bims-proteo Biomed News
on Proteostasis
Issue of 2026–05–03
58 papers selected by
Eric Chevet, INSERM
  1. IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.
  2. Autophagy reshapes the aging ER.
  3. Proteotoxic stress response is governed by ER-associated sorting of proteasome transcriptional activators.
  4. Small heat shock proteins and biomolecular condensates.
  5. The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
  6. Chromogranin B plays an essential role in post-endoplasmic reticulum sorting of dense-core vesicle cargo.
  7. Protein entanglement misfolding determines divergent fates: proteasomal degradation or persistence in near-native misfolded states.
  8. The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.
  9. Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.
  10. Biogenesis of TNF-α-insights into proteostasis and inflammation.
  11. Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
  12. The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells.
  13. The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.
  14. New Reversible Covalent Warheads: Cyanobenzothiazoles Recruiting DCAF16 for Targeted Protein Degradation.
  15. Hijacking client instability to selectively disrupt HSP90-driven glucocorticoid receptor activation.
  16. Multivalent recognition of ferritin by full-length NCOA4 enables robust ferritinophagy.
  17. Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
  18. The E3 Ligase RNF8 Promotes Ubiquitination and Degradation of ChREBPα During Liver Stress Response.
  19. Time-resolved proteomics reveals five modules of stress granule disassembly and identifies SYNCRIP as a late-phase clearance factor.
  20. Quality control of protein import into mammalian mitochondria.
  21. FlyPredictome: A structural atlas of predicted protein-protein interactions in Drosophila.
  22. The interferon-stimulated gene product HERC5 inhibits human LINE-1 retrotransposition with an ISGylation-independent mechanism.
  23. Nuclear envelope budding enables export of large transcripts in muscle cells.
  24. Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
  25. The past, present and future of de novo protein design.
  26. eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
  27. A proximity-labeling map of PI5P4K phosphoinositide kinases interaction networks.
  28. Sensing endoplasmic reticulum redox state by ethylene receptors.
  29. Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
  30. Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.
  31. A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.
  32. Proximity Mapping of the ER Proteome Reveals Metastasis-specific Candidate Biomarkers in Breast Cancer Cell Lines.
  33. A family of ribosome hibernation factors widespread in Archaea.
  34. Indole-bipyridyl fluorophores as dual-functional probes for endoplasmic reticulum imaging and Zn2+ sensing in live cells.
  35. Autophagy-related protein 1 orchestrates autophagy initiation and feedback degradation in Alternaria alternata.
  36. ATP modulates holdase activity of fungal and human 110-kilodalton heat shock proteins to promote protein folding.
  37. A network-based map of the chemical exposome connects molecular interactions to public health.
  38. A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2.
  39. Translatable circular RNAs are degraded via nonsense-mediated mRNA decay.
  40. K63-linked ubiquitylation of S2P-RNAPII regulates transcription in a DNAPK inter-dependent manner in response to double-strand breaks.
  41. Condensates as Conformation Editors of Disordered Client Proteins.
  42. Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader.
  43. Nuclear N-glycosylation maintains H3K9me3 heterochromatin and genomic stability.
  44. NAE1/UBA3-UBE2M are E1 and E2 enzymes for the URM1 modification.
  45. Reprogramming of bacterial virulence by lysine acetylation.
  46. Temporal gating dictates stress-induced transcript export from the nucleus.
  47. Programmable artificial RNA condensates in mammalian cells.
  48. ATI-1 mediated disruption of the VCP-UFL1-Beclin1 axis thwarts autophagy initiation to trigger metabolic catastrophe in autophagy-addicted cancers.
  49. Proteome-wide prediction of the functional impact of missense variants with ProteoCast.
  50. ATG9A-mediated plasma membrane repair is linked to Vps13A and regulated by glycosylation.
  51. Structural basis of chaperone mechanisms in cells and the evolutionary emergence of the protein world.
  52. Bioinspired Molecular Engineering of IRE1-Gated DNAzymes for Self-Adaptive Bidirectional Modulation of ER Stress.
  53. Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.
  54. A Hybrid Physics-Deep Learning Framework for Combinatorial De Novo Design of Small-Molecule Binding Proteins.
  55. LEP-AD: language embedding of proteins and attention to drugs predicts drug-target interactions.
  56. Biomolecular condensates provide a unique environment for redox-mediated protein crosslinking.
  57. Native entanglement misfolding contributes to age-associated structural changes across the Saccharomyces cerevisiae proteome.
  58. Small heat shock and J-domain proteins direct defense against areca palm velarivirus 1 by degrading coat protein via autophagy.
  1. Cell Mol Biol Lett. 2026 Apr 30.
    IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.
    Chen Lenchisky, Areen Muhammad Majadly, Irena Bronshtein Berger, Danielle Biton, Alaa Daoud Sarsour, Narkis Arbeli, Tamar Cohen, Naama Amos, Sara Kinstlinger, Ortal Cohen, Elad Horwitz, Moran Dvela-Levitt.
       BACKGROUND: The endoplasmic reticulum (ER) plays a central role in protein homeostasis by facilitating the folding, modification, and quality control of secretory and membrane proteins. Disruption of ER function results in protein misfolding and ER stress, which activate the unfolded protein response (UPR). While the three canonical UPR branches, inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), have been extensively studied, the mechanisms that coordinate their activities and ultimately dictate survival or death remain poorly understood. Transmembrane P24 trafficking protein 9 (TMED9), a cargo receptor that cycles between the ER and Golgi, has been implicated in protein quality control under pathological conditions, but its physiological role in ER proteostasis and UPR signaling is unclear.
    METHODS: The ER stress response was studied in cellular human models including normal epithelial cells and patient-derived pediatric glioma cultures. To define the regulatory mechanisms dictating TMED9 expression, quantitative Reverse Transcription polymerase chain reaction (qRT-PCR), luciferase reporter assay, and western blotting were employed. To elucidate TMED9 function, loss-of-function approaches, including clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated knockout and small interfering RNA knockdown were used in combination with RNA-seq and live imaging. Protein stability was tested by pulse-chase experiments, ubiquitination, and degradation analyses. To study the implications of TMED9 activation, we screened curated gene expression datasets from the European Molecular Biology Laboratory- European Bioinformatics Institute (EMBL-EBI) Expression Atlas and employed live-cell imaging-based assays and functional assays (cell viability, apoptosis, migration, and self-renewal).
    RESULTS: Our study uncovers a physiological role for TMED9 in ER proteostasis and UPR signaling. We show that, under ER stress, TMED9 expression is transcriptionally induced by the IRE1-spliced X-box binding protein 1 (XBP1s) pathway via a conserved unfolded protein response element (UPRE)-like element in its promoter. Removal of TMED9 selectively impairs ATF6 activation without altering IRE1 or PERK signaling, resulting in increased sensitivity to ER stress-induced apoptosis. Mechanistically, we identify TMED9 as a stress-induced stabilizer of ATF6 that prevents its ubiquitin-dependent proteasomal degradation. Functionally, TMED9 regulation is exploited by tumor cells, which sustain IRE1-XBP1s activity to upregulate TMED9, thereby enhancing survival under ER stress conditions.
    CONCLUSIONS: Collectively, our findings establish TMED9 as a critical regulator of ER stress adaptation. TMED9 emerges as a molecular mediator that links IRE1-dependent transcriptional response to ATF6 stabilization, ultimately supporting increased secretory demand under stress conditions and in cancer development.
    Keywords:  ATF6; DIPG; ER stress; Glioma; IRE1–XBP1s pathway; Proteostasis; TMED9; UPR; p24 proteins
    DOI:  https://doi.org/10.1186/s11658-026-00931-x
  2. Autophagy. 2026 Apr 27. 1-2
    Autophagy reshapes the aging ER.
    Eric K F Donahue, Kristopher Burkewitz.
      Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.Abbreviations: ER: endoplasmic reticulum; TMEM-131: transmembrane protein 131; UPR: unfolded protein response; IRE-1: inositol-requiring enzyme 1; XBP-1: X-box binding protein 1; mTOR: mechanistic target of rapamycin.
    Keywords:  ER-phagy; Endoplasmic reticulum; mTOR; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1080/15548627.2026.2662429
  3. Mol Cell. 2026 Apr 30. pii: S1097-2765(26)00238-8. [Epub ahead of print]
    Proteotoxic stress response is governed by ER-associated sorting of proteasome transcriptional activators.
    Gautier Langin, Margot Raffeiner, David Biermann, Mirita Franz, Daniela Spinti, Frederik Börnke, Boris Macek, Suayib Üstün.
      Proteotoxic stress, characterized by the accumulation of damaged proteins, poses a significant challenge to cellular homeostasis. To mitigate proteotoxicity, eukaryotes rely on the proteasome, which is regulated by proteasome transcriptional activators. As proteotoxicity can originate in different compartments, cells must integrate signals from multiple locations, yet the mechanisms coordinating this response remain unclear. Here, we show that the proteasome autoregulatory feedback loop functions as a gatekeeper enabling the communication between the nucleus and chloroplast. At the endoplasmic reticulum (ER), the plant proteasome transcriptional activators NAC53 and NAC78 undergo either ER-associated degradation (ERAD) or are released for nuclear translocation. We define this dual mechanism as ER-associated sorting (ERAS). While NAC53/78 activate proteasome gene expression, they repress photosynthesis-associated nuclear genes during proteotoxicity through a conserved cis-element. Together, our findings reveal a trade-off between proteasome activity and energy metabolism and establish a framework in which the proteasome feedback loop coordinates subcellular proteostasis and growth-defense balance.
    Keywords:  pathogen; photosynthesis; proteasome; proteotoxicity; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.004
  4. Cell Mol Life Sci. 2026 May 01.
    Small heat shock proteins and biomolecular condensates.
    Samuele Crotti, Valentina Secco, Marialaura Morini, Serena Carra.
      Proteins comprise well-ordered structural domains and intrinsically disordered regions that explore broad conformational ensembles, a pervasive feature of the human proteome that underlies key aspects of cellular physiology. In the crowded intracellular environment, stress can shift protein conformational equilibria toward aggregation-prone states, exposing hydrophobic regions that can drive aberrant protein-protein interactions, promoting aggregation. To maintain proteome integrity, cells depend on an integrated protein‑quality‑control network in which molecular chaperones, their co‑factors and dedicated degradation systems act in concert. Within this network, small heat shock proteins serve as an ATP-independent first line of defense that stabilizes non-native proteins and limits irreversible aggregation. Recent work shows that small heat shock proteins can also safeguard the liquid‑like dynamics of biomolecular condensates formed by liquid-liquid phase separation. These membraneless compartments organize cellular biochemistry but are susceptible to stress- and disease-induced arrest or aggregation. Rather than undergoing phase separation autonomously, small heat shock proteins can be recruited into pre-existing condensates such as stress granules, nuclear speckles, p62 bodies, and condensates formed by disease-associated proteins, where they help preserve condensate fluidity. Together, these findings position small heat shock proteins as modulators of condensate dynamics that link protein quality control to mesoscale cellular organization, with important implications for cell biology, aging, and human disease.
    Keywords:  Biomolecular condensates; Liquid-liquid phase separation; Molecular chaperones; Protein quality control.; Small heat shock proteins
    DOI:  https://doi.org/10.1007/s00018-026-06216-y
  5. Nat Cell Biol. 2026 Apr 30.
    The atypical E3 ligase HOIL-1 safeguards the ribosome during cellular stress.
    Todd Douglas, Pengju Nie, Jiasheng Zhang, Kyrillos S Abdallah, Zhiping Wu, Meghan McReynolds, Kazuhiro Iwai, Junmin Peng, Wendy V Gilbert, Lawrence H Young, Craig M Crews.
      The ribosome has emerged as a signalling hub that can sense metabolic perturbations and coordinate responses that either restore homeostasis or initiate cell death. The range of insults that signal via the ribosome and the mechanisms governing such cell fate decisions remain uncharacterized. Here we identify the atypical E3 ligase HOIL-1 as an unexpected node in the ribosome signalling network that resolves cellular stress. We find that truncating HOIL-1 mutations associated with dilated cardiomyopathy exacerbate cardiac dysfunction in mice and broadly sensitize cells to nutrient and translational stress. These diverse signals converge on the MAP3K ZAKα, a sentinel of ribotoxic stress. Mechanistically, HOIL-1 promotes ribosome ubiquitination and facilitates cytoprotective ribosome-associated quality control. HOIL-1 loss of function causes glucose starvation to become ribotoxic, leading to ZAKα-dependent ATF4 activation and disulfidptosis driven by the cystine-glutamate antiporter xCT. These data reveal a molecular circuit controlling cell fate during nutrient stress and establish the ribosome as a signalosome that responds to cellular glucose levels.
    DOI:  https://doi.org/10.1038/s41556-026-01936-6
  6. J Cell Sci. 2026 Apr 15. pii: jcs264703. [Epub ahead of print]139(8):
    Chromogranin B plays an essential role in post-endoplasmic reticulum sorting of dense-core vesicle cargo.
    Chandramouli Mukherjee, Palki Chauksey, Mohima Mukherjee, Sushma Dagar, Souren Sadhukhan, Judith Klumperman, Bhavani Shankar Sahu.
      Chromogranin B (ChgB) is a major dense-core vesicle (DCV) matrix protein whose mechanistic role in DCV function remains ambiguous. To address this, we used CRISPR-Cas9-mediated genetic ablation, combined with quantitative microscopy and biochemical analyses, in PC12 and INS-1 cell lines and mouse models, demonstrating its essential role in DCV function. ChgB knockout cells exhibit severely impaired stimulus-coupled DCV exocytosis, while constitutive and synaptic-like vesicle secretion remain intact. Ultrastructural analyses reveal reduced dense-core area, altered vesicle numbers and sizes, and mislocalisation of DCVs away from the plasma membrane. ChgB deletion further causes Golgi fragmentation and prevents DCV cargo from entering the trans-Golgi network, delaying cargo exit. Subsequently, this possible effect, attributable to augmented endoplasmic reticulum stress, alters the SNARE signature and impairs full-fusion exocytosis. Finally, rescue experiments reversed defective sorting kinetics and exocytosis, suggesting a specific role of ChgB in DCV function. Together, these findings identify ChgB as a central regulator of DCV biogenesis, cargo sorting, and fusion competence.
    Keywords:  Cargo sorting; Chromogranin B; Dense-core vesicles; ER stress; Regulated exocytosis; SNARE machinery
    DOI:  https://doi.org/10.1242/jcs.264703
  7. bioRxiv. 2026 Apr 16. pii: 2026.04.15.718748. [Epub ahead of print]
    Protein entanglement misfolding determines divergent fates: proteasomal degradation or persistence in near-native misfolded states.
    Yang Jiang, Anushka Jain, Sina Ghaemmaghami, Edward P O'Brien.
      A novel class of protein misfolding, involving changes in entanglement status, occurs across the cytosolic proteome of a bacterium and likely occurs in many other organisms. Here, we examine if this class of misfolding has measurable downstream consequences for protein homeostasis. Specifically, we test the hypothesis that proteins that misfold in this way are more likely to be degraded by the ubiquitin-proteosome system immediately after synthesis. We do this by cross-referencing protein structural information with ubiquitin mass spectrometry (Ubq-MS) data from human fibroblast cells. Ubq-MS identifies proteins that have been covalently modified with ubiquitin in a particular pattern and is a cellular signal for that protein to be degraded by the proteosome. We find that nascent proteins with native entanglements, which were previously shown to be twice as likely to misfold, are 93% (95% Confidence Interval: [44%, 160%]) more likely to be tagged with ubiquitin and targeted to the proteasome compared to proteins that do not contain such entanglements. Simulating the folding of these proteins using a coarse-grained model, we find that the ubiquitin-tagged proteins containing native entanglements are four times more likely to misfold than the non-ubiquitinated proteins that are devoid of entanglements. These results indicate that entanglement misfolding, primarily involving a failure to form native entanglements, leads to an increased likelihood that those proteins will be degraded in human cells. Finally, we estimate that approximately one-third of the globular proteome likely misfolds in this way but bypasses proteasomal degradation because their misfolded states are structurally similar to their native ensemble. These consequences for protein degradation are likely common across organisms as entanglement misfolding is inherent to the polymeric nature of proteins.
    DOI:  https://doi.org/10.64898/2026.04.15.718748
  8. Nat Commun. 2026 Apr 27.
    The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50.
    Admire Munanairi, David A Rudnick, Jiansheng Huang, David H Perlmutter.
      In previous studies we have shown that accumulation of the polymerogenic variant ATZ that causes α1-antitrypsin deficiency (ATD) activates NFκB DNA binding. Here we discovered that this response, which we are naming the polymerized protein response (PPR), is characterized by NFκB p50 homodimers, distinct from the p50/p65 heterodimers in the canonical NFκB inflammatory response and the unfolded protein response (UPR). The PPR is also activated by other disease associated variants that polymerize in the ER whereas disease-associated variants that do not form polymers activate p50/p65 heterodimers and UPR. The PPR elicits a unique gene expression profile, including changes that stabilize p50 homodimers in cytoplasm and nucleus. The PPR is blocked by specific genetic substitutions within the luminal and cytosolic domains of Derlin-2 providing evidence that the ERAD retrotranslocation complex is a proximal transducer of this signaling mechanism. We hypothesize that the PPR is a proteostasis response pathway complementary to the UPR, designed to protect the cell from the specific proteotoxic effects of polymers that form aberrantly in the ER.
    DOI:  https://doi.org/10.1038/s41467-026-72369-w
  9. Nat Commun. 2026 Apr 29.
    Aging-associated modulation of UFMylation impairs proteostasis in C. elegans.
    Reut Bruck-Haimson, Hana Boocholez, Huadong Zhu, Adam Zaretsky, Irit Cohen, Xiaofeng Feng, Yong-Hong Yan, Meng-Qiu Dong, Ehud Cohen.
      The attachment of Post-Translational Modifications (PTMs) to proteins regulates their activities and stability. Here we utilized the nematode Caenorhabditis elegans to test whether UFMylation, a PTM which affects key biological functions, regulate aging and protein homeostasis (proteostasis). We find that lowering UFMylation extends lifespan and mitigates the toxicity of aggregation-prone proteins that underlie the development of neurodegenerative disorders in humans. Mass spectrometric analysis suggests that UFMylation of aging-regulating proteins, including of the nucleolar FIB-1-NOL-56 complex and the germline-resident proteins CAR-1 and CGH-1, governs proteostasis, probably across tissues. Functional analyses indicate that the proteostasis-regulating transcription factors DAF-16 and SKN-1 are crucial for the protective effects of reduced UFMylation. Counter-proteotoxic effect of reduced UFMylation are mediated by enhanced nascent protein quality control, reduced protein aggregation, and increased protein degradation by the ubiquitin-proteasome system. These insights highlight the important roles of PTMs in the regulation of proteostasis and point at research directions for the development of therapies for neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-026-72479-5
  10. FEBS J. 2026 Apr 25.
    Biogenesis of TNF-α-insights into proteostasis and inflammation.
    Bailasan Haidar, Céline Philippe, Eric Chevet, Jiří Zahradník.
      Tumour necrosis factor-α (TNF-α) is a central pro-inflammatory cytokine whose biogenesis, secretion, and signalling are tightly interconnected with cellular protein-quality control systems. Current evidence shows that TNF-α maturation, co-translational and post-modifications, ER-luminal folding and trimerisation, Golgi trafficking, and ectodomain shedding by ADAM17 are constrained by ER chaperones and ER-associated degradation (ERAD). Furthermore, TNF-α signalling reciprocally interfaces with the proteostasis network (PN) largely through inflammatory stress pathways such as NF-κB-dependent transcriptional control of chaperones, ubiquitin-proteasome components, and autophagy regulators. However, dysregulation of this bidirectional crosstalk mechanistically contributes to disease, including chronic inflammatory disorders, cancer, and degenerative diseases. In this study we provide a synthesis of the current literature on pathways related to protein homeostasis control that determines whether TNF-α exposure is adaptive or proteotoxic. We also discuss the translational implications this could have by including rational combinations of TNF-α targeted blockers with PN modulators (chemical chaperones, proteasome or autophagy modulators), which reduce the proteotoxic burden. Therefore, understanding the crosstalk between TNF-α signalling and components of the PN system promises new mechanistic insights and translational targets for TNF-α-driven diseases.
    Keywords:  ER‐associated degradation; NF‐κB pathway; autophagy; cytokine signalling; endoplasmic reticulum stress; inflammation; protein aggregation; proteostasis network; tumor necrosis factor‐alpha; unfolded protein response
    DOI:  https://doi.org/10.1111/febs.70553
  11. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2518812123
    Suppression rather than activation of the integrated stress response (GCN2-ATF4) pathway extends lifespan in the fly.
    Miriam S Götz, Dan J Hayman, Gracie Adams, Fumiaki Obata, Mirre J P Simons.
      Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress-responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway), is prolongevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in longevity in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed that dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signaling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown may upregulate proteostasis and DNA repair pathways. Our work reveals that ATF4 may exhibit a dual, dose-, and context-dependent role in aging. Chronic dATF4 activation is detrimental in flies, while chronic suppression is prolongevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.
    Keywords:  aging; borrelidin; integrated stress response; tRNA; transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2518812123
  12. Sci Adv. 2026 May;12(18): eaea6630
    The nuclear cap-binding complex safeguards stress-resistant protein synthesis and proliferation of stem cells.
    Seyoun Oh, Jeeyoon Chang, Hodam Jo, Jungwon Yoon, Sung Key Jang, Yoon Ki Kim, Jiwon Jang.
      The integrated stress response (ISR) suppresses global translation while allowing selective synthesis of key regulatory proteins. However, how translation persists during ISR remains unclear. In eukaryotes, the 5'-cap of mRNAs is bound by either the cap-binding complex (CBC) or eIF4E. We show that under stress, CBC-bound mRNAs recruit eIF2A, an alternative initiation factor, to sustain translation when eIF4E-dependent translation is inhibited. Human embryonic stem cells (hESCs), which inherently exhibit ISR, continue proliferating due to a compensatory increase in eIF2A. This increase ensures CBC-dependent translation (CT) of essential cell cycle regulators. Notably, yes-associated protein (YAP), a key proliferation factor, is a major CT target driving stress-resistant stem cell proliferation. Our findings reveal CT as a critical pathway that preserves protein synthesis and proliferation under stress.
    DOI:  https://doi.org/10.1126/sciadv.aea6630
  13. Biochem Soc Trans. 2026 Apr 29. 54(4): 363-374
    The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.
    Elias Maldonado, Emily McIsaac, Josie Ursini-Siegel.
      Cancer cells face continual stressors, which they must overcome to proliferate and survive in the body. Under these conditions, essential biochemical pathways are disrupted, contributing to various stress responses that either promote adaptation and survival or eventual cell death. The evolutionarily conserved integrated stress response (ISR) is a key adaptive mechanism that transiently rewires the transcriptome and translatome in response to various stressors. While the ISR is activated in healthy cells under moderate stress, cancers especially rely on this pathway to overcome harsh conditions experienced during tumor growth and metastasis. We explore the pro-tumorigenic role of the ISR, along with the upstream stress-sensing kinases that activate it. These include protein kinase R-like endoplasmic reticulum kinase, general control non-derepressible 2, double-stranded RNA-dependent protein kinase, and heme-regulated eukaryotic translation initiation factor 2α kinase (HRI), which initiate an ISR in response to diverse stressors by phosphorylating their shared substrate, eukaryotic initiation factor-2α. An in-depth understanding of the pro-survival functions of the ISR and the contexts in which it is pro-tumorigenic is necessary to leverage the ISR as a therapeutic strategy.
    Keywords:  ATF4; Integrated Stress Response; cancer; eIF2alpha
    DOI:  https://doi.org/10.1042/BST20250133
  14. J Med Chem. 2026 Apr 27.
    New Reversible Covalent Warheads: Cyanobenzothiazoles Recruiting DCAF16 for Targeted Protein Degradation.
    Jixian Zhang, Lei Huang, Shengrong Li, Yifang Li, Yi Tan, Tongzheng Liu, Zhengqiu Li.
      Protein N-terminal cysteines (NCys) are valuable for selective modification and posttranslational regulation, but their proteome-wide landscape remains unexplored. We constructed a library of electrophilic probes, including cyanobenzothiazole (CBT), to systematically map ligandable native NCys residues. Modifiable NCys sites were identified in proteins such as GFPT1 and CSTB, revealing accessible NCys in the human proteome. Integrating CBT into a BRD4-targeting ligand generated a reversible covalent degrader (DC50 = 16.7 nM, Dmax = 98%). Mechanistic studies showed that CBT modifies DCAF16 at Cys58, promoting ternary complex formation and enabling efficient ubiquitination and degradation. The platform achieved potent and selective degradation of challenging targets like EGFRL858R/T790M/C797S and HER2 without hook effects, outperforming clinical inhibitors. This work provides the first proteome-wide map of ligandable NCys residues and establishes CBT as a versatile platform for covalent targeted protein degradation (TPD), opening new avenues for precision therapeutics.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00889
  15. Pharmacol Res. 2026 Apr 27. pii: S1043-6618(26)00120-9. [Epub ahead of print]228 108205
    Hijacking client instability to selectively disrupt HSP90-driven glucocorticoid receptor activation.
    Elisa Longhi, Andrea Magni, Luca Torielli, Giulia Lodigiani, Elena Carlessi, Patrizia Borsotti, Filippo Doria, Valentina Pirota, Stefano A Serapian, Cristina Arrigoni, Marco Lolicato, Elisabetta Moroni, Greta Bergamaschi, Giulia Taraboletti, Giorgio Colombo.
      The molecular chaperone HSP90 drives the folding and activation of a broad spectrum of client proteins through dynamic, transient multiprotein assemblies. Although HSP90 has been widely pursued as an anticancer target, ATP-competitive inhibitors can trigger indiscriminate client depletion and protective heat shock responses, limiting clinical utility. Here, we report a client-directed strategy to perturb HSP90-dependent maturation by targeting unstable client regions that act as transient recognition sites for chaperone networks. Using energy-decomposition analysis of the ligand-binding domain of the stringent HSP90 client glucocorticoid receptor (GR), we identified surface-exposed, weakly coupled substructures predicted to sample locally unfolded conformations. We translated these motifs into a set of short GR-derived peptide mimics designed to compete with chaperone engagement events required for productive GR folding. The peptides selectively bind purified HSP90, are cell permeable, and induce GR degradation in triple-negative breast cancer cells. Functionally, the most active mimic potentiates paclitaxel response under hormone-supplemented conditions and suppresses glucocorticoid-induced tumor cell quiescence. These results establish a framework that integrates computation-guided identification of client unfolding regions to the rational design of chemical probes that modulate chaperone-dependent signaling pathways, with relevance for cancer progression. More broadly, our study illustrates how targeting weak, client-specific interactions within proteostasis assemblies can yield new entry points for therapeutic development.
    Keywords:  Antineoplastic Therapy; Breast Cancer; Chaperone Machinery; Drug Design; Drug Response/Resistance; Pharmacological Targeting of Protein Folding; Protein Degradation; Protein-Protein Interactions
    DOI:  https://doi.org/10.1016/j.phrs.2026.108205
  16. Protein Sci. 2026 May;35(5): e70589
    Multivalent recognition of ferritin by full-length NCOA4 enables robust ferritinophagy.
    Ayush K Srivastava, Genki Terashi, Rosa Viner, Audrey Kishishita, Arun P Wiita, Anitha Rajendran, Yeonni Zoo, Georgia C Papaefthymiou, Daisuke Kihara, Fadi Bou-Abdallah.
      Ferritinophagy is a central pathway in cellular iron homeostasis, yet the molecular basis by which the selective autophagy receptor NCOA4 recognizes and engages ferritin remains poorly defined, largely due to the long-standing inability of working with a soluble form of the full-length human NCOA4 (NCOA4FL). Here, we present an integrated biochemical and biophysical analysis of NCOA4FL and its interaction with human ferritin, complemented by structure-guided modeling. We show that NCOA4FL is predominantly intrinsically disordered and exists in a dynamic monomer-dimer equilibrium in solution, yet forms a stable, nanomolar-affinity complex with ferritin. Using crosslinking mass spectrometry, together with integrative modeling informed by low-resolution structural context, we demonstrate that NCOA4FL engages ferritin through a multivalent, distributed interface that is not confined to a short motif, in contrast to prior fragment-based models. Multiple interaction hotspots are identified on ferritin helices B and D, while NCOA4FL employs both central and terminal regions to wrap around the ferritin nanocage, enabling avidity-driven recognition. We further show that NCOA4FL coordinates a redox-sensitive [4Fe-4S] cluster, introducing a chemically defined feature that may contribute to its conformational plasticity and regulation. Together, these findings establish NCOA4FL as a flexible, multivalent ferritin receptor and define the recognition logic by which ferritin assemblies are selectively recognized and targeted for lysosomal degradation during ferritinophagy.
    Keywords:  NCOA4; ferritin; ferritinophagy; intrinsically disordered protein (IDP); multivalent binding
    DOI:  https://doi.org/10.1002/pro.70589
  17. bioRxiv. 2026 Feb 06. pii: 2026.02.04.703776. [Epub ahead of print]
    Single-cell profiling reveals pervasive heterogeneity in subcellular RNA localization.
    Xiaojuan Fan, Markus Hafner.
      Subcellular RNA localization is a fundamental layer of gene regulation, yet its heterogeneity across individual cells remains poorly understood. Here, we introduce the RNA Localization Profiler (RLP), a proximity-based RNA-editing strategy that maps compartment-specific RNAs in living cells. Across the cytoplasm, endoplasmic reticulum (ER), and plasma membrane, RLP identifies robust and highly specific RNA localization programs linked to translation and membrane organization. Single-cell RLP (scRLP) reveals that individual cells harbor roughly 5,000-7,000 cytoplasmic RNAs, with <10% associated with the ER. These measurements uncover pervasive subcellular heterogeneity in RNA localization that is undetectable by bulk assays. Spatial RNA patterns define an orthogonal axis of cell-state identity that is independent of gene expression. For example, ZWINT mRNA relocalizes to the cytoplasm in a cell cycle-dependent manner. These findings establish heterogeneous levels of subcellular RNA localization as a variable dimension of intracellular organization and cell identity.
    DOI:  https://doi.org/10.64898/2026.02.04.703776
  18. FASEB J. 2026 May 15. 40(9): e71830
    The E3 Ligase RNF8 Promotes Ubiquitination and Degradation of ChREBPα During Liver Stress Response.
    Yuee Zhao, Sujuan Wang, Jian Zhang, Sarah Cooke, Gary Zhang, Zifeng Zhao, Joon Oh, Xin Tong, Lei Yin.
      As the most common chronic liver disease, MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH) driven by accumulated metabolic and inflammatory stresses. We previously reported that liver ChREBPα protein is markedly downregulated in mouse models of diet-induced MASH and hepatotoxin-induced liver injury. Yet the impact of stress pathways on hepatocyte ChREBPα proteolysis has not been examined. Here, we show that a combined metabolic (palmitate, PA) and inflammatory (TNFα) stress signal promotes ubiquitination and proteasome-mediated degradation of ChREBPα in hepatocytes. More importantly, we identify the stress-induced E3 ligase RNF8 as interacting with and promoting ChREBPα ubiquitination and degradation in a JNK2-dependent manner. In vivo, acute depletion of JNK2 or RNF8 stabilizes ChREBPα in mouse liver, increases some but not all ChREBPα transcriptional targets, and reduces diet-induced liver steatosis, inflammation, and fibrosis. Overall, our findings reveal the biochemical machinery underlying stress-induced ChREBPα proteolysis and suggest that targeting RNF8-mediated ChREBPα ubiquitination could be a new strategy for treating MASH.
    DOI:  https://doi.org/10.1096/fj.202600106R
  19. Int J Biochem Cell Biol. 2026 Apr 28. pii: S1357-2725(26)00065-8. [Epub ahead of print]197-198 106961
    Time-resolved proteomics reveals five modules of stress granule disassembly and identifies SYNCRIP as a late-phase clearance factor.
    Suguru Fujita, Miyu Murata, Hyun-Woo Rhee, Shin-Ichi Tate, Kyota Yasuda.
      Stress granules (SGs) are membraneless ribonucleoprotein condensates that form under stress and dissolve during recovery. While assembly mechanisms are well characterized, the temporal organization of disassembly remains incompletely understood. Here, we performed time-resolved proximity proteomics across SG disassembly (0-50 min recovery; n = 3) using G3BP1 as bait, identifying 79 proteins with robust temporal dynamics. Unsupervised clustering resolved five kinetic modules: early-increase, early-decrease/late-increase, transient-drop at ∼40 min, early-decrease, and zig-zag patterns. The transient-drop module was enriched for RNA-processing factors, consistent with transient changes in RNA-processing factor engagement. SYNCRIP, an hnRNP family protein in the early-decrease/late-increase module, showed characteristic biphasic dynamics during recovery. Functional validation demonstrated that SYNCRIP knockdown specifically impairs late-phase SG clearance-increasing granule size at 50 min recovery-without affecting formation. Together, our data provide a modular temporal map of SG disassembly and establish SYNCRIP as a functionally validated factor required for late-phase clearance.
    Keywords:  Phase separation; RNA-binding proteins; SG disassembly; SYNCRIP; Stress granules; Time-resolved proteomics
    DOI:  https://doi.org/10.1016/j.biocel.2026.106961
  20. Protein Sci. 2026 May;35(5): e70585
    Quality control of protein import into mammalian mitochondria.
    Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.
      Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.
    Keywords:  Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses
    DOI:  https://doi.org/10.1002/pro.70585
  21. bioRxiv. 2026 Apr 16. pii: 2026.04.14.718529. [Epub ahead of print]
    FlyPredictome: A structural atlas of predicted protein-protein interactions in Drosophila.
    Ah-Ram Kim, Aram Comjean, Austin Veal, Jonathan Rodiger, Myeonghoon Han, Yanhui Hu, Norbert Perrimon.
      Protein-protein interactions (PPIs) are fundamental to cellular function. Yet most Drosophila PPIs remain structurally uncharacterized despite the wealth of genetic and biochemical data available for this organism. Here we present FlyPredictome, a structural interactome based on 1.5 million pairwise AlphaFold-Multimer predictions. Using a local confidence metric that performs robustly for interactions involving flexible and disordered proteins, we systematically assess experimentally reported Drosophila PPIs and predict direct binding interfaces at residue-level resolution. Testing their functional relevance, we find that phenotype-associated missense mutations are enriched at predicted interaction interfaces. Building on these validated predictions, we construct an evidence-supported PPI network, revealing modular organization from signaling pathways to individual pro-tein complexes. FlyPredictome is available as an open database, providing a structural foundation for interaction discovery in Drosophila .
    DOI:  https://doi.org/10.64898/2026.04.14.718529
  22. Nucleic Acids Res. 2026 Apr 23. pii: gkag334. [Epub ahead of print]54(8):
    The interferon-stimulated gene product HERC5 inhibits human LINE-1 retrotransposition with an ISGylation-independent mechanism.
    Kei Nishimori, Ahmad Luqman-Fatah, Yuzo Watanabe, Mari Takahashi, Takuhiro Ito, Fuyuki Ishikawa, Tomoichiro Miyoshi.
      Mobilization of Long INterspersed Element-1 (LINE-1 or L1) compromises genome stability and can cause sporadic genetic diseases. Accordingly, cells have evolved multiple mechanisms to restrict L1 retrotransposition. Several interferon-stimulated genes (ISGs) that interact with cytoplasmic L1 ribonucleoproteins (RNPs), which contain the L1-encoded proteins ORF1p and ORF2p, have been identified as suppressors of L1 retrotransposition. We previously reported that the ISG protein HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5) efficiently inhibits L1 retrotransposition. While HERC5 is known to restrict numerous viruses through ISGylation, how HERC5 inhibits L1 remains to be elucidated. Here, we show that HERC5 inhibits L1 retrotransposition through an ISGylation-independent mechanism. HERC5 interacts with L1 RNA and selectively reduces ORF1p levels in a manner that requires the full-length ORF1p expression. We further demonstrate that HERC5 decreases L1 translation efficiency and alters L1 RNP composition. Our comparative analysis further suggests that HERC5 may have acquired its L1-inhibitory function during the evolution of the small HERC family. These findings uncover a previously unidentified mechanism by which an ISG protein associates with and inhibits L1 and suggest a role for HERC5 as an evolutionarily adapted restriction factor that expands the repertoire of cellular defenses against retrotransposons.
    DOI:  https://doi.org/10.1093/nar/gkag334
  23. Cell. 2026 Apr 24. pii: S0092-8674(26)00386-7. [Epub ahead of print]
    Nuclear envelope budding enables export of large transcripts in muscle cells.
    Sofia Zaganelli, Janet B Meehl, Robert G Abrisch, Gia K Voeltz.
      Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UAP56-interacting factor (UIF) in regulating mRNA cargo targeting into NE buds and show that this pathway requires the endosomal sorting complex required transport III (ESCRT-III) membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.
    Keywords:  ESCRT; RNA trafficking; membrane remodeling; nuclear envelope budding; nuclear export; sarcomeric transcripts
    DOI:  https://doi.org/10.1016/j.cell.2026.03.050
  24. bioRxiv. 2026 Apr 17. pii: 2026.04.16.719038. [Epub ahead of print]
    Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
    Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.
      Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.
    DOI:  https://doi.org/10.64898/2026.04.16.719038
  25. Nature. 2026 Apr;652(8112): 1139-1152
    The past, present and future of de novo protein design.
    Wei Yang, Shunzhi Wang, Gyu Rie Lee, Jason Z Zhang, Alexis Courbet, David Juergens, Xinru Wang, Thomas Schlichthaerle, Mohamad Abedi, Robert Ragotte, Linna An, Indrek Kalvet, Sam Pellock, Ljubica Mihaljevic, Cameron Glasscock, Arvind Pillai, Adam Broerman, Nathan Ennist, Ella Haefner, Nora McNamara-Bordewick, Ian Haydon, Lance Stewart, Gaurav Bhardwaj, David Baker.
      With deep-learning-powered advances in protein design methods, there is an ongoing paradigm shift in protein engineering from random selection to intentional computational design methods. Here we describe the current state of de novo protein design. While there is still room for improvement in success rates and activities, the long-standing challenges of designing new protein structures, assemblies and protein binders are close to being solved. The key current questions in these areas are not how to design, but what to design, and open-source design methodology such as RFdiffusion and ProteinMPNN together with protein structure prediction tools enable biochemists and molecular biologists to broadly explore possible applications. There has also been considerable progress in the de novo design of small-molecule target binders, enzymes and multistate protein systems. Current challenges for methods development include design of catalysts for reactions with high energy barriers and, more generally, design of switches and nanomachines that integrate binding, conformational change and catalysis. Over the next five to ten years, we anticipate the design of sophisticated protein nanomachines and materials with functionality ranging far beyond that generated during natural evolution for a wide range of applications in medicine, technology and sustainability.
    DOI:  https://doi.org/10.1038/s41586-026-10328-7
  26. Cell Stem Cell. 2026 Apr 30. pii: S1934-5909(26)00146-3. [Epub ahead of print]
    eIF4G2-mediated selective translation of chromatin regulators safeguards adult intestinal stem cell identity and differentiation.
    Haruko Kunitomi, Aye Myat Khaine, Radia Jamee, Vanessa Arreola, Mariselle Lancero, Amba Raychaudhuri, Samuel Perli, Yoshiko Sato, Mio Iwasaki, Pedro Ruivo, Kiichiro Tomoda, Mari Mito, Yuichi Shichino, Shintaro Iwasaki, Shinya Yamanaka.
      eIF4G2 (DAP5/NAT1) is a non-canonical translation initiation factor, but its role in homeostasis is unclear. Using inducible Eif4g2 knockout mice and intestinal organoids, we show that eIF4G2 loss collapses Lgr5+ intestinal stem cell (ISC) and secretory maturation programs while preserving villus architecture. Transcriptomic and single-nucleus multiome analyses reveal a durable fetal-like/regenerative state with YAP-TEAD activation and regenerative absorptive cells. Ribosome profiling identifies selective translation-efficiency loss among chromatin regulators, especially the KAT3 coactivators CREBBP and EP300, resulting in reduced KAT3 abundance and global histone acetylation; chemical KAT3 inhibition phenocopies this state. CUT&Tag and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrate that reduced eIF4G2-KAT3 output drives locus-selective enhancer remodeling, with loss of adult ISC/Wnt-Notch elements and activation of TEAD-enriched fetal loci, without inflammatory or integrated stress response programs driving the transition. Fetal intestinal spheroids remain viable despite similar biochemical defects, highlighting a stage-specific requirement for translational buffering in maintaining adult identity.
    Keywords:  differentiation; eIF4G2 (NAT1/p97/DAP5); epigenetic gene regulation; histone modification; intestinal stem cell; translation initiation
    DOI:  https://doi.org/10.1016/j.stem.2026.04.006
  27. J Biol Chem. 2026 Apr 24. pii: S0021-9258(26)01943-5. [Epub ahead of print] 113071
    A proximity-labeling map of PI5P4K phosphoinositide kinases interaction networks.
    Alicia Llorente, Gurpreet K Arora, Ryan M Loughran, Rabi Murad, Svetlana Maurya, Sophia Crabtree, Benji Portillo, Pratima Chapagain, Hundaol Huluka, Scott Eron, Krista Goodman, Guosen Ye, Raymond D Blind, Brooke M Emerling.
      Phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) have emerged as candidate drug targets in cancer, neurological, inflammatory, and infectious diseases. Although their canonical function is to phosphorylate PI(5)P to generate PI(4,5)P2, growing evidence points to additional catalytic-independent roles, but how these functions are organized within protein interaction networks remains unclear. Here, we use proximity-dependent biotin identification (BioID) in HeLa cells to map isoform-resolved interactomes of human PI5P4Kα, PI5P4Kβ, and PI5P4Kγ. This approach captures PI5P4K-proximal proteins in intact cells and reveals interaction networks positioning these kinases within trafficking-associated signaling modules. Importantly, BioID analysis indicates that PI5P4Kγ has the most extensive set of proximal interactors among the three PI5P4Ks, consistent with its comparatively low catalytic activity and a prominent scaffold-like function. Among PI5P4Kγ-enriched partners, we highlight the endosomal cargo adaptor SNX17 as a proximal interactor that links PI5P4Kγ to β1-integrin recycling and to cell migration and invasion. By providing a proximity map for all three PI5P4Ks, this study offers a framework to help define contexts in which targeted protein degradation may offer advantages over catalytic inhibition and provides a resource for future mechanistic studies on these phosphoinositide kinases.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113071
  28. Cell. 2026 Apr 28. pii: S0092-8674(26)00393-4. [Epub ahead of print]
    Sensing endoplasmic reticulum redox state by ethylene receptors.
    Dongdong Hao, Zhina Xiao, Wei Yan, Chenliang Pan, Yanting Yang, Wen Song, Zhiren Chen, Ying Xing, Lian Jin, Yang Peng, Yuping Qiu, Kai Jiang, Xing Wen, Kai Huang, Shi Xiao, Haodong Chen, Hongwei Guo.
      Endoplasmic reticulum (ER) redox homeostasis is critical for ER functionality and is implicated in various human diseases, yet its physiological significance in plants remains largely elusive. Ethylene, a key phytohormone, is perceived and transduced at the ER, suggesting an underexplored connection between the ER and ethylene signaling. Here, we show that ethylene receptors sense the ER redox state via lumen-localized intermolecular disulfide bonds. ER reductive stress, rather than ethylene, disrupts the disulfide-linked dimers of the receptors, repressing their function and thereby activating downstream ethylene signaling. Moreover, modulating disulfide bond formation in the receptor ETHYLENE RESPONSE 1 (ETR1) through ER redox shifts supports plant resilience under hypoxia and during photomorphogenesis. Finally, our findings suggest that sensing ER redox may be an ancestral receptor function, predating the substantial emergence of ethylene biosynthesis. This study illuminates a deeper nexus between organelle homeostasis and hormone signaling.
    Keywords:  ETR1; disulfide bond; endoplasmic reticulum; ethylene receptor; redox state
    DOI:  https://doi.org/10.1016/j.cell.2026.04.004
  29. bioRxiv. 2026 Apr 13. pii: 2026.04.12.718032. [Epub ahead of print]
    Mechanistic dissection of BLTP2 targeting to ER-PM contact sites.
    Sarah D Neuman, Amy T Cavanagh, Nicole Sheffels, Elizabeth Conibear, Arash Bashirullah.
      The bridge-like lipid transfer proteins (BLTPs) are a novel superfamily of rod-shaped lipid transporters that engage in bulk non-vesicular movement of lipids at organelle membrane contact sites. The molecular and cellular functions of these proteins are still emerging; however, it is clear that one key aspect that regulates BLTP function is targeting to the appropriate membrane contact site(s). Here, we use Drosophila as a model system to dissect the mechanisms that drive targeting of BLTP2 ( hobbit in Drosophila ) to endoplasmic reticulum-plasma membrane (ER-PM) contact sites. We demonstrate that a conserved adapter protein, which we name bilbobaggins ( bbo ), is required for targeting of Hobbit to ER-PM contacts; importantly, loss of bbo phenocopies loss of hobbit , indicating that bbo is required for hobbit function. Additionally, our structure-function analyses show that cis -acting sequences in the C-terminal tail of Hobbit are also required for ER-PM targeting. Crucially, our data indicates that that these cis -acting sequences and Bbo binding are independent and likely sequential mechanisms that we propose function like a "hook" and "latch" to govern Hobbit targeting. Thus, we define a new regulatory paradigm governing targeting of BLTPs to membrane contact sites.
    DOI:  https://doi.org/10.64898/2026.04.12.718032
  30. EMBO Rep. 2026 Apr 27.
    Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.
    Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.
      Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.
    DOI:  https://doi.org/10.1038/s44319-026-00774-9
  31. Sci Adv. 2026 May;12(18): eaeb2995
    A dynamic gateway: Uncovering the expanded human TOM complex interactome and its regulatory complexity.
    Mayra A Borrero-Landazabal, Vanessa Linke, Tereza Kadavá, Zeshi Li, Piotr Draczkowski, Kacper Kaszuba, Lea Bertgen, Remigiusz A Serwa, Albert J R Heck, Agnieszka Chacinska.
      The translocase of the outer mitochondrial membrane (TOM) is the conserved entry gate for nuclear-encoded proteins. While structurally similar from yeast to humans, the human TOM complex operates in a cellular environment of vastly greater complexity. Here, we present a high-confidence map of the human TOM interactome using a membrane-permeable cross-linker to capture both stable and transient interactors. Alongside extensive overlap with known yeast partners, we uncover a set of human-specific interactors including regulatory factors and TOM-associated proteins. Mapping unique interprotein cross-links reveals conformational flexibility of the receptor TOM20 and enhanced recovery of peripheral components such as TOM70 and several associated quality control factors. Notably, we identify FKBP8 (FK506 binding protein 8) as a human-specific interactor that binds multiple TOM subunits and promotes organization of the complex. Our work redefines the human TOM complex as a dynamic, multifaceted hub coordinating biogenesis, quality control, and signaling. This expanded TOM landscape offers a rich resource for exploring mitochondrial regulation in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.aeb2995
  32. Cancer Genomics Proteomics. 2026 May-Jun;23(3):23(3): 483-502
    Proximity Mapping of the ER Proteome Reveals Metastasis-specific Candidate Biomarkers in Breast Cancer Cell Lines.
    Mehmet Sarihan, Elifcan Kocyigit, Murat Kasap, Gurler Akpinar.
       BACKGROUND/AIM: Breast cancer is the most frequently diagnosed cancer among women. While biomarkers are critical for early detection and therapy, current markers lack sufficient specificity and sensitivity. The endoplasmic reticulum (ER) plays a central role in protein folding, post-translational modification, and lipid metabolism, and its alterations are linked to tumor progression. This study aimed to map ER proteome changes associated with breast cancer invasiveness and identify novel candidate biomarkers.
    MATERIALS AND METHODS: We compared the ER proteomes of non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cell lines using an ER-targeted TurboID proximity labelling approach, followed by LC-MS/MS analysis. Bioinformatic analyses were performed to determine functional associations and differential expression related to invasion and metastasis for the candidate biomarkers.
    RESULTS: A total of 2,079 proteins were identified, including 1,378 ER proteins. Analysis revealed that more than four hundred ER-resident or associated proteins were differentially regulated in invasive MDA-MB-231, many of which were linked to invasion and metastasis. Upregulated proteins were involved in cellular localization, ECM remodeling, cell mobility, adhesion, vesicle trafficking, and ER stress, whereas downregulated proteins were primarily associated with energy metabolism. Additionally, in this study, 36 ER-associated proteins were identified for the first time as candidates linked to breast cancer, highlighting their potential as novel biomarkers and therapeutic targets.
    CONCLUSION: ER-targeted TurboID proximity labelling effectively maps the proteomic landscape of breast cancer cells, revealing functional adaptations that support invasive and metastatic phenotypes. Notably, 36 ER proteins were identified as novel candidates not previously linked to breast cancer, highlighting new potential biomarkers and therapeutic targets. These findings provide valuable insights into ER proteome remodeling, offering avenues for understanding breast cancer progression and strategies to prevent metastasis.
    Keywords:  Breast cancer; ER-proteome; biomarker; biotinylation; invasion and metastasis
    DOI:  https://doi.org/10.21873/cgp.20586
  33. Nat Commun. 2026 Apr 27.
    A family of ribosome hibernation factors widespread in Archaea.
    Clément Madru, Gabrielle Bourgeois, Rémi Dulermo, Régine Capeyrou, Gwendoline Joncour, Karima Figuigui, Magalie Duchateau, Julia Chamot-Rooke, Claire Duboc, Stéphane l'Haridon, Logan Mc Teer, Marta Kwapisz, Béatrice Clouet-d'Orval, Marie Bouvier, Yves Mechulam, Guillaume Borrel, Emmanuelle Schmitt, Didier Flament.
      Ribosome hibernation preserves translation machinery during stress, yet its mechanisms in Archaea remain poorly defined. Using cryo-EM analysis, we studied hibernation pathways in Pyrococcus abyssi stressed cells. We identified HibA, a previously unrecognized family of hibernation factors widespread in Archaea. HibA consists of a bacterial-like HPF/RaiA domain fused to a Cystathionine Beta Synthase module. Unexpectedly, HibA binds to the ribosome in three different conformations, occupying the A, P and E sites of tRNAs, as well as that of mRNA, enhancing its ability to protect the ribosome from degradation. Idle ribosomes also frequently accumulate the archaeal homolog of eukaryotic ribosome maturation protein SBDS (aSBDS), suggesting that stressed archaeal cells may engage parallel hibernation routes in which aSBDS can complement HibA. Deletion of hibA in Thermococcus barophilus delays recovery from stationary phase and reduces 70S ribosome pools, establishing its role in ribosome preservation. Taxonomic profiling shows that many archaeal lineages encode distinct repertoires of ribosome-associated protection factors, underscoring the modular and multi-layered nature of archaeal hibernation systems. In addition, a comprehensive phylogenetic analysis highlights the evolutionary relationships between prevalent ribosome hibernation factors across Bacteria and Archaea.
    DOI:  https://doi.org/10.1038/s41467-026-72341-8
  34. J Mater Chem B. 2026 Apr 28.
    Indole-bipyridyl fluorophores as dual-functional probes for endoplasmic reticulum imaging and Zn2+ sensing in live cells.
    Mohini Ghorpade, Sayan Bera, Gayatri Bhattad, Paramasivam Mahalingam, Sriram Kanvah.
      The endoplasmic reticulum (ER) plays a central role in protein folding, lipid biosynthesis, and calcium regulation, and its dysfunction is closely linked to diseases such as cancer, neurodegeneration, and metabolic disorders. Here, we report a new class of indole-bipyridyl (IBP) fluorophores designed for high-contrast visualisation of ER architecture and dynamic ER-associated processes in living cells. Three derivatives (IBP-1, IBP-2, and IBP-3) were synthesised through a condensation-alkylation strategy and exhibited strong absorption around 420-430 nm, large Stokes shifts, and pronounced environment-sensitive emission. All derivatives display excellent biocompatibility and rapid cellular uptake, producing a distinct reticular fluorescence pattern with high colocalization to commercial ER trackers (PCC = 0.92-0.96) in HeLa and COS-7 cells. The probes sensitively report ER stress and reticulophagy-like morphological changes, revealing treatment-dependent ER fragmentation, enhanced ER-lysosome interactions, and increased lipid-droplet formation following DTT or CCCP exposure. In addition to organelle selectivity, the bipyridyl core imparts reversible Zn2+ responsiveness, with the probes showing pronounced fluorescence response accompanied by spectral shifts attributed to coordination-induced electronic modulation upon Zn2+ binding in both solution and cellular environments. Altogether, these findings establish the fluorophores as versatile dual-function tools for ER imaging and Zn2+ sensing, offering a valuable platform for investigating ER homeostasis, organelle crosstalk, and metal-ion-associated cellular processes.
    DOI:  https://doi.org/10.1039/d5tb02797g
  35. Res Sq. 2026 Feb 11. pii: rs.3.rs-8345089. [Epub ahead of print]
    Autophagy-related protein 1 orchestrates autophagy initiation and feedback degradation in Alternaria alternata.
    Celine Yen Ling Choo, Hsin-Yu Lu, Kuang-Ren Chung, Pei-Ching Wu.
      Background Autophagy plays an essential role in fungal development and stress adaptation, yet its regulatory mechanisms in filamentous fungi remain incompletely understood. We functionally characterized Alternaria alternata Atg1 (AaAtg1), a serine/threonine kinase, and demonstrated its dual roles in autophagy initiation and flux modulation. Results Deletion of AaAtg1 abolishes autophagosome formation and autophagic flux, impairs peroxisome degradation, and leads to hypersensitivity to oxidative stress, as well as reduced virulence. AaAtg1 physically interacts with core autophagy proteins AaAtg13 and AaAtg8, and its vacuolar degradation is AaAtg8-dependent. Structure-guided mutagenesis of the Atg8-family interacting motif (AIM) disrupts AaAtg1-AaAtg8 binding in yeast two-hybrid assays but not in bimolecular fluorescence complementation, suggesting partial functional retention in vivo . Intriguingly, AIM mutations do not impair autophagy; instead, some transformants exhibit elevated autophagic activity, suggesting a potential negative regulatory role of AIM in autophagy tuning. Conclusions These findings reveal a noncanonical feedback mechanism in which AaAtg8 facilitates AaAtg1 degradation to modulate autophagic output. Our study elucidates the structure-function relationship of AaAtg1 and uncovers a dual regulatory mechanism that coordinates autophagy progression and stress adaptation in the plant-pathogenic fungus.
    DOI:  https://doi.org/10.21203/rs.3.rs-8345089/v1
  36. Protein Sci. 2026 May;35(5): e70575
    ATP modulates holdase activity of fungal and human 110-kilodalton heat shock proteins to promote protein folding.
    Justin M Kidd, Cancan Sun, Alissa Garay, Mitchell Keplinger, Colin Richter, Aaron E May, Qinglian Liu.
      Heat shock proteins of the 70-kDa family (Hsp70s) are highly abundant and conserved molecular chaperones that help preserve proteostasis primarily by facilitating proper protein folding. Heat shock protein of the 110-kDa family (Hsp110s), a specialized branch of the Hsp70/Hsp110 superfamily, function both as nucleotide exchange factor (NEF) cochaperones for Hsp70s and as independent "holdase" chaperones that stabilize non-native polypeptides to prevent aggregation and facilitate downstream refolding by Hsp70s. While Hsp110 NEF activity is well characterized, the consequences of adenosine 5'-triphosphate (ATP) binding for Hsp110 holdase behavior have remained largely unexplored. Although holdase activity is generally considered nucleotide-independent, reports of ATP-dependent effects have raised questions about the underlying mechanism. Here, we examined the biochemical properties of Multicopy Suppressor of ira1 3 (Msi3), the sole Hsp110 in Candida albicans, to dissect the role of ATP in holdase function. We first identified an inhibitory effect of elevated Mg2+ concentrations on Msi3 holdase activity. This inhibitory effect is counteracted by the intrinsically disordered C-terminal segment, revealing a distinct stabilization role for this region, previously of unknown function. In addition, ATP alleviates inhibition by elevated Mg2+, providing an explanation for an apparent ATP-dependence observed previously. Interestingly, although dispensable for aggregation suppression, ATP modulates Msi3 holdase activity for refolding competence by broadening the concentration range over which it remains productive. Increasing Msi3 concentration improved overall downstream refolding recovery but slowed refolding kinetics, and ATP alleviated this kinetic constraint. Analyses of Hsp105, the major human Hsp110, suggest that these biochemical properties are largely conserved. Together, these findings suggest that ATP modulates Hsp110 holdase activity by tuning the balance between substrate sequestration and engagement dynamics, revealing an ATP-dependent regulatory dimension of Hsp110 holdase function that is mechanistically distinct from its NEF activity.
    Keywords:  ATP; Hsp110; Hsp70; holdase; molecular chaperones; protein aggregation; protein folding
    DOI:  https://doi.org/10.1002/pro.70575
  37. Nat Commun. 2026 Apr 27.
    A network-based map of the chemical exposome connects molecular interactions to public health.
    Salvo D Lombardo, Christiane V R Hütter, Miriam M Unterlass, Jörg Menche.
      Chemical exposures significantly affect individual and public health, yet there is no unifying framework describing how diverse chemical compounds may interfere with biological processes and contribute to disease risk. Here, we use a network-based approach to construct a comprehensive map linking 9887 exposures through their shared genetic effects. This map can be used to define classes of exposures that affect common biomolecular processes, even when they are chemically distinct. We find that exposures target specific modules in the human interactome of protein-protein interactions, and that exposure harmfulness relates to interactome connectivity. Systematically comparing exposure modules with disease modules suggests that their interactome proximity predicts exposure-disease relationships. We validate these predictions by integrating nationwide disease prevalence data with reported environmental exposures, finding higher disease incidence where exposure and disease modules overlap. Together, our study provides a blueprint for the systematic investigation of the pathobiological impact of chemical exposures ranging from the molecular to the population level.
    DOI:  https://doi.org/10.1038/s41467-026-72402-y
  38. Cancer Discov. 2026 May 01. 16(5): 829-830
    A New Class of Molecular Glues: Double Allostery Restores KEAP1 Control of NRF2.
    Jordi C J Hintzen, George M Burslem.
      Roy and colleagues describe VVD-065, a covalent allosteric molecular glue that binds KEAP1 at Cys151 to enhance KEAP1-CUL3 assembly, restore NRF2 ubiquitination and degradation, and selectively suppress NRF2-driven tumors by reactivating endogenous E3 ligase function. See related article by Roy et al., p. 953.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0342
  39. J Mol Biol. 2026 Apr 26. pii: S0022-2836(26)00201-9. [Epub ahead of print] 169828
    Translatable circular RNAs are degraded via nonsense-mediated mRNA decay.
    Eunchae Kang, Dahyeon Kang, Yeo Kyung Cho, Min-Kyung Shin, Sung Ho Boo, Jeeyoon Chang, Hyeong-In Kim, Jae Hee Jo, Yoon Ki Kim.
      Endogenous circular RNAs (circRNAs) are predominantly generated by a back-splicing process. Due to their lacking 5' and 3' termini, circRNA degradation is exclusively dependent on endoribonucleolytic cleavage. In addition, translation occurring on circRNAs depends solely on internal ribosome entry site (IRES) or IRES-like features, such as an exon junction complex (EJC) deposited after back-splicing. However, the potential relationship between the translatability and stability of circRNAs has yet to be explored. Here, we demonstrate that translatable circRNAs can be subject to canonical EJC-dependent nonsense-mediated mRNA decay (NMD), a well-known mRNA surveillance mechanism, as long as circRNAs contain EJC(s) downstream of a translation termination codon. We find that the NMD of translatable circRNAs involves UPF1 and the NMD-specific endoribonuclease SMG6. This distinct pathway is termed NMD-like circRNA decay (NCD). The differences in factor requirements between canonical EJC-dependent NMD and NCD lead to variations in RNA regulation under cellular stress conditions. Our observations provide an additional layer in the molecular regulation of circRNA dynamics.
    Keywords:  NMD; SMG6; UPF1; circular RNA; mRNA decay
    DOI:  https://doi.org/10.1016/j.jmb.2026.169828
  40. Nucleic Acids Res. 2026 Apr 23. pii: gkag347. [Epub ahead of print]54(8):
    K63-linked ubiquitylation of S2P-RNAPII regulates transcription in a DNAPK inter-dependent manner in response to double-strand breaks.
    Vasiliki Pantazi, Paul Smith, Zoltan G Pahi, Manuela Katona, Adam Pap, Zsuzsanna Darula, Roman Fischer, Iolanda Vendrell, Benedikt M Kessler, Marcel A T M van Vugt, Vincenzo D'Angiolella, Tibor Pankotai.
      DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to genomic instability. DSBs can also interfere with other DNA-based processes, including transcription, and thereby jeopardizing cellular function. In situations of persistent DSBs, RNA polymerase II (RNAPII) needs to be removed to facilitate DNA repair. DSB-induced RNAPII removal involves multifaceted ubiquitylation, but the mechanisms involved remain elusive. Our data show that in response to DSBs, the E3 ubiquitin ligase NEDD4, and to a lesser extent CRL3 complexes, catalyse the ubiquitylation of elongating RNAPII, facilitating efficient DSB repair. Specifically, NEDD4 is identified as the specific writer of K63-linked ubiquitin chains on Serine2 phosphorylated (S2P)-RNAPII under stress, while the total pool of RNAPII is found to be modified mainly with K48-linked ubiquitin chains. We find that the ubiquitin ligases NEDD4, WWP2, and CUL3-based complexes exhibit a DNAPK inter-dependency, driving NHEJ repair and proper resolution of transcription defects caused by DSBs.
    DOI:  https://doi.org/10.1093/nar/gkag347
  41. J Am Chem Soc. 2026 Apr 29.
    Condensates as Conformation Editors of Disordered Client Proteins.
    Liguo Wang, Siewert J Marrink.
      Biomolecular condensates organize cellular biochemistry not only by passive concentration modulation of molecules but also by potentially remodeling client protein conformations. However, the systematic principles governing such conformational editing are unknown. Here, we use coarse-grained simulations to demonstrate that diverse condensate environments remodel disordered client proteins in a scaffold-specific manner. Additionally, we explore the factors of this remodeling, establishing that the linear patterning of scaffold interaction motifs along sequence (sticker clustering) plays an important role, whereas an increased scaffold chain length primarily slows client dynamics while leaving their sequence-specific intrachain contact patterns largely preserved. This conformational remodeling is mediated by varied and nonuniform client-condensate interaction maps that are not solely encoded by primary sequence grammar but are cooperatively shaped by the emergent condensate architecture. Our work reveals that condensates function as sophisticated regulators of recruited disordered client conformation, with broad implications for cellular regulation and therapeutic intervention.
    DOI:  https://doi.org/10.1021/jacs.6c00501
  42. ACS Chem Biol. 2026 May 01.
    Discovery and Development of a Potent LIMK2 Isoform-Specific Degrader.
    Kamal Rayees Abdul Azeez, Hayuningbudi Saraswati, Thorsten Mosler, Thomas Hanke, Hung Ho-Xuan, Noah Neder, Saran Aswathaman Sivashanmugam, Marcel Heinz, Martin-Peter Schwalm, Giulio Giuliani, Rajeshwari Rathore, Rubina Kazi, Rahul Kumar, Marko Mitrovic, Cristian Prieto-Garcia, Henry J Bailey, Sebastian Mathea, Gerhard Hummer, Ivan Đikić, Susanne Müller, Alexandra Stolz, Daniela S Krause, Stefan Knapp.
      The LIM kinases (LIMK1/2) are key mediators in signaling cascades that regulate actin cytoskeleton dynamics via cofilin phosphorylation. Dysregulation of these pathways and overexpression of LIMKs are implicated in disease development, including cancer, Fragile X syndrome, and glaucoma. Positioned downstream of actin-regulating Rho GTPase signaling pathways, LIM kinases are attractive drug targets. Here, we targeted LIMKs with PROTACs to disrupt both catalytically and noncatalytically mediated functions. Despite employing a dual LIMK1/2 inhibitor warhead and high structural conservation between the two human LIM kinases, we discovered isoform-specific LIMK2 degradation by initial PROTACs that we optimized into a highly potent and selective LIMK2 degrader. Cell-based assays and structural analysis indicated that isoform specificity was likely driven by favorable orientation bias and/or lysine accessibility, along with enhanced ternary complex formation. We comprehensively characterized the PROTAC as a chemical probe that induces isoform-specific degradation, offering a powerful alternative to conventional reversible pan-LIMK inhibitors.
    DOI:  https://doi.org/10.1021/acschembio.6c00137
  43. Nat Cell Biol. 2026 Apr 28.
    Nuclear N-glycosylation maintains H3K9me3 heterochromatin and genomic stability.
    Xiuxiao Tang, Ranran Dai, Li Qing, Zhida Zhang, Hongmei Li, Lizi Lu, Hancheng Lin, Danling Ji, Wei Dan, Yuqi He, Xinyi Liu, Tao Yang, Wakam Chang, Yang Mao, Shisheng Sun, Junjun Ding.
      Polysaccharides are known to be synthesized by enzymes in the endoplasmic reticulum and Golgi apparatus and transported through the secretory pathway to the cell surface or extracellular space, where they mediate essential biological processes. While classical localization and functions of polysaccharides are well established, their presence and potential roles in the nucleus remain unclear. Here we demonstrate that N-glycans, a type of polysaccharides, modify inner nuclear membrane (INM) proteins and are present in the cell nucleus across diverse cell types-a modification referred to as N-linked glycosylation (N-glycosylation). N-glycosylation is enriched in chromatin regions marked by H3K9me3 and long interspersed nuclear element-1 (LINE-1) retrotransposons. N-glycosylation inhibition and INM protein N-glycosylation site mutation both downregulate H3K9me3 within lamina-associated domains and lead to genomic instability. Mechanistically, N-glycosylation regulates the interaction between the histone H3K9 methyltransferase SETDB1 and INM proteins, promotes the association of SETDB1 with the INM, and maintains H3K9me3. Moreover, we reveal that canonical N-glycan biosynthetic machinery in the endoplasmic reticulum contributes to the N-glycosylation of INM proteins. These findings uncover a previously unrecognized nuclear role for polysaccharides, broadening our understanding beyond their traditional subcellular distributions and functional profiles.
    DOI:  https://doi.org/10.1038/s41556-026-01941-9
  44. Nat Commun. 2026 Apr 29.
    NAE1/UBA3-UBE2M are E1 and E2 enzymes for the URM1 modification.
    Swatadipta Chakraborty, Saibal Chanda, Zhongwen Cao, Alan Pham, Zihan Zhang, Yinsheng Wang, Logan Herring, Wenyue Cao, Wenshe Ray Liu.
      Ubiquitin-related modifier 1 (URM1) is an evolutionarily conserved ubiquitin-like protein. In eukaryotes, it serves dual roles as a sulfur donor for tRNA modification and a posttranslational protein modifier. URM1 is proposed to be a primitive protein modifier and a potential precursor to the more complex ubiquitin system. However, no specific activating enzyme (E1), conjugating enzyme (E2), or ligase (E3) has been reported for the URM1 modification cascade in human cells. In this study, we design an activity-based URM1 probe to covalently capture cysteine enzymes functioning in the URM1 signaling pathway. Through proteomic characterization and cell-based validation, we identify NAE1/UBA3 and UBE2M as E1 and E2 enzymes, respectively, for the urmylation pathway under both normal and oxidative stress conditions. Pharmacologic perturbation of the UBE2M-DCN1 module suggests DCN1 may contribute to URM1 conjugation. Bioinformatic analysis further reveals that genetic knockdown of NAE1, UBE2M, and URM1 affects overlapping genes associated with pathways controlling cellular response to stress conditions or with implications in liver diseases. URM1 serves a protective role against oxidative stress. Pevonedistat, a potent NAE1 inhibitor that blocks protein urmylation in human cells, exhibits strong synergy with cisplatin, an agent known to induce oxidative stress, in killing liver cancer cells effectively.
    DOI:  https://doi.org/10.1038/s41467-026-72296-w
  45. Nat Commun. 2026 Apr 27. pii: 3859. [Epub ahead of print]17(1):
    Reprogramming of bacterial virulence by lysine acetylation.
    Ole Schmöker, Britta Girbardt, Sabrina Schulze, Gottfried J Palm, Leona Berndt, Jens Hoppen, Nilüfer Kara, Xenia Schöps, Ruba Al-Abdulla, Klara Garz, Heike Junker, Sophie Wolfgramm, Leif Steil, Christian Hentschker, Katrin Schoknecht, Lea-Maria Mayer, Leonie Speth, Vanessa Lachmayer, Mark Dörr, Stefan Kemnitz, Stefan Müller, Jan-Wilm Lackmann, Marcus Krüger, Kay Hofmann, Uwe T Bornscheuer, Uwe Völker, Elke Krüger, Vera Kozjak-Pavlovic, Michael Lammers.
      Gram-negative bacteria use a plethora of virulence factors to infect eukaryotic cells. CE-clan protease-related virulence factors were reported to act as deubiquitinases/ubiquitin-like specific proteases. Some have an additional acetyl-transferase activity. The molecular mechanisms underlying this dual activity and the physiological consequences are only marginally understood. Here, we report crystal structures for the Simkania negevensis virulence factor SnCE1 in apo-states and in complex with SUMO1. We confirm SnCE1 acting as an efficient deSUMOylase and discover an intrinsic autoacetyltransferase activity. Acetylation impairs SnCE1 tetramer formation structurally being incompatible with SUMO1 binding. We provide a model for regulation of SnCE1-mediated virulence by lysine acetylation modulating autoproteolytic processing and its subcellular distribution in the host cell. SnCE1 localizes to the endoplasmic reticulum in human cells and increases fragmentation of mitochondria. Our data provide mechanistic insights into how lysine acetylation of virulence factors is used to reprogram virulence adjusting it to the host cells' metabolic state.
    DOI:  https://doi.org/10.1038/s41467-026-72244-8
  46. bioRxiv. 2026 Apr 16. pii: 2026.04.14.718555. [Epub ahead of print]
    Temporal gating dictates stress-induced transcript export from the nucleus.
    Noah S Helton, Benjamin Dodd, Stephanie L Moon.
      Prior studies have largely focused on transcriptional and translational control during stress, but how regulated nuclear mRNA export contributes to the stress response remains unresolved. We show that nuclear mRNA export is progressively inhibited during arsenite and heat stress in human cells. In contrast to previous work largely in yeast that suggests nuclear export of stress-induced transcripts is prioritized through sequence-specific mechanisms, we demonstrate that temporal gating determines the nucleocytoplasmic distribution of mRNAs during stress. Using single molecule mRNA imaging and transcriptome-wide analyses, we find the majority of stress-induced mRNAs, including heat shock protein transcripts, accumulate in the nucleus during stress. However, a subset of stress-induced mRNAs, notably HMOX1, JUN , and FOS, escape nuclear retention. mRNAs transcribed early during stress, including those encoding immediate early genes, redox mediators, and protein chaperones, are exported from the nucleus prior to the global inhibition of mRNA export. In contrast, mRNAs transcribed later are retained in the nucleus until stress is resolved. Reporter RNA assays confirm that transcriptional timing determines mRNA export competence. This work reveals that the timing of transcription, rather than transcript-specific sequence features, is the major determinant of nuclear export efficiency of stress-induced transcripts in human cells.
    DOI:  https://doi.org/10.64898/2026.04.14.718555
  47. Nat Nanotechnol. 2026 Apr 29.
    Programmable artificial RNA condensates in mammalian cells.
    Shiyi Li, Yuna Kim, Kevin Wang, Eric John Payson, Anli A Tang, Maria Villalba Nieto, Dino Osmanovic, Madison Yang, Diego Dilao, Alexandra Bermudez, Wen Xiao, Melody M H Li, Neil Y C Lin, Kathrin Plath, Douglas L Black, Elisa Franco.
      Artificial biomolecular condensates have emerged as powerful tools for controlling cellular behaviour. Here we introduce a method to build artificial condensates within living mammalian cells by designing modular RNA motifs composed of a single short RNA strand. These condensates emerge spontaneously, creating RNA-rich compartments that remain separated from their surrounding environment. The RNA sequences include stem-loop domains that fold as the RNA is transcribed, and then condense in the nucleus and cytoplasm through loop-loop interactions. These sequences can be optimized and diversified, enabling the generation of distinct, non-mixing condensate populations and the programmable control of their subcellular localization. The RNA motifs can also be modified to recruit small molecules, proteins and RNA molecules in a sequence-specific manner to the RNA-rich phase. By introducing RNA linkers, we can build condensates with multiple subcompartments, whose organization can be controlled by tuning the linker stoichiometry. These artificial condensates provide a versatile platform for studying and manipulating molecular functions inside living cells.
    DOI:  https://doi.org/10.1038/s41565-026-02164-7
  48. Bioorg Chem. 2026 Apr 25. pii: S0045-2068(26)00459-1. [Epub ahead of print]177 109923
    ATI-1 mediated disruption of the VCP-UFL1-Beclin1 axis thwarts autophagy initiation to trigger metabolic catastrophe in autophagy-addicted cancers.
    Tong Liu, Min Zhao, Jing Gao, Jie Liu, Jifa Zhang.
      Targeting autophagy initiation represents a promising strategy to disrupt the metabolic resilience of cancer cells. In this study, we identified ATI-1 as a novel small-molecule inhibitor that selectively blocks the early stages of autophagosome formation. Importantly, we discovered that ATI-1-mediated de novo inhibition of autophagy initiation leads to a synergistic surge in cell death under nutrient-deprived conditions, revealing a critical, context-specific vulnerability in autophagy-dependent malignancies. Mechanistically, ATI-1 appears to target valosin-containing protein (VCP/p97) and disrupt its interaction with the UFM1-specific E3 ligase UFL1. This disruption may promote the polyubiquitination and subsequent degradation of Beclin1, thereby contributing to the inhibition of autophagy initiation. Furthermore, ATI-1 demonstrates potent antitumor efficacy in xenograft models with minimal overt toxicity. This work collectively suggests that the VCP-UFL1-Beclin1 axis may represent a potentially targetable node in autophagy regulation, and identifies ATI-1 as a potential small-molecule modulator of this pathway, thereby providing a promising therapeutic lead for cancer treatment.
    Keywords:  Antitumor efficacy; Inhibition of autophagy initiation; Small-molecule inhibitor; VCP–UFL1–Beclin1 axis
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109923
  49. Nat Commun. 2026 Apr 27. pii: 3813. [Epub ahead of print]17(1):
    Proteome-wide prediction of the functional impact of missense variants with ProteoCast.
    Marina Abakarova, Maria Inés Freiberger, Arnaud Liehrmann, Michael Rera, Elodie Laine.
      Dissecting the functional impact of genetic mutations is essential to advancing our understanding of genotype-phenotype relationships and identifying therapeutic targets. Despite progress in sequencing and genome editing technologies, proteome-wide mutation effect prediction remains challenging. Here we show that evolutionary information alone enables accurate prediction of mutation effects across entire proteomes. ProteoCast is a scalable and interpretable computational method that leverages protein sequence conservation to classify genetic variants and identify functionally important protein sites. We apply ProteoCast to the complete Drosophila melanogaster proteome (22,000 isoforms, 300 million mutations) and validate it against nearly 400,000 natural and experimental variants. It correctly classifies 85% of known lethal mutations as functionally impactful versus 13-18% of population variants. ProteoCast-guided genome editing experiments confirm these predictions. Moreover, ProteoCast successfully identifies functionally important protein modification sites and binding motifs. ProteoCast provides a publicly available resource and deployable pipeline for studying gene function and mutations in any organism.
    DOI:  https://doi.org/10.1038/s41467-026-72140-1
  50. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2508391123
    ATG9A-mediated plasma membrane repair is linked to Vps13A and regulated by glycosylation.
    Natali H Muskat, Inbar Nevo-Yassaf, Madhuri Chaurasia, Shani Reiss, Inna Goliand, Meital Kupervaser, Yoseph Addadi, Yishai Levin, Milana Fraiberg, Zvulun Elazar.
      Biological membranes provide a resilient framework for cellular structure and stability. Disrupting its integrity may result in irreparable damage, altering cellular homeostasis and ultimately leading to cell death. ATG9A, a transmembrane protein, has recently been implicated in plasma membrane repair. However, its role in the process and the mechanism by which it is targeted to the plasma membrane upon damage are unclear. We show here that glycosylation of ATG9A is essential for its membrane repair activity. This has been corroborated by using different mutant cells that are defective in their ability to process proteoglycan in the Golgi complex. Specifically, sialylation of the sugar moiety appears vital for plasma membrane repair activity. Additionally, we provide evidence indicating that ATG9A is targeted to the plasma membrane through interaction with the endosomal sorting complex required for transport complex. Finally, we found that ATG9A lipid scramblase activity and the lipid transfer protein VPS13A are needed for efficient membrane repair.
    Keywords:  ATG9A; ESCRT-comples; Plasma membrane repair; VPS13A; glycosylation
    DOI:  https://doi.org/10.1073/pnas.2508391123
  51. bioRxiv. 2026 Apr 16. pii: 2026.04.15.718697. [Epub ahead of print]
    Structural basis of chaperone mechanisms in cells and the evolutionary emergence of the protein world.
    Ahhyun Son, Catherine Durso, Timothy A Whitehead, Scott Horowitz.
      How chaperones mediate protein folding in the crowded cell environment remains poorly understood. To gain insight, we developed CHAP-SEQ to examine how chaperones affect protein folding in cells at high throughput and amino acid resolution. Performing CHAP-SEQ using three chaperone proteins and one chaperone RNA reveals distinct modes of folding assistance. Chaperone proteins act preferentially on hydrophobic core residues, whereas chaperone RNA primarily targets structural or dynamic signatures. Furthermore, while the chaperone RNA has little preference for clients' baseline foldability, the chaperone proteins favor clients with greater intrinsic foldability. These differences are consistent with an evolutionary hypothesis in which greater chaperone complexity played a role in the formation of stable hydrophobic cores, suggesting a potential link between chaperone function and the evolution of protein folding.
    DOI:  https://doi.org/10.64898/2026.04.15.718697
  52. Angew Chem Int Ed Engl. 2026 Apr 28. e2970755
    Bioinspired Molecular Engineering of IRE1-Gated DNAzymes for Self-Adaptive Bidirectional Modulation of ER Stress.
    Chuangui Sheng, Jian Zhao, Nan Liu, Yuliang Zhao, Lele Li.
      Precise regulation of endoplasmic reticulum (ER) stress signaling in cancer remains a central challenge for nucleic acid-based therapeutics, largely due to their inability to discriminate ER-stressed malignant cells and non-stressed normal cells. Here we report an ER stress-responsive regulatory platform that couples the disease-associated endoribonuclease activity of inositol-requiring enzyme 1 (IRE1) to the conditional activation of DNA-based effectors. By rationally grafting an X-box binding protein 1 (XBP1)-mimetic stem-loop "gate" onto canonical DNAzymes (IR-Dz), we generate constructs that remain catalytically inert under basal IRE1 activity but are activated upon ER stress-induced IRE1 cleavage. The resulting IR-Dz mediates cell-selective c-MYC silencing in ER-stressed cancer cells, thereby attenuating ER stress while sparing normal counterparts. Redirecting IR-Dz to IRE1 mRNA achieves the opposite outcome-self-silencing of IRE1 and amplification of ER stress in tumor cells. This modular architecture can be adapted to other nucleic-acid modalities, such as antisense oligonucleotides. By establishing IRE1 as an endogenous molecular trigger for spatially and contextually precise activation of nucleic acid effectors, our study introduces a general strategy for programmable, condition-dependent gene regulation and dynamic modulation of ER stress signaling in cancer.
    Keywords:  DNAzyme; ER stress; IRE1; cell selectivity; gene regulation
    DOI:  https://doi.org/10.1002/anie.2970755
  53. Cell. 2026 Apr 29. pii: S0092-8674(26)00226-6. [Epub ahead of print]
    Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.
    Nicole E Scharping, Xuezhen Ge, Maria Inês Matias, Fulin Jiang, Allison Cafferata, Maximilian Heeg, Alexander Monell, Giovanni Galletti, Kitty P Cheung, Angelica Rock, Nick Thao, Sydnye L Shuttleworth, Michael A Bauer, Kennidy K Takehara, Amir Ferry, Sara Quon, Brian Koss, Samuel A Myers, Eric J Bennett, Ananda W Goldrath.
      Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (TRM) maintain protection from infection for years in healthy tissues, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins despite functional proteasome activity. Enforced expression of these ligases in T cells preserved stem-like TCF1+ populations and improved function in tumors and chronic infection, whereas deficiency impaired TIL and altered T cell differentiation during acute infection. Sustained ligase expression rescued the accumulation of unfolded proteins in TIL and improved immunotherapy outcomes in preclinical models, underscoring the critical role of proteostasis in TIL function and highlighting a promising avenue for advancing cancer immunotherapy.
    Keywords:  CD8(+) T cell; E3 ubiquitin ligase; T cell exhaustion; cancer; immunotherapy; proteostasis; tumor; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.cell.2026.02.019
  54. bioRxiv. 2026 Apr 15. pii: 2026.04.12.717919. [Epub ahead of print]
    A Hybrid Physics-Deep Learning Framework for Combinatorial De Novo Design of Small-Molecule Binding Proteins.
    Connor V Galvin, Amy B Guo, Maple N Chen, Isabella L Alfonso, Dominic Grisingher, Simon Kretschmer, Divya Kranthi, Mark Js Kelly, Tanja Kortemme.
      Engineering small-molecule binding proteins de novo remains a significant challenge as even advanced generative models struggle to model the atom-level details of protein-ligand interactions with sufficient accuracy. Higher experimental success rates have resulted from methods that explicitly scaffold predefined binding interactions into helical bundles. Here we introduce a scaffolding strategy that generalizes to alpha-beta architectures. By screening thousands of combinatorially assembled protein-ligand interactions against diverse de novo backbones with finely varied pocket geometries, the protocol allows for high-fidelity accommodation of target interaction geometries. Our protocol then integrates physics-based and deep learning methods for optimization of interfacial interactions and sequence-structure compatibility, considerably improving in silico design metrics. Applying this method to two chemically similar steroids achieved a notable experimental success rate (4/26 designs bind their targets), and NMR structures of two designs are in good agreement with design models. Our generalizable, atomically precise approach offers a robust framework for small-molecule binder design, effectively eliminating the need for high-throughput screening.
    DOI:  https://doi.org/10.64898/2026.04.12.717919
  55. J Cheminform. 2026 Apr 27.
    LEP-AD: language embedding of proteins and attention to drugs predicts drug-target interactions.
    Reem Alsulami, Robert Lehmann, Anuj Daga, Sumeer A Khan, Raik Grünberg, Ahmed Abogosh, David Gomez Cabrero, Stefan T Arold, Robert Hoehndorf, Jesper Tegner, Narsis A Kiani.
       INTRODUCTION: Predicting drug-target interactions remains a significant challenge in drug development and lead optimization. Recent advances have leveraged machine learning algorithms to model drug-target interactions from molecular and sequence data.
    MATERIALS AND METHODS: In this work, we use Evolutionary Scale Modeling (ESM-3) to construct a transformer-based protein language representation for drug-target interaction prediction. We introduce LEP-AD (Language Embedding of Proteins and Attention to Drugs), a modular architecture that combines pretrained protein language models with graph-based molecular encoders to predict binding affinity values.
    RESULTS: We systematically benchmark LEP-AD alongside a range of established deep learning methods across multiple datasets-Davis, KIBA, DTC, Metz, ToxCast, and STITCH. To assess predictive validity, we compare model-derived rankings of drug-target interactions with experimental results reported in the literature. In addition, we perform new experimental assays to evaluate the binding of three ATP-competitive Src kinase inhibitors-Dasatinib, UM-164, and Saracatinib-where experimentally measured IC₅₀ and pKᵢ values are consistent with the predicted rankings.
    CONCLUSION: In summary, our benchmark highlights the strengths and limitations of current drug-target interaction models across diverse datasets and evaluation settings. The results emphasize the impact of pretrained protein and molecular representations on predictive performance and illustrate the persistent challenges of generalization, while the modular LEP-AD framework provides a flexible reference point for comparative evaluation.
    SCIENTIFIC CONTRIBUTION: This study presents LEP-AD, a modular deep learning framework for drug-target interaction prediction that integrates pretrained protein language representations with graph-based molecular encoders. Beyond introducing the architecture, we provide a systematic benchmark under similarity-aware evaluation settings and experimental validation, highlighting the impact of pretrained protein embeddings on predictive behavior across diverse datasets.
    Keywords:  Binding affinity; DTI; Drug discovery; Drug target affinity; ESM; GAT; GCN
    DOI:  https://doi.org/10.1186/s13321-026-01167-9
  56. bioRxiv. 2026 Apr 16. pii: 2026.04.14.718453. [Epub ahead of print]
    Biomolecular condensates provide a unique environment for redox-mediated protein crosslinking.
    Huan Wang, Bruna Favetta, Jinying Wang, Christian Hoffmann, Elton Maloku, Yuzhou Xia, Jean Baum, Dragomir Milovanovic, Benjamin S Schuster, Zheng Shi.
      Biomolecular condensates, often formed through liquid-liquid phase separation, are dynamic cellular compartments. Here, we demonstrate that a wide range of fluorescently tagged proteins undergo inadvertent, condensate-mediated crosslinking, resulting in rapid solidification of condensates under common fluorescence imaging conditions. The process is driven by excitation-induced, short-lived reactive oxygen species (ROS), whose otherwise limited crosslinking potential becomes uniquely enabled in the dense phase. In live cells, excitation-induced ROS potently trigger stress granule formation, while the ROS-driven solidification of condensates is modulated by compartment-dependent antioxidant buffering. Our findings demonstrate that condensates create a distinct environment that enables ROS chemistry unlikely to occur in the bulk cytosol. Furthermore, the cellular redox level can be a general regulator of condensate rheology. Beyond biological insights, our findings underscore the need for scrutiny when examining fluorophore-labeled condensates.
    DOI:  https://doi.org/10.64898/2026.04.14.718453
  57. bioRxiv. 2026 Apr 17. pii: 2026.04.15.717356. [Epub ahead of print]
    Native entanglement misfolding contributes to age-associated structural changes across the Saccharomyces cerevisiae proteome.
    Quyen V Vu, Ian Sitarik, Daniel A Nissley, Edward P O'Brien.
      Aging at the subcellular level involves the simultaneous decline in the cell's ability to maintain protein homeostasis and rise in misfolded proteins through a positive feedback loop. Here, we test if a widespread class of protein misfolding could contribute to proteome aging by examining if statistical associations exist between age-related changes in protein structure, measured by limited proteolysis mass spectrometry data of the aging Saccharomyces cerevisiae proteome, with structural annotations and molecular simulations. We find that globular proteins that are likely to exhibit entanglement misfolding are 121% more likely to exhibit age-related structural changes, and these changes are 59% more likely to be localized to natively entangled regions. Proteins containing native entanglements are seven-fold more likely to misfold, according to simulations, and populate long-lived, near-native misfolded states. Thus, the age-related structural changes in yeast proteins can be explained in part by the accumulation of misfolded proteins involving entanglements.
    DOI:  https://doi.org/10.64898/2026.04.15.717356
  58. Nat Commun. 2026 Apr 28.
    Small heat shock and J-domain proteins direct defense against areca palm velarivirus 1 by degrading coat protein via autophagy.
    Ruibai Zhao, Jie Lu, Zengyu Xing, Jinling Zhai, Hongxing Wang, Xianmei Cao, Xi Huang.
      Both autophagy and heat shock proteins (HSPs) play dual roles in viral infections, yet their coordination in antiviral defense remains unclear. Here, we show that a cytosolic small heat shock protein (AcsHSP) and a type II J-domain protein (AcDNAJB13) from areca palm interact with the coat protein (CP) of areca palm velarivirus 1 (APV1) independently of HSP70 chaperones. Their closest Nicotiana benthamiana homologs also bind CP. Both APV1 infection and CP expression induces the transcription of sHSP and DNAJB13, which in turn inhibits CP accumulation. Silencing of these genes enhances APV1 infection and CP accumulation, while overexpression of AcsHSP reduces viral accumulation. Mechanistically, CP is degraded via autophagy. Both AcsHSP and AcDNAJB13 interact with the autophagosome marker ATG8f1. However, AcsHSP strengthens CP-ATG8f1 binding, whereas AcDNAJB13 weakens it. These findings reveal distinct yet complementary mechanisms by which sHSP and DNAJB13 coordinate with autophagy to restrict viral infection.
    DOI:  https://doi.org/10.1038/s41467-026-72498-2
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