receptor trafficking to enable aversive learning under systemic mitochondrial stress.
    Keywords:  C. elegans; autophagy; memory; neuropeptides; synapse
    DOI:  https://doi.org/10.1073/pnas.2531054123
  30. Nat Commun. 2026 Jun 10.
    SEC14L2 couples chaperone-mediated autophagy to microtubule stability by targeting Stathmin 1.
    Guangyuan Li, Hanfang Xu, Bo Gong, Shunji Jia.
      Microtubule dynamic instability underpins cellular architecture, division, and intracellular trafficking, yet how selective proteolytic pathways tune core microtubule regulators remains incompletely understood. Here, we identify SEC14L2 (SEC14-like lipid binding 2), a multidomain lipid transfer protein, as a determinant of microtubule organization and cellular architecture by limiting the accumulation of the microtubule-destabilizing factor Stathmin 1 (STMN1). We further show that STMN1 is a substrate of chaperone-mediated autophagy (CMA) and that SEC14L2 is required for efficient CMA-dependent STMN1 turnover. SEC14L2 loss is associated with reduced CMA activity, STMN1 stabilization, collapse of the microtubule network, and perinuclear organelle clustering. In breast cancer cell models, perturbation of this SEC14L2-CMA-STMN1 axis alters responses to microtubule-targeting agents.
    DOI:  https://doi.org/10.1038/s41467-026-74325-0
  31. Cell Rep. 2026 Jun 10. pii: S2211-1247(26)00566-8. [Epub ahead of print]45(6): 117488
    Cell size-dependent mRNA transcription drives proteome remodeling.
    Dong Shin You, Christopher H Bohrer, Purva H Rumde, Ioannis Sanidas, Matthew P Swaffer, Daniel R Larson, Josh E Elias, Michael C Lanz, Jan M Skotheim.
      Increasing cell size drives proteomic changes that impact cell physiology. However, the molecular basis of size-dependent proteome remodeling has remained unclear. Here, we develop an inducible Cyclin D1 expression system in human cells to generate proliferating cells spanning over a 2-fold size range. We use this system to make comprehensive genome-wide measurements of mRNA and protein concentrations and stability. We find that protein and mRNA turnover rates are weakly related to cell size but that mRNA concentrations are strongly size-dependent. This establishes that transcriptional regulation is the basis of proteome remodeling. Live-cell imaging of nascent mRNAs using the MS2 system is used to measure how transcriptional dynamics change with cell size. Larger cells prolong transcriptional bursts but maintain similar burst amplitudes to achieve transcriptional scaling. Together, our results show how transcription is modulated by cell size to remodel the proteome and alter cell physiology.
    Keywords:  CP: molecular biology; bursting; cell biology; cell size; homeostasis; lysosome; scaling; single-molecule imaging; transcription; turnover
    DOI:  https://doi.org/10.1016/j.celrep.2026.117488
  32. bioRxiv. 2026 Jun 02. pii: 2026.06.01.729410. [Epub ahead of print]
    Chaperones shape the conformational landscape of 26S-proteasome-base assembly for allosteric ATPase motor activation.
    Hao-Hsuan Hsieh, Andreas Martin.
      Protein homeostasis depends on the 26S proteasome, the most complex ATP-dependent protease in eukaryotic cells. The proteasome base subcomplex is responsible for mechanical substrate unfolding and translocation into an internal degradation chamber. It contains three non-ATPase subunits, Rpn1, Rpn2, and Rpn13, and a heterohexameric AAA+ motor with six distinct ATPases, Rpt1 - Rpt6. Correct base assembly requires four dedicated chaperones that initially form the Hsm3 module (Hsm3-Rpt1-Rpt2-Rpn1), the Rpn14/Nas6 module (Rpn14-Rpt6-Nas6-Rpt3-Rpn2-Rpn13), and the Nas2 module (Nas2-Rpt5-Rpt4). However, the mechanisms underlying module assembly and formation of the mature base remain unknown. Here, we in vitro reconstitute the base subcomplex of the S. cerevisiae 26S proteasome from recombinant modules. Using biochemical assays, mass photometry, single-molecule fluorescence measurements, and single-particle cryo-EM, we reveal how the chaperones direct the conformational transitions through several intermediates toward the ATP-hydrolysis-active base. The Nas2 and Rpn14/Nas6 modules associate first, and binding of the Hsm3 module creates a state in which the chaperones stabilize an open ATPase ring that lacks hydrolysis activity. Sequential chaperone release then leads to a gradual ATPase-ring closure, whereby Hsm3's unstructured C-terminal tail mimics a substrate polypeptide in the central channel and induces a processing motor state with a spiral-staircase arrangement of Rpt subunits and a closed ATPase site at Rpt4. Inaugural ATP hydrolysis in Rpt4 is subsequently required to eject Hsm3 and transition to the Nas6-bound base that is ATPase active and competent for 26S-proteasome incorporation. Our studies thus provide exciting insights into how chaperones assure correct assembly, guide the complex through an intricate conformational landscape, and thereby prevent premature ATP-hydrolysis activation or incorporation of faulty assemblies into holoenzymes.
    DOI:  https://doi.org/10.64898/2026.06.01.729410
  33. J Biol Chem. 2026 Jun 12. pii: S0021-9258(26)02119-8. [Epub ahead of print] 113247
    Exploring the organismal role of UFMylation in development, stress resilience and neurological function in C. elegans.
    Charlotte Sophia Kaiser, Janina Kahl, Emily Jeanne Kouekem, Emma Schröder, Luka Ressmann, Antonio Miranda-Vizuete, Eva Liebau.
      UFMylation is a post-translational modification that conjugates ubiquitin-fold modifier 1 (UFM1) to substrate proteins, regulating fundamental processes including ribosomal homeostasis, the endoplasmic reticulum (ER) stress response and DNA damage repair. While loss-of-function mutations in the UFMylation cascade cause lethality in mammals, they are viable in Caenorhabditis elegans, offering a unique opportunity to investigate its physiological role at the organismal level. We demonstrate that UFM-1 expression progressively increases from larval stages to adulthood, with predominant localization in intestinal cells. Its expression is upregulated during ER stress and autophagy induction, linking it to these pathways. We used CRISPR/Cas9 to create a targeted ufm-1 loss-of-function mutant, which revealed that UFMylation is crucial for lifespan, development and reproduction, with mutants exhibiting increased gonadal dysfunction and sterility. Deletion of ufm-1 enhanced tolerance to various stressors, a resilience potentially arising from a hormetic response to persistent ER stress. Loss of ufm-1 selectively activated the unfolded protein response in the ER but not in mitochondria. Notably, ufm-1 loss exacerbated proteotoxicity in C. elegans muscle-expressed models of protein aggregation, accelerating paralysis and increasing the number and size of amyloid-β, α-synuclein and polyQ aggregates. Furthermore, mutant worms displayed impaired locomotion, including altered swimming patterns resembling those of aging worms, stemming from accelerated, age-dependent sensory neuron dysfunction and structural neurodegeneration.
    Keywords:  C. elegans; UFM1; UFMylation; endoplasmic reticulum stress; neurodegeneration; ubiquitin-fold modifer 1
    DOI:  https://doi.org/10.1016/j.jbc.2026.113247
  34. Angew Chem Int Ed Engl. 2026 Jun 12. e9595531
    Multicomponent Stapling of Glucagon-Like Peptide-1 Enables Receptor-Guided PROTAC Delivery.
    Jan L Venne, Sona Krajcovicova, Graeme Davies, Hannah Bolt, Jefferson Revell, David R Spring.
      Achieving cell-selective targeted protein degradation remains a major challenge for translating proteolysis-targeting chimeras (PROTACs) into therapeutics. Although pancreatic β-cells are well vascularised and readily accessible to circulating peptides, selective receptor-mediated drug delivery remains challenging. Here, we exploit the glucagon-like peptide-1 receptor (GLP-1R) as a β-cell-specific entry route and report, for the first time, a multicomponent stapled glucagon-like peptide-1 (GLP-1) analogue constructed by tryptophan-mediated multicomponent Petasis reaction (TMPR). This modular stapling strategy affords a conformationally stabilised GLP-1 peptide bearing a chemically orthogonal handle for late-stage conjugation, displaying markedly enhanced α-helicity and improved receptor potency, compared with the wild-type peptide. Linking this improved analogue to a bromodomain-containing protein 4 (BRD4)-directed degrader furnishes the first GLP-1-guided PROTAC, which retains GLP-1R agonism and induces selective BRD4 degradation in GLP-1R-positive cells, consistent with receptor-guided uptake and intracellular activation of the degrader payload. Together, these results provide strong proof-of-concept evidence that a TMPR-stapled GLP-1 peptide can serve as a β-cell-directed delivery platform for receptor-defined protein degradation.
    Keywords:  brd4; glp‐1; peptide stapling; protac; tryptophan modification
    DOI:  https://doi.org/10.1002/anie.9595531
  35. Res Sq. 2026 Jun 01. pii: rs.3.rs-9372626. [Epub ahead of print]
    Dimeric architecture and membrane thinning govern substrate recognition by human signal peptide peptidase.
    Susan Lea, Owain Bryant, Nikita Sergejevs, Fiorin Giacomo, Jacob Robson-Tull, Justin Deme, Lucy Forrest, Pedro Carvalho.
      Signal peptide peptidase (SPP) is an intramembrane aspartyl protease that cleaves transmembrane segments of diverse origin, such as remnant signal peptides of secretory proteins or transmembrane helices of tail-anchored proteins. Consistent with its ability to cleave multiple substrates, SPP is essential in mammals, and its activity is linked to a wide range of processes from immune regulation to protein quality control and cancer. Here we determine cryo-EM structures of human SPP in its apo form and bound to a signal peptide substrate. Together with molecular dynamics simulations and functional assays, our data show that SPP forms a constitutive homodimer that locally curves and thins the membrane, placing the conserved active site within the bilayer. Substrate engagement drives major conformational changes, including movement of a "latch" helix that positions the signal peptide for cleavage. The substrate adopts a tilted helix-unwound-β-strand architecture that defines the cleavage register independently of sequence. Steric exclusion by folded luminal domains or additional transmembrane helices explains selective processing of certain protein termini.
    DOI:  https://doi.org/10.21203/rs.3.rs-9372626/v1
  36. STAR Protoc. 2026 Jun 09. pii: S2666-1667(26)00277-7. [Epub ahead of print]7(2): 104624
    Protocol for massively parallel RNA assay combined with immunoprecipitation for high-throughput analysis of RNA-protein interactions in cells.
    Yu Hsuan Lee, John L Rinn, Taeyoung Hwang.
      RNA functions are largely mediated through interactions with RNA-binding proteins (RBPs), and defining the molecular principles underlying these interactions is essential for understanding RNA biology. Here, we present a massively parallel RNA assay combined with immunoprecipitation (MPRNA-IP) that enables high-throughput analysis of RNA-protein interactions in cells. We describe detailed steps for oligonucleotide design, cloning, transfection, sequencing, and computational analysis. Together, these procedures allow high-throughput interrogation of RNA sequences to identify sequence and structural elements that contribute to protein binding. For complete details on the use and execution of this protocol, please refer to Lee et al.1.
    Keywords:  Genomics; High Throughput Screening; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104624
  37. Nucleic Acids Res. 2026 Jun 08. pii: gkag587. [Epub ahead of print]54(11):
    TRAINSPOTTER: profiling nascent protein N-termini indicative of bacterial translation initiation via deformylation-assisted N-terminomics.
    Petra Van Damme.
      Accurate delineation of bacterial translation initiation sites (TISs) remains a major challenge, as conventional genome annotation and ribosome profiling (Ribo-seq) often lack the resolution to discriminate closely spaced start codons. To overcome these limitations, we developed TRAINSPOTTER (TRAnslation INitiation SPOTTER), a deformylation-assisted N-terminomics workflow that enables direct, proteome-wide detection of nascent N-termini indicative of active translation initiation. TRAINSPOTTER exploits the universal N-terminal formylation of initiator methionine in bacteria: in vitro enzymatic deformylation by peptide deformylase (PDF) generates a diagnostic hydrophilic shift, allowing selective isolation of previously formylated, initiation-derived peptides by COFRADIC-based chromatography. Optional in vivo PDF inhibition transiently enriches formylated N-termini, primarily enhancing detection sensitivity. Integration of pulse SILAC (Stable Isotope Labeling by Amino acids in Cell Culture) labeling confirmed that deformylation-shifted peptides represent newly synthesized N-termini, validating TRAINSPOTTER's specificity for nascent translation products. Application to Escherichia coli enabled precise mapping of >1000 TIS-indicative N-termini, including numerous alternative and near-cognate start sites, providing direct proteomic evidence for co-expressed N-terminal proteoforms. The method complements and refines Ribo-seq datasets, offering amino acid-level resolution for otherwise ambiguous initiation events. TRAINSPOTTER thus establishes a robust biochemical framework for proteome-wide identification of TISs and advances the experimental annotation of bacterial proteomes.
    DOI:  https://doi.org/10.1093/nar/gkag587
  38. bioRxiv. 2026 Jun 07. pii: 2026.06.03.729952. [Epub ahead of print]
    Chaperonin recognition of protein dynamics drives drug resistance.
    Junlang Liu, Zhihui Qi, João V Rodrigues, Zhouyu Zhang, Qianxiang Xu, Abhinav Dubey, Harrison K Wang, Dongtao Cui, Zeyang Li, Fatima Aly, Doeke R Hekstra, Eugene I Shakhnovich.
      The emergence of drug resistance is typically driven by mutations that alter drug-target affinity, yet the role of host cellular machinery regulating these processes remains unclear. Here, we reveal that the chaperonin GroEL/S promotes drug resistance through recognition of protein dynamics. Using directed evolution of E. coli DHFR under antibiotic stress and varying GroEL/S expression, we identify a well-folded resistance variant whose fitness, despite tight inhibitor binding, is critically potentiated by GroEL/S engagement. X-ray crystallography, NMR, molecular dynamics and kinetic modeling reveal that millisecond-timescale flipping of the M20 loop generates steric accessibility and a kinetic window for chaperonin interaction that forcibly displaces tightly bound inhibitors, thereby overriding thermodynamic equilibrium of inhibitor binding to restore the active enzyme pool and preserve metabolic flux. Our findings not only reveal a novel paradigm of "dynamic recognition" where both conformational kinetics and distribution govern chaperonin recognition but also establish chaperonins as "deligandases" that actively modulate in vivo drug binding, suggesting that chaperone surveillance of the cellular proteome extends beyond quality control to govern native protein function. This mechanism defines a previously unrecognized route for the rapid development of drug resistance, with implications for understanding therapeutics of microbial infections and human malignancies.
    DOI:  https://doi.org/10.64898/2026.06.03.729952
  39. EMBO Rep. 2026 Jun 09.
    The EF-hand domain of MINDY3 is a ubiquitin and RAD23 UBL-binding domain.
    Lee A Armstrong, Matthew R McFarland, Rachel O'Dea, Roscislaw Krutyholowa, Magdalena Gorka, Thomas Carroll, Sebastian Glatt, Yogesh Kulathu.
      The MINDY family of deubiquitinases (DUBs) are exemplified by their preference for cleaving K48-linked polyubiquitin. MINDY3 is architecturally distinct from other MINDY DUBs as its catalytic domain spans the entire length of the protein except for an atypical EF-hand insertion. We uncover this EF-hand (MINDY3EF-hand) to be a ubiquitin-binding domain with three distinct binding sites, enabling MINDY3 to bind and effectively cleave long polyubiquitin chains. Furthermore, the MINDY3EF-hand domain binds not only to polyubiquitin but also to the UBL domain of the proteasome shuttling and DNA repair factors RAD23A and RAD23B. The MINDY3EF-hand facilitates this interaction with RAD23s in cells and mediates MINDY3 recruitment to DNA damage sites, establishing this unique DUB as a potential regulator of cellular DNA damage responses. MINDY3 binds specifically to the UBL domain of RAD23s, and none of the other UBLs tested. The crystal structure of the MINDY3EF-hand:RAD23AUBL domain complex reveals the molecular basis for specificity. We find that MINDY3 can form a ternary complex with RAD23A/B and polyubiquitin, and our findings suggest a model wherein MINDY3 can deubiquitylate RAD23A/B-bound clients.
    DOI:  https://doi.org/10.1038/s44319-026-00825-1
  40. Cell Rep. 2026 Jun 11. pii: S2211-1247(26)00575-9. [Epub ahead of print]45(6): 117497
    STING dampens the unfolded protein response to enable the presentation of self-antigens on MHC-I during inflammation.
    Ahmed M Fahmy, Ali Ahmadi, Joël Lanoix, Tyler Cannon, Moustafa N Elemeery, Camberly Hernandez Paredes, Benoit Barrette, Eric Bonneil, Yong Zhong Xu, Maha Ibrahim, Guillermo Arango-Duque, Eric Olivier Audemard, Sébastien Lemieux, Eric Chevet, Erwin Schurr, Philippe Pierre, Samantha Gruenheid, Pierre Thibault, Heidi M McBride, Michel Desjardins.
      A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8+ T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is engaged through a pathway involving cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which acts as a rheostat to dampen the unfolded protein response (UPR). Without STING, the stress response is amplified, leading to a translational attenuation that inhibits the expression of XBP1s, a transcription factor required for MitAP. STING activity also regulates the repertoire of peptides displayed at the cell surface during inflammation, highlighting a potential role in immunosurveillance. These findings establish STING and the UPR as key immune regulators targetable for therapeutic intervention during autoimmune diseases and PD.
    Keywords:  CP: cell biology; CP: molecular biology; Parkinson’s disease; STING; UPR; antigen presentation; immunopeptidomics; immunosurveillance; inflammation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117497
  41. Nucleic Acids Res. 2026 Jun 08. pii: gkag576. [Epub ahead of print]54(11):
    Observing intersubunit dynamics in single yeast ribosomes.
    Ananya Das, Amy K Grove, Aleksandr V Ivanov, Hironao Wakabayashi, Dmitri N Ermolenko.
      Translation is accompanied by the rotation of the small and large ribosomal subunits relative to each other. Here, we use single-molecule Förster resonance energy transfer between fluorophores introduced into ribosomal proteins uS15 and eL30 to follow the intersubunit dynamics of Saccharomyces cerevisiae ribosomes. Similar to their bacterial counterparts, yeast ribosomes are observed to sample two predominant FRET states corresponding to the nonrotated (NR) and rotated (R) conformations. Our data yield further evidence that intersubunit rotation is coupled to tRNA transitions between the classical and hybrid binding states. The elongation cycle, which comprises tRNA binding, peptide transfer, and mRNA-tRNA translocation, is accompanied by switching from NR to R, and then back to the NR conformation. We find that fungal elongation factor 3 (eEF3) stabilizes the NR conformation of the ribosome. Our data are consistent with the model suggesting that eEF3 facilitates E-site tRNA release at the late step of mRNA-tRNA translocation, following the reverse intersubunit rotation induced by the universally conserved elongation factor 2 (eEF2). Our uS15-eL30 smFRET assay provides the basis for investigating eukaryotic mechanisms of translation regulation, including ribosome pausing, stalling, and frameshifting.
    DOI:  https://doi.org/10.1093/nar/gkag576
  42. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2524190123
    A protective role for APP in nuclear waste clearance via lysosomal exocytosis.
    Godfried Dougnon, Takayoshi Otsuka, Yuka Nakamura, Akiko Sakai, Tomoyuki Yamanaka, Noriko Matsui, Asa Nakahara, Ai Ito, Atsushi Hatano, Masaki Matsumoto, Hironaka Igarashi, Akiyoshi Kakita, Masaki Ueno, Hideaki Matsui.
      Amyloid precursor protein (APP) is widely known for its role in Alzheimer's disease (AD) pathogenesis through its proteolytic processing into amyloid-β peptides. However, its physiological functions remain incompletely understood. Here, we uncover a protective role for full-length APP in facilitating the disposal of nuclear-derived debris under genotoxic stress. In both cultured cells and in vivo mouse models, loss of APP leads to nuclear waste accumulation, increased inflammation, and cell death, whereas APP overexpression mitigates these effects. Mechanistically, we show that APP supports the extracellular release of nuclear waste material through lysosomal exocytosis. APP mutants associated with familial AD fail to mediate this process. Consistently, human AD brain tissue exhibits abnormal nuclear morphology, accumulation of nuclear waste in the cytoplasm, and reduced APP levels per neuron. These findings highlight a conserved cellular mechanism by which APP contributes to nuclear and cellular homeostasis, and suggest that impaired nuclear waste clearance may represent an underappreciated contributor to neurodegeneration.
    Keywords:  amyloid precursor protein; cellular homeostasis; lysosomal exocytosis; neurodegeneration; nuclear waste clearance
    DOI:  https://doi.org/10.1073/pnas.2524190123
  43. bioRxiv. 2026 Jun 06. pii: 2026.06.05.729624. [Epub ahead of print]
    Lysosomal lipid metabolism promotes tumor cell invasion through local energetics and membrane lipid remodeling.
    Roseanne E Nooren, Katherine M Johnson, Maxwell G Marley, Cody N Rozeveld, Daniel F Gibbard, Zinnarky K Ortiz Correa, Mustafa Emre Gedik, Tianna Espe, Taro Hitosugi, Ian R Lanza, Douglas G Brownfield, Jun Liu, Mark A McNiven, Gina L Razidlo.
      Metabolic vulnerabilities in cancer have been targeted primarily to suppress tumor growth, but less is known about the metabolic requirements for tumor cell invasion. Here we report that lipid catabolism by cytosolic and lysosomal lipases supports pancreatic cancer cell invasion through both overlapping and distinct functional and metabolic mechanisms. Lysosomal acid lipase (LAL)-dependent lipid droplet catabolism promotes invadopodia formation and stabilization, enabling extracellular matrix degradation. In addition to modulating cellular energetics, lipidomics revealed that lipid droplet catabolism regulates cholesterol and membrane phospholipid levels. Using spatially resolved biosensors and cholesterol imaging, we found that lysosomal lipid catabolism occurs at invadopodia and sustains local ATP and membrane cholesterol. These findings identify spatially organized lipid catabolism as a mechanism that couples local energetics and membrane remodeling during the earliest steps of pancreatic cancer cell invasion.
    DOI:  https://doi.org/10.64898/2026.06.05.729624
  44. Cell. 2026 Jun 12. pii: S0092-8674(26)00586-6. [Epub ahead of print]
    Mechanism of lipid transfer by bridge-like protein VPS13A and the scramblase XK.
    Bodan Hu, Daniel Álvarez, Cristian Rocha-Roa, Valentin Guyard, Dazhi Li, Yara Ahmed, Xinbo Wang, Pietro De Camilli, Stefano Vanni, Karin M Reinisch.
      In eukaryotes, bridge-like lipid-transfer proteins (BLTPs) are central in mediating vesicle-independent lipid transfer between organelles. BLTPs span the cytosolic space between organelles at contact sites, featuring hydrophobic channels for lipids to travel between membranes. How BLTPs cooperate with partner proteins to orchestrate lipid delivery remains a mystery. Here, we used cryo-electron microscopy to visualize a complex comprising the prototypical BLTP VPS13A and the plasma membrane-localized scramblase XK at near-atomic resolution. VPS13A interacts with XK via its pleckstrin homology domain, priming VPS13A's bridge-like lipid-transfer domain to deliver lipids directly to the cytosolic leaflet of the acceptor membrane. In molecular dynamics simulations, this arrangement allows for robust lipid transfer. Newly delivered lipids can then be equilibrated between leaflets of the membrane bilayer by the scramblase, allowing for membrane growth. Mechanistic insights regarding lipid delivery by VPS13A are directly applicable to all VPS13 proteins and, more broadly, to all BLTP family members.
    Keywords:  VPS13; XK; bridge-like lipid-transfer protein; cryo-EM; lipid transfer; membrane contact sites; molecular dynamics simulations; scramblase
    DOI:  https://doi.org/10.1016/j.cell.2026.05.027
  45. Sci Adv. 2026 Jun 12. 12(24): eadx6378
    Bacterial extracellular vesicles promote membrane repair and tolerance to polymyxin B.
    Julia Bos, Yasmina Abou Haydar, Olena Mayboroda, Anaïs Backland, Pierre-Henri Commere, Didier Mazel.
      Bacterial extracellular vesicles (EVs) are nanosized lipid structures released under stress, yet their interactions with antibiotics remain poorly understood. We tracked real-time interactions between Escherichia coli, EVs, and fluorescent polymyxin B (Pmb) using single-cell imaging and cytometric approaches. EVs rapidly sequester Pmb, facilitating its removal from bacterial envelopes, and act as plugs by adhering to or fusing with damaged sites. Pmb triggers early Cpx/σE- and Rcs-dependent stress responses, linked to a ∼25% reduction in cell surface area, a ∼50-fold increase in vesiculation, and remodeling of membrane properties. After an adaptive lag phase, sustained EV release supports detoxification and envelope repair, enabling growth recovery and transient tolerance to Pmb. Together, these findings reveal previously unrecognized functions of EVs in membrane repair and tolerance to membrane-active antibiotics.
    DOI:  https://doi.org/10.1126/sciadv.adx6378
  46. JCI Insight. 2026 Jun 08. pii: e203262. [Epub ahead of print]11(11):
    Endoplasmic reticulum-resident α-glucosidase II drives non-small cell lung cancer progression via regulation of secretory glycoproteins.
    Shike Wang, Na Ding, Angelo Chen, Derrick Cardin, Yuting Xu, Kate Grimley, William K Russell, Jun Xu, Jonathan M Kurie, Guan-Yu Xiao, Xiaochao Tan.
      Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, yet its molecular drivers are not fully defined. Emerging evidence highlights the importance of tumor-stroma interactions mediated by secreted glycoproteins. However, the mechanisms by which cancer cells regulate the secretion of these protumorigenic proteins remain largely unknown. Endoplasmic reticulum-resident (ER-resident) N-glycan-processing enzymes regulate proper protein folding, a prerequisite for glycoproteins to exit the ER and undergo secretion. By evaluating their prognostic significance in lung tumors and conducting functional screening in lung cancer cells, we identify α-glucosidase II (α-Glc II) as a key regulator of NSCLC progression. α-Glc II promotes tumor growth and dissemination in a glucosidase activity-dependent manner in orthotopic mouse lung tumor model. Genetic disruption of α-Glc II induced ER stress and reduced cell proliferation and motility. Mechanistically, α-Glc II-mediated N-glycan modification regulated the ER-to-Golgi trafficking and secretion of specific oncogenic glycoproteins, including lysyl hydroxylase 2 (LH2), Tissue Inhibitor of Metalloproteinase 1 (TIMP1), and TGF-β, which are known to be associated with extracellular matrix remodeling. These findings uncover a role for ER glycosylation machinery in shaping the NSCLC secretome and highlight α-Glc II as a potential therapeutic target.
    Keywords:  Cancer; Cell biology; Lung cancer; Oncology; Protein traffic
    DOI:  https://doi.org/10.1172/jci.insight.203262
  47. Adv Sci (Weinh). 2026 Jun 09. e75988
    Discriminator-Guided Inverse Folding for Multi-Property Protein Design.
    Yuchuan Zheng, Chuyi Liu, Zhaoming Liu, Mao Su, Chenyu Tang, Xiang Zheng, Hao Zhang, Jingyuan Li.
      Designing proteins for real-world applications requires the simultaneous satisfaction of multiple physicochemical properties. Structure-based de novo protein design has become the prominent design paradigm, successfully creating numerous proteins. Property optimization is commonly introduced during the sequence generation stage of protein design, i.e., inverse folding. Existing methods primarily rely on fine-tuning inverse folding models to design sequences with desired characteristics. However, multi-property optimization through fine-tuning demands datasets annotated with multiple properties-resources that remain extremely limited. Consequently, structure-based protein design has not yet achieved joint optimization of multiple properties. Here, we present Discriminator-Guided Inverse Folding (DGIF), a framework that guides the inverse folding model by adjusting its internal history states through an auxiliary discriminator module. The discriminator integrates multiple property predictors, each trained independently on a single-property dataset, thereby enabling multi-property optimization in the absence of datasets annotated with multiple properties. In addition to substantial improvements in key traits like thermostability and solubility, DGIF can generate protein sequences optimized for both properties simultaneously, with the designed proteins shifting markedly toward the Pareto front that represents optimal trade-offs. Experimental results validate the effectiveness of DGIF for multi-property protein design.
    Keywords:  discriminator‐guided optimization; inverse folding model; multi‐property optimization; structure‐based protein design
    DOI:  https://doi.org/10.1002/advs.75988
  48. FEBS Open Bio. 2026 Jun 12.
    Transcripts enriched in codons that trigger P-site tRNA-mediated mRNA decay possess stable mRNA.
    Rodolfo Lopes Carneiro, Fernando Lucas Palhano.
      Synonymous codon usage significantly influences mRNA stability in yeast by guiding mRNA decay during translation. The CCR4-NOT complex is central to this process, interacting with ribosomes when the A and E sites are unoccupied, a state that arises when a nonoptimal codon with low tRNA availability is at the A site. This triggers recruitment of decay factors, reducing the stability of transcripts enriched in such codons. In humans, codon-mediated mRNA decay is less well-understood. Recent research has identified a related but distinct mechanism called P-site tRNA-mediated decay (PTMD). Unlike yeast, human CCR4-NOT recruitment depends on specific arginine codons (CGG, CGA, or AGG) at the P site and slow decoding at the A site, allowing E-site vacancy and CNOT3-dependent binding. Through analysis of public datasets, we explored the characteristics of human transcripts enriched in PTMD codons. Interestingly, these codons are mostly found in transcripts with longer half-lives. This suggests that, rather than targeting already unstable mRNAs as in yeast, PTMD in humans selectively reduces the stability of otherwise long-lived transcripts, indicating a regulatory role distinct from the decay associated with codon usage.
    Keywords:  Translation; codon usage; mRNA decay; mRNA turnover; tRNA
    DOI:  https://doi.org/10.1002/2211-5463.70277
  49. mBio. 2026 Jun 09. e0282025
    Opposing roles of deubiquitinases in the regulation of IRF7 transcriptional activity.
    Shumin Fan, Pracheta Sengupta, Karan Chawla, Manoj Veleeparambil, Ritu Chakravarti, Saurabh Chattopadhyay.
      Virus infection rapidly induces the production and secretion of interferons (IFNs), which amplify the antiviral responses in infected and neighboring uninfected cells. IFN regulatory factor 7 (IRF7), the "master transcription factor," is pivotal in IFN induction, particularly in myeloid cells. Ubiquitination of IRF7 is essential for its transcriptional activation; however, the underlying molecular mechanisms remain poorly understood. We hypothesized that deubiquitinases (DUBs) act as endogenous regulators of IRF7 activity, and conducted a genetic screen using an siRNA library of human DUBs. The screen identified USP2 as a positive regulator and OTUD5 as a negative regulator of IRF7 activity. OTUD5, an inducible DUB, interacted with IRF7 and inhibited its K63-linked ubiquitination, thereby suppressing IRF7 activation. Conversely, USP2 promoted IRF7 activity by binding to IRF7 and removing K27-linked ubiquitin chains, which we found to be inhibitory. Specifically, K27-linked ubiquitination impeded phosphorylation of IRF7, a critical step for its activation. Collectively, our independent lines of investigation, coupled with genetic screens and mechanistic studies, uncovered USP2 and OTUD5 as novel modulators of IRF7 function, providing novel insights into the regulation of antiviral immunity.
    IMPORTANCE: IFN regulatory factor 7 (IRF7) is a central protein that launches type I interferon responses, and its timely activation is essential for antiviral immunity. Our study uncovers a mechanism by which IRF7 activation is controlled by enzymes that specifically remove small molecular tags, known as ubiquitin, from proteins. Through a focused screen, we identified two enzymes with opposing roles in modulating IRF7 activity. OTUD5, one of these enzymes, suppresses IRF7 activity by removing a ubiquitin tag that is essential for its transcriptional function. In contrast, USP2, the other enzyme, activates IRF7 by removing a ubiquitin tag that is inhibitory to IRF7 functions. These findings reveal previously unrecognized layers of IRF7 regulation and highlight how these enzymes can be targeted therapeutically in diseases driven by abnormal IRF7 functions.
    Keywords:  IFN regulatory factor 7; K27 ubiquitination; OTUD5; USP2; deubiquitinases; innate immunity; ubiquitination
    DOI:  https://doi.org/10.1128/mbio.02820-25
  50. BMC Bioinformatics. 2026 Jun 12.
    Protein language models are accidental taxonomists.
    Logan Hallee, Tamar Peleg, Nikolaos Rafailidis, Jason P Gleghorn.
      Protein-protein interactions (PPIs) are fundamental to nearly all biological processes, yet their experimental characterization remains costly and time-consuming. While computational methods, particularly those using protein language models (pLMs), offer higher-throughput solutions, they often report unexpectedly high performance on multi-species datasets. Here, we introduce the accidental taxonomist hypothesis, proposing that neural networks can exploit the phylogenetic distances across labels in protein datasets rather than genuine interaction features. We show that in standard multi-species PPI datasets, positive pairs typically share a taxonomic origin, while randomly sampled negatives do not. We then demonstrate that pLM embeddings can be used to accurately distinguish whether two proteins share a taxonomic origin, allowing models to "cheat" by learning phylogeny instead of genuine PPI features. By employing a strategic sampling strategy that restricts negative examples to protein pairs from the same species, we reveal a marked drop in model performance, confirming our hypothesis. Compellingly, these strategically trained models still outperform single-species models, suggesting that multi-species data can improve performance if carefully curated. These findings suggest that accidental taxonomist behavior is a particularly influential confounder for PPI, and it is also broadly applicable to any supervised-learning protein dataset.
    Keywords:  Confounders; Negative sampling; Phylogenetics; Protein language modeling; Protein-protein interactions; Reward hacking; Taxonomy
    DOI:  https://doi.org/10.1186/s12859-026-06491-3
  51. bioRxiv. 2026 Jun 04. pii: 2026.05.28.728263. [Epub ahead of print]
    Structural basis for regulation of the proteasome 20S core particle by the Parkinsonism-associated proteins FBXO7 and PI31.
    Frank Adolf, Ellen A Goodall, Ekampreet Singh, Susanne von Gronau, Erignacio Fermin Perez, Darlene Fung, Benedikt Müller, Joao A Paulo, John Hanna, J Wade Harper, Brenda A Schulman.
      FBXO7 and PI31 variants are linked to rare Parkinsonian syndromes, implicating their dysfunction in neurodegeneration. We define how both engage each other and regulate the proteasome 20S core particle (CP). In cells, each can associate independently with the proteasome, with multiple domains in FBXO7 contributing. Utilizing cryo-EM we visualized how FBXO7's C-terminal domain engages multiple subunits within the CP interior, blocking the β5 peptidase activity. In contrast, we visualized PI31 engagement of all three catalytic sites within the 20S CP, revealing the previously unknown structural basis for β1 inhibition. Furthermore, we establish how disease-associated variants impact both FBXO7 and PI31 function, including disruption of proteasome inhibition and SKP1-FBXO7-PI31 complex assembly. These results establish an unexpected function for FBXO7, providing a mechanistic basis for investigation of its role in proteasome regulation in Parkinson's disease.
    DOI:  https://doi.org/10.64898/2026.05.28.728263
  52. JCI Insight. 2026 Jun 08. pii: e197924. [Epub ahead of print]11(11):
    Serum starvation drives ALIX-dependent extracellular vesicle biogenesis and determines tumor progression.
    Xueqiang Peng, Jiaxing Liu, Guolong Zeng, Yafei Xiao, Zhixiong Hao, Guangpeng He, Hongyuan Jin, Yu Gao, Shilei Tang, Shibo Wei, Yan Li, Yifan Yu, Liang Yang, Hangyu Li.
      Tumor cells are constantly confronted with nutrient deprivation; however, the effect of serum starvation on the remodeling of endosomal compartments and extracellular vesicles (EVs) in tumor cells remains unclear. Here, we found that serum starvation pronouncedly promotes multivesicular body (MVB) biogenesis, EV formation, and cargo selection. Specifically, by generating a constitutively active Rab5Q79L mutant to induce the enlargement of MVB, we revealed for the first time to our knowledge that ANXA3 is sorted into intraluminal vesicles (ILVs) of MVB. Mechanistically, we confirmed that serum starvation regulates the endosomal sorting complex required for transport-associated (ESCRT-associated) protein ALG-2 interacting protein X (ALIX), which recruits ESCRT-III to MVB and binds to annexin A3 (ANXA3) to mediate its sorting into ILVs of MVB. Our study highlights that serum starvation promotes an ALIX-dependent ESCRT-III recruitment pathway, which loads protumor ANXA3 cargo to exert a profound effect on tumor progression.
    Keywords:  Cancer; Cell biology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.197924
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