bims-proteo Biomed News
on Proteostasis
Issue of 2026–07–05
fifty-four papers selected by
Eric Chevet, INSERM
  1. Receptor-cargo coupling during ER-autophagy depends on coat proteins and ER membrane properties.
  2. Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.
  3. Biomolecular condensates for proteostasis and potential therapeutic applications.
  4. Proteostasis and unfolded protein response dynamics in human neuron/mouse glia co-cultures reveal a cell-specific maturation response.
  5. Allosteric disordering of eIF2B regulates the integrated stress response.
  6. Navigating Misfolded Terrain: ER-Associated Degradation of Membrane Proteins.
  7. ER sensing of lipid metabolism drives PRA family-dependent regulation of COPII vesicle transport.
  8. Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.
  9. Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
  10. Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis.
  11. Native Mass Spectrometry Analysis of Cullin-RING Ubiquitin E3 Ligase Complexes in the Context of Targeted Protein Degradation.
  12. Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2.
  13. A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.
  14. TUSC3 serves as a rate-limiting gatekeeper of a glycan-mediated ER triage checkpoint for BMP4/Dpp.
  15. Structural and mutational insights define ERMA as the ER Mg2+ ATPase and reservoir gatekeeper.
  16. Cryo-EM structure of the naked mole-rat ribosome reveals a stabilized split 28S rRNA.
  17. Design, synthesis, and biological evaluation of HSP70-mediated HEMTACs as novel androgen receptor degraders.
  18. Mechanistic dissection of SMARCA2/4 molecular glues reveals programmable switching between DCAF16 and FBXO22.
  19. Centrosome linker protein CEP68 modulates cellular stress responses via nuclear condensate formation and HSP27 interaction.
  20. Phosphatidylinositol diphosphate binding by ESCRT-III filaments.
  21. Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response.
  22. Proteomic Analysis Identifies ATE1-Dependent Arginylation Dysregulation across Meningioma Grades.
  23. VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair.
  24. Cannabidiol Activates Integrated Stress Response Signaling and Immune Trafficking Programs in an A375 Melanoma-Jurkat T Cell Coculture Model: A Multi-Omics Analysis.
  25. Disentangling the response to lysosomal damage.
  26. Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma.
  27. Functional Suppression of SCAP Triggers Endoplasmic Reticulum Stress-Dependent Ferroptosis by Impairing Cholesterol Metabolism in Gastric Cancer.
  28. Co-option of lysosomal machinery shapes the evolution of the intracellular photosymbiosis supporting coral reefs.
  29. RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis.
  30. Two-pore channel-2 controls calmodulin-dependent STIM1 inactivation.
  31. COPII meets autophagy at the ER membrane.
  32. A Systematic Direct-to-Biology Approach Identified Potent Cereblon HaloPROTACs.
  33. Blockade of FGFR1 Trafficking to the Cell Surface Results in the Partial Mistargeting of the Receptor to Peroxisomes.
  34. Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
  35. Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
  36. Remodeling of mRNA by eIF4F in human translation initiation.
  37. The nucleus-vacuole junction at a glance.
  38. ESCRT-0 regulates AMPA receptor currents and Ca 2+ - dependent signaling.
  39. Spliceosomal proofreading factors safeguard 3' splice-site fidelity and prevent proteotoxicity and inflammation.
  40. Dynamic redistribution of eIF4F controls cap-dependent translation initiation.
  41. AARS2-mediated lactylation of ULK1 promotes autophagy-dependent progression of clear cell renal cell carcinoma.
  42. Multitargeted Degradation of Cell Surface Receptors by Modular Glyco-Nanosheets.
  43. Dual Targeting of Nucleotidase-Dependent and -Independent Functions via PROTAC-Mediated CD73 Degradation.
  44. Arsenic Promotes Nonalcoholic Steatohepatitis via MCFD2-Induced PERK/eIF2α-Mediated Integrated Stress Response.
  45. A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.
  46. Membrane protein solubilization and structure determination using de novo-designed proteins.
  47. ER stress amplifies inflammation via a dual mechanism involving IκBζ-XBP1s synergism and Regnase-1 degradation.
  48. Gravitational and mechanical forces shape mitochondrial translation.
  49. The Temporal Architecture of Human Cells: Organelle Clocks and Distributed Circadian Time.
  50. Protocol for integrated ubiquitination analysis of in vitro E3 ligase-DUB regulation and in vivo ubiquitin chain linkage characterization.
  51. A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis.
  52. N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity.
  53. The role of ATF4 in neurons under mitochondrial stress.
  54. A NACHT domain-containing protein Ncp is required for appendage-associated unconventional protein secretion in the fungus Penicillium herquei.
  1. Autophagy. 2026 Jul 03. 1-3
    Receptor-cargo coupling during ER-autophagy depends on coat proteins and ER membrane properties.
    Shuliang Chen, Subhrajit Banerjee, Peter Novick, William A Prinz, Susan Ferro-Novick.
      Selective autophagy of the endoplasmic reticulum (reticulophagy) is driven by receptor-mediated ER remodeling. Reticulophagy receptors are essential for ER turnover. Productive cargo recognition during autophagosome-mediated reticulophagy depends on the interaction of the receptor with the COPII subunit Sfb3/Lst1 (SEC24C in mammals) as well as the phospholipid composition of the ER. We unexpectedly found that the conserved reticulophagy receptor Atg40 traffics to the vacuole/lysosome without cargo (ER membrane proteins) or Sfb3/Lst1 in neutral lipid-deficient mutant cells. Comprehensive lipidomic profiling of this lipid mutant revealed a shift in the phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) ratio, a compositional change predicted to alter biophysical properties of the ER, including membrane bendability. The discovery that membrane properties regulate receptor - cargo coupling efficiency at autophagic sites, as they do at secretory exit sites, extends current mechanistic models of reticulophagy and suggests membrane properties may also affect cargo selection on other types of selective autophagy pathways.
    Keywords:  Coat proteins; membrane curvature; neutral lipid; receptor–cargo coupling; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2695313
  2. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00686-8. [Epub ahead of print]45(7): 117608
    Cadherin regulation of endoplasmic reticulum-plasma membrane contact sites.
    Sonam Lhamo, Navaneetha Krishnan Bharathan, William Giang, Kandice R Levental, Cory L Simpson, Stephanie E Zimmer, Thomas Saba, Julie Beaucousin, Mélina L Heuzé, Andrew P Kowalczyk.
      The spatial organization and dynamics of the endoplasmic reticulum (ER) govern when and where ER tubules engage with other organelles and the plasma membrane. We previously found that ER tubules are closely associated with desmosomes, but the mechanisms of ER recruitment to these adhesive intercellular junctions were unclear. Here, we demonstrate that recruitment of ER tubules to intercellular junctions is dependent upon E-cadherin association with α-catenin. During junction formation, adherens junctions and ER tubules appear nearly simultaneously at nascent cell-cell contacts, followed by desmosome formation. ER recruitment allows the formation of ER-plasma membrane contact sites (ER-PMCSs) and an assembly comprising adherens junctions, ER-PMCS, and desmosomes. Ablating adherens junctions disrupts this tripartite assembly and perturbs global lipid levels. Collectively, our findings identify cadherins as key organizers of ER-PMCS positioning and suggest that the cell-cell adhesion-organelle unit integrates cellular mechanical elements with plasma membrane homeostasis.
    Keywords:  CP: cell biology; ER-plasma membrane contact sites; adherens junctions; desmosomes; endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.celrep.2026.117608
  3. Mol Cell. 2026 Jun 30. pii: S1097-2765(26)00387-4. [Epub ahead of print]
    Biomolecular condensates for proteostasis and potential therapeutic applications.
    Wen Jia, Pilong Li.
      Proteostasis is essential for cellular function, and its dysregulation underlies a wide spectrum of diseases. Growing evidence underscores liquid-liquid phase separation (LLPS) as a central mechanism governing protein degradation through the formation of condensates for proteostasis. These membraneless biomolecular condensates concentrate or sequester key degradation factors, substrates, and enzymes, enabling spatiotemporally regulated protein clearance. Condensates for proteostasis represent a mechanism for degrading pathogenic proteins that remain refractory to conventional therapeutics. In this perspective, we explore how LLPS drives the assembly of condensates for proteostasis, outline their physiological functions, and highlight their emerging utility as a versatile platform for targeted protein degradation. Harnessing these condensates offers a promising route to eliminate "undruggable" targets and reestablish proteostasis, opening new avenues for precision medicine across a range of major diseases.
    Keywords:  E3 ligase; autophagy; biomolecular condensate; degradation condensate; liquid-liquid phase separation; proteasome; proteostasis; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.016
  4. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2521663123
    Proteostasis and unfolded protein response dynamics in human neuron/mouse glia co-cultures reveal a cell-specific maturation response.
    Lea A Barny, Sarah K Garcia, Aiden J Houcek, Burak Uzay, Minsoo Kim, Ege T Kavalali, Lars Plate.
      Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their postmitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development and maturation. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to recapitulate and investigate cell type-specific, maturation-related changes in the proteostasis network using data-independent acquisition LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during in vitro neuronal maturation between 30 d and 60 d. Species-specific analysis revealed that mature neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in endoplasmic reticulum (ER)-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR over time. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in matured neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during in vitro maturation and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in human neurons.
    Keywords:  activating transcription factor 6; data-independent acquisition (DIA) mass spectrometry; inositol requiring enzyme 1; neuronal maturation; protein kinase R-like ER kinase
    DOI:  https://doi.org/10.1073/pnas.2521663123
  5. Nat Chem Biol. 2026 Jun 29.
    Allosteric disordering of eIF2B regulates the integrated stress response.
    Udit Dalwadi, Advait Subramanian, Aniliese Deal, Julia E Conrad, Tamara Nadjsombati, Meera Venkatesh, Morgane Boone, Pascal F Egea, Lingjie He, Nimit Jain, D John Lee, Yuwei Liu, Lucas C Reineke, Kazuki Saito, Nathaniel Talledge, Hannah Toutkoushian, Maxence Le Vasseur, Francesca Zappa, Raoul J de Groot, Diego Acosta-Alvear, Christopher P Arthur, Jodi Nunnari, Susan Marqusee, Rosalie E Lawrence, Mauro Costa-Mattioli, James J Crawford, Frank J M van Kuppeveld, Tristan I Croll, Peter Walter, Adam Frost.
      The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.
    DOI:  https://doi.org/10.1038/s41589-026-02256-4
  6. Chem Rev. 2026 Jun 30.
    Navigating Misfolded Terrain: ER-Associated Degradation of Membrane Proteins.
    Devanshi Agarwal, Kristina Solorio-Kirpichyan, Eric M Jordahl, Gayathri Ramakrishnan, Nicola A Scott, Sonya E Neal.
      Integral membrane proteins face unique folding challenges in the endoplasmic reticulum (ER) due to their hydrophobic transmembrane domains and complex topologies. Membrane protein misfolding disrupts ER homeostasis, contributing to diseases such as neurodegeneration, metabolic disorders, cystic fibrosis, and cancers. ER-associated degradation (ERAD) is a protein quality control pathway that detects, ubiquitinates, and retrotranslocates terminally misfolded proteins for proteasomal degradation in the cytosol. Recognition of membrane substrates involves multiple determinants, including topological lesions, exposed hydrophobic patches, and sequence-specific degrons. Recent advances in cryo-EM, functional genomics, and biochemical reconstitution studies have revealed new insights into the mechanistic actions of ERAD. This review addresses the current understanding of ERAD machinery dedicated to targeting misfolded membrane proteins, highlights emerging mechanistic models, and discusses how ERAD drives pathology. Understanding these principles will inform strategies for targeted manipulation of ER membrane protein quality control in health and disease.
    DOI:  https://doi.org/10.1021/acs.chemrev.5c00780
  7. Nat Commun. 2026 Jul 03.
    ER sensing of lipid metabolism drives PRA family-dependent regulation of COPII vesicle transport.
    Kazuki Hanaoka, Mitsuki Nakazato, Philipp Schlarmann, Hiroki Nakamura, Mei Kato, Ryoko Ikema, Mizuki Iguchi, Katsuki Eto, Takefumi Karashima, Atsuko Ikeda, Yukari Yabuki, Javier Manzano-Lopez, Auxiliadora Aguilera-Romero, Susana Sabido-Bozo, Ana Maria Perez-Linero, Muneyoshi Kanai, Haruyuki Iefuji, Isabelle Riezman, Howard Riezman, Manuel Muñiz, Kouichi Funato.
      Newly synthesized secretory proteins and lipids are transported from the endoplasmic reticulum (ER) to the Golgi prior to their ultimate destinations, which is tightly regulated during adaptation to environmental stress. However, regulatory pathways governing the formation of COPII vesicles budded from the ER remain insufficiently explored. Here, we present evidence indicating that COPII-mediated vesicle transport is transcriptionally controlled through the phosphatidic acid (PA)-dependent Opi1-Ino2/Ino4 regulatory circuit. Our analysis shows that YIP3, a target gene of Ino2/Ino4, exerts a negative regulatory impact on COPII-mediated vesicle transport. We demonstrate that Ino2/Ino4, but not Yip3 modulates Sar1 activation, the initial step in COPII vesicle formation, whereas Yip3 hinders Sec16 assembly on the ER membrane, thereby implying that Ino2/Ino4 governs COPII vesicle formation at multiple steps. Finally, we show that under ER stress conditions which are accompanied by elevated PA, vesicular transport is restricted in a PA and Yip3-dependent manner. Thus, this study provides the first evidence for an ER sensing system that transcriptionally fine-tunes vesicle formation in response to alterations in lipid composition of the ER membrane during ER stress.
    DOI:  https://doi.org/10.1038/s41467-026-75057-x
  8. Nat Commun. 2026 Jul 02. pii: 5784. [Epub ahead of print]17(1):
    Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.
    Anne Sophie Lau, Sreedhar Nellaepalli, R Paul Jarvis.
      The ubiquitin-proteasome system (UPS) is the preeminent proteolytic system in eukaryotes. While soluble nucleocytosolic proteins are readily accessed by the UPS, organelle-localised proteins present major, membrane-related accessibility challenges. Cells overcome this problem by employing the conserved AAA+ ATPase Cdc48 to extract organellar proteins to the cytosol, thereby enabling proteasomal degradation. Major Cdc48-dependent proteolytic systems exist at the endoplasmic reticulum, mitochondria and chloroplasts, and are uniquely adapted to deliver protein homeostasis within the respective organelles. We provide a focused comparison of these systems, analysing similarities and differences between them. Better understanding of underlying principles has important implications spanning human health and agriculture.
    DOI:  https://doi.org/10.1038/s41467-026-74728-z
  9. Autophagy. 2026 Jun 30.
    Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
    Wenxin Zhang, Thomas Litschel, Anne Schreiber, Rocco D'Antuono, Sharon A Tooze.
      Macroautophagy/autophagy, a conserved intracellular catabolic pathway, removes deleterious cytosolic material to maintain homeostasis and survival. Upon autophagy induction, a unique double-membraned structure, the phagophore, forms and engulfs cytosolic material, the cargo, as it closes to become an autophagosome. Mammalian Atg8-family proteins (ATG8s) are ubiquitin-like proteins which are essential for engulfment of the cargo and membrane closure. ATG8s are recruited to the phagophore by ATG12-ATG5-ATG16L1, an E3-like ligase which is recruited by PtdIns3P-binding WIPI proteins. Covalent lipidation of the ATG8s to phosphatidylethanolamine by the E3 ligase occurs specifically on the phagophore membrane allowing recruitment of cytosolic cargo and cargo receptors, such as SQSTM1/p62. While ATG8-cargo receptor interactions are well established, how the ATG8s bind cargo and cargo receptors on the inner membrane of the phagophore has not been studied. To recapitulate these events, we use giant unilamellar vesicles (GUVs) and encapsulate protein machinery and cargo, generating a membrane platform to which ATG8 proteins can be recruited. Inside the GUVs we reconstituted WIPI2B-directed and cargo-directed ATG8 lipidation revealing distinct roles of WIPI2B and SQSTM1 in initiating ATG8 conjugation. We show that SQSTM1 and SQSTM1 droplets are recruited to the GUV inner membrane through interaction with membrane bound ATG8s. Through the development of a bead-based membrane deformation assay, we show redistribution and local enrichment of membrane-bound ATG8s occurs upon binding to SQSTM1 droplets. Our work demonstrates fundamental molecular mechanisms into phagophore-ATG8-cargo interactions providing novel model systems to investigate ATG8-cargo interactions on the inner phagophore membrane.Abbreviations:ATG: autophagy related; cDICE: continuous droplet interface crossing encapsulation; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; GABARAP: GABA type A receptor-associated protein; GUV: giant unilamellar vesicle; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; LUV: large unilamellar vesicle; NBD: 7-nitrobenz-2-oxa-1,3-diazol-4-yl; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PolyUb: K63-linked polyubiquitin; POPC: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine; POPE: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; Rh-PE: 18:1 Liss Rhod PE; SQSTM1/p62: sequestosome 1; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.
    Keywords:  ATG8 lipidation; giant unilamellar vesicles; in vitro reconstitution; liquid-liquid phase separation; membrane expansion
    DOI:  https://doi.org/10.1080/15548627.2026.2697432
  10. J Mol Biol. 2026 Jun 29. pii: S0022-2836(26)00292-5. [Epub ahead of print] 169919
    Antibody-secreting cells integrate efficient NMD with non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis.
    Praité Antoine, Lambert Jean-Marie, Ashi Mohamad Omar, Troadec Estelle, Oblet Christelle, Carle Bastien, Terro Faraj, Srour Nivine, Dézé Ophélie, Cogné Michel, Le Pennec Soazig, Sirac Christophe, Laffleur Brice, Al Hayek Sandy, Delpy Laurent.
      Plasma cells are terminally differentiated B lymphocytes specialized in the high‑level production and secretion of antibodies. To accommodate the persistent load imposed on the endoplasmic reticulum (ER), plasma cell differentiation engages a sustained unfolded protein response (UPR). Although the UPR is known to attenuate nonsense‑mediated mRNA decay (NMD) in many cell types, the interplay between these pathways during plasma cell differentiation remains poorly defined. We show that NMD is rapidly enhanced during B cell activation and remains high in antibody‑secreting cells (ASCs), even as these cells activate the UPR. Using mouse models enabling in vivo monitoring of NMD under enforced ER stress, we identify limited activation of the PERK-eIF2α axis as a key determinant preserving NMD activity while supporting robust immunoglobulin synthesis. Supporting a key role for NMD in B cell activation and ASC differentiation, antisense oligonucleotide‑mediated knockdown of Upf1 severely compromised cell viability. Moreover, we provide evidence for efficient degradation of endogenous NMD substrates in myeloma cells, suggesting a functional role for NMD in multiple myeloma. Taken together, these findings reveal an integrated protein quality‑control network in ASCs that relies on the coordinated action of NMD and non‑canonical UPR signaling to maintain proteostasis and support massive immunoglobulin synthesis.
    Keywords:  Immunoglobulin; Myeloma cells; NMD (nonsense-mediated mRNA decay); Plasma cell differentiation; UPR (unfoldedprotein response)
    DOI:  https://doi.org/10.1016/j.jmb.2026.169919
  11. Anal Chem. 2026 Jun 30.
    Native Mass Spectrometry Analysis of Cullin-RING Ubiquitin E3 Ligase Complexes in the Context of Targeted Protein Degradation.
    Louise M Sternicki, Charlotte Crowe, Lianne H E Wieske, Alessio Ciulli, Sally-Ann Poulsen.
      The binding of PROTACs to their partner ubiquitin E3 ligase (E3) and a protein of interest (POI) is critical for PROTAC development and validation. Characterization of PROTAC complexes by cryo-electron microscopy and X-ray crystallography is not always feasible, especially where species may be transient and protein structures may not resolve due to flexible domains or intrinsically disordered regions or where the air-water interface poses risks such as dissociation. More routine biophysical methods with broader applicability to varied samples are essential to support the rapidly expanding targeted protein degradation field. The majority of PROTACs in development and in the clinic act through a Cullin-RING E3 ligase (CRL), of which the pentameric von Hippel-Lindau (VHL) Cullin 2 RING E3 complex (CRL2VHL) is the premier example. Native mass spectrometry (nMS) can be used to characterize protein complexes but has not previously been used to characterize any full E3 or any E3-E2 interactions. Here, we show for the first time that CRL2VHL (a full E3) is amenable to characterization by nMS and, notably, that all its key interactions with the other protein components integral to the targeted protein degradation mechanism can be observed. Specifically, we characterize binary, ternary, and higher-order complexes that comprise CRL2VHL, including the multiprotein systems of POI-PROTAC-CRL2VHL, CRL2VHL-E2-Ub, and POI-PROTAC-CRL2VHL-E2-Ub, all of which are essential in facilitating productive POI ubiquitination and degradation. We benchmarked the nMS with two POI examples (BRD4BD2 and KRAS) with their respective PROTACs (MZ1 and ACBI3) and were able to observe all of the relevant complexes across both systems. We anticipate that our findings will open avenues for nMS to integrate as an alternative experimental method enabling scalable characterization of the intricate high-mass multiprotein interactions central to biological mechanisms of action.
    DOI:  https://doi.org/10.1021/acs.analchem.6c01970
  12. J Med Chem. 2026 Jun 29.
    Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2.
    Hua Tang, Yaxian Liao, Tsung-Yu Yeh, Kazuya Nishibayashi, Milad Rouhimoghadam, Ka Yang, Chunrong Li, Regina Stasser de Gonzalez, Yuan Zhao, Nina J Hawkins, Justin M Reitsma, Steven P Gygi, Weiping Tang.
      Targeted protein degradation (TPD) has emerged as a transformative strategy in drug discovery, yet the repertoire of E3 ligase recruiters remains limited. Here, we report the discovery of an aldehyde-anchored PROTAC that covalently engages the E3 ligase FBXO22 to induce degradation of the histone methyltransferase NSD2 and CDK12. Competitive electrophile screening identified a phenyl aldehyde warhead as optimal, with SAR studies revealing that degradation is highly sensitive to the steric and electronic environment of the aldehyde moiety. The lead degrader, T9, effectively and selectively induces NSD2 degradation across multiple cancer cell lines. Mechanistic investigations confirmed that degradation is dependent on FBXO22, the ubiquitin-proteasome system, and the neddylation pathway, with mutagenesis identifying Cys326 as the critical residue for covalent engagement. This work establishes a stable covalent ligand for FBXO22, expanding chemical space of PROTAC design by introducing an accessible aldehyde-based E3 ligase ligand with broad potential for protein degradation.
    Keywords:  E3; FBXO22; NSD2; PROTAC; aldehyde; covalent; degradation; ligand; ligase; protein
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00020
  13. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2609132123
    A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.
    Felix Kraus, Yuchen He, Yizhi Jiang, Delong Li, Yohannes A Ambaw, Federico M Gasparoli, Joao A Paulo, Tobias C Walther, Robert V Farese, Steven P Gygi, Florian Wilfling, J Wade Harper.
      Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and by recycling building blocks for organelle biogenesis. Lysosomal storage disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons. In-depth abundance and correlation profiling across organelles and suborganelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein-protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryoelectron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.
    Keywords:  iNeurons; lysosome; organelle; protein interactions; proteomics
    DOI:  https://doi.org/10.1073/pnas.2609132123
  14. Cell Rep. 2026 Jun 29. pii: S2211-1247(26)00706-0. [Epub ahead of print]45(7): 117628
    TUSC3 serves as a rate-limiting gatekeeper of a glycan-mediated ER triage checkpoint for BMP4/Dpp.
    Antonio Galeone, Emilio Solazzo, Francesco Lavezzari, Seung Yeop Han, Gaia Consonni, Bruna My, Riccardo Rizzo, Giuseppe Gigli, Hamed Jafar-Nejad, Thomas Vaccari.
      Trimming of the three glucose residues decorating nascent N-glycoproteins is a critical step for their entry into the endoplasmic reticulum quality control (ERQC) and recognition by ER chaperones. However, the functional relevance of the second glucose (G2) and the regulatory step upstream of its removal by glucosidase II (GCS2) remain poorly understood. Here, we report that TUSC3, a component of the oligosaccharyltransferase (OST) complex, regulates G2 to G1 trimming on N-glycosylated bone morphogenetic protein 4 (BMP4) and its Drosophila homolog Dpp to promote their ERQC entry. Loss- and gain-of-function genetic experiments and biochemical assays in mammalian cells and flies indicate that TUSC3 serves as a dosage-sensitive gatekeeper that influences the decision between proper folding and secretion versus elimination by ER-associated degradation for the BMP4 molecules, thereby tuning BMP signaling. Together, these data reveal an unrecognized role for an OST component in early glycoprotein maturation, relevant to a major developmental signaling pathway.
    Keywords:  BMP signaling; CP: cell biology; Drosophila; ER-associated degradation; OST complex; TUSC3; deglycosylation; endoplasmic reticulum; glucosidase II; glycosylation; oligosaccharyltransferase complex; quality control
    DOI:  https://doi.org/10.1016/j.celrep.2026.117628
  15. Sci Adv. 2026 Jul 03. 12(27): eaef4971
    Structural and mutational insights define ERMA as the ER Mg2+ ATPase and reservoir gatekeeper.
    Manigandan Venkatesan, Michael L Oldham, Ning Shi, Adhishree Chidambaram, Neelanjan Vishnu, Abitha K Madesh, Kristen Bentz, Peter B Stathopulos, Ravi C Kalathur, Youxing Jiang, Muniswamy Madesh.
      Magnesium (Mg2+) is the most abundant divalent cation in cells, yet the mechanisms mediating its organellar transport remain poorly defined. We identify endoplasmic reticulum (ER) Mg2+ adenosine triphosphatase (ATPase) (ERMA) as the transporter that drives Mg2+ uptake into the ER lumen, establishing the ER as a bi-ionic intracellular reservoir. MagFRET biosensors targeted to the ER demonstrate that ERMA mediates dynamic ER Mg2+ storage and robust adenosine 5'-triphosphate-dependent Mg2+ uptake reaching 15 to 30 millimolar. Cryo-electron microscopy structures of human and mouse ERMA reveal a P-type ATPase fold with an unwound transmembrane 4 (TM4) that coordinates Mg2+ via the unique PILP backbone and the TM5 residue Q1110, whose mutation markedly impairs ERMA-mediated Mg2+ uptake. Functional reconstitution of domain mutants, ERMA-SERCA chimeras, and pathogenic variants confirm ERMA as an ER-resident Mg2+ pump and gatekeeper of ER Mg2+ ionic equilibrium.
    DOI:  https://doi.org/10.1126/sciadv.aef4971
  16. Nat Commun. 2026 Jul 03. pii: 5841. [Epub ahead of print]17(1):
    Cryo-EM structure of the naked mole-rat ribosome reveals a stabilized split 28S rRNA.
    Mehmet Gül, Alice Rossi, Christian M T Spahn, Gary R Lewin, Mikhail Kudryashev.
      The naked mole-rat (Heterocephalus glaber) is a long-lived mammal with resistance to cancer and hypoxia, suggesting the evolution of robust proteostasis networks. The ribosome, central for protein synthesis, is key to cellular stress responses and has an unusual feature: the 28S rRNA split; however, the details of its organization remain unknown. Here, we present high-resolution cryo-EM structures of the naked mole-rat 80S ribosome in four states of the elongation cycle. The structures reveal a conserved overall architecture and rRNA modification landscape compared to other mammals, and provide an atomic-level view of the distinct break in the 28S rRNA. This cleavage event, located in the D6 expansion segment, is structurally stabilized by a network of interactions with surrounding ribosomal proteins, maintaining the integrity of the large subunit. Our comparative analysis revealed that this compensatory network preserves a canonical architecture that is nearly indistinguishable from intact mouse and human ribosomes. These findings resolve the structural basis of this distinct cleavage, showing that it is a stable, integrated feature whose function is likely linked to more subtle regulatory mechanisms, rather than inducing major structural rearrangements.
    DOI:  https://doi.org/10.1038/s41467-026-75143-0
  17. Eur J Med Chem. 2026 Jun 29. pii: S0223-5234(26)00552-0. [Epub ahead of print]317 119107
    Design, synthesis, and biological evaluation of HSP70-mediated HEMTACs as novel androgen receptor degraders.
    Zhenzhen Li, Xinru Han, Shuxian Guo, Lupei Du.
      Targeted protein degradation (TPD) has emerged as an important therapeutic strategy for addressing challenging protein targets. While Proteolysis-Targeting Chimeras (PROTACs) are the leading TPD approach, their reliance on a limited set of E3 ligases poses challenges, including tissue-specific restrictions and the emergence of drug resistance. To address these limitations, we previously developed the HEMTAC (HEat shock protein-Mediated TArgeting Chimeras) platform, which recruits HSP90 to induce target protein degradation. Building on this concept, the current study expands the HEMTAC framework by integrating HSP70, a key molecular chaperone, to target the androgen receptor (AR). We designed and synthesized a series of novel HSP70-recruiting HEMTACs by linking an HSP70 ligand (a derivative of VER-155008) with an AR-binding ligand. Biological evaluation identified compound 39 as an active degrader that induced substantial AR degradation in LNCaP prostate cancer cells. This work supports the feasibility of recruiting HSP70 for TPD and provides a molecular tool for AR-degradation research, thereby expanding the TPD toolbox for future drug discovery.
    Keywords:  AR; HEMTAC; HSP70; Targeted protein degradation; Ubiquitination
    DOI:  https://doi.org/10.1016/j.ejmech.2026.119107
  18. Cell Chem Biol. 2026 Jul 02. pii: S2451-9456(26)00198-4. [Epub ahead of print]
    Mechanistic dissection of SMARCA2/4 molecular glues reveals programmable switching between DCAF16 and FBXO22.
    Milad Rouhimoghadam, Christie J Kang, Jackson A Gartman, Sameera Senaweera, Ioanna Zoi, Alex Y Jiu, Judith A Ronau, Andrea G Shergalis, Hua Tang, Shaun M McLoughlin, Panga Jaipal Reddy, Qi Sun, Loren M Lasko, Tiffany A Thibaudeau, Xiaoli Huang, Violeta L Marin, Elyse C Freiberger, Ashish Thakur, Zhaozhong J Jia, Daniel T Ladror, Marc J Scanio, Alexey Rivkin, Kevin R Woller, Scott E Warder, Anil Vasudevan, Justin M Reitsma, Xiaoyu Lin.
      Molecular glue degraders (MGDs) represent a powerful strategy for targeted protein degradation, yet the rules governing ligase selectivity remain elusive. Here, we characterize a class of SMARCA2/4 MGDs with tunable E3 ligase engagement. Compound 1 degraded SMARCA2/4 exclusively via DCAF16, driven by covalent capture of Cys173. Strikingly, 1-carbon analogs rewired ligase preferences: compounds 2 and 3 recruited both DCAF16 and FBXO22, whereas compound 4 remained strictly DCAF16 dependent despite weak FBXO22 binding, although all compounds shared an alkynyl pyridine moiety essential for covalent attachment. Mutational analysis further pinpointed Cys228 and Cys326 in FBXO22 as indispensable for degradation. These findings reveal that subtle scaffold modifications dictate ligase preference and that only productive ternary geometries drive ubiquitination and degradation. By exposing new cysteine liabilities and showcasing precise control over ligase engagement, this work highlights how single-atom edits in MGDs can unlock tunable, switchable degradation mechanisms.
    Keywords:  DCAF16; FBXO22; SMARCA2; SMARCA4; cysteine residues; molecular glue degraders; targeted protein degradation; ternary complex formation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.05.019
  19. iScience. 2026 Jul 17. 29(7): 116491
    Centrosome linker protein CEP68 modulates cellular stress responses via nuclear condensate formation and HSP27 interaction.
    Hui-Fang Hung, Peng-Peng Zhu, Craig Blackstone.
      CEP68 is best known for its role at the centrosome linker, but its functions beyond the centrosome remain largely unexplored. Here, we show that CEP68 also localizes to the Golgi apparatus and nucleus, where it contributes to the stress response. CEP68 associates with stress response proteins, modulating eIF2α phosphorylation and stress granule (SG) formation during oxidative stress. In the nucleus, CEP68 forms liquid-like nuclear condensates adjacent to nuclear speckles (NSs), influencing their protein dynamics. The small heat shock protein HSP27, which translocates to NSs during stress, interacts with CEP68 under normal conditions, with this interaction markedly enhanced during stress. HSP27 regulates CEP68 condensate dynamics, while CEP68 nuclear condensates displace HSP27 from NSs. Both neuropathy-associated HSP27 mutants and a disease-linked CEP68 variant alter their interaction. These findings uncover a new role for CEP68 in stress response and provide insights into HSP27's functions in stress adaptation, neuropathy, and immune regulation.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.116491
  20. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2616668123
    Phosphatidylinositol diphosphate binding by ESCRT-III filaments.
    Akram Alian, John McCullough, Frank R Moss, Nathaniel Talledge, Arshad Mohammed, Cecilia D Gerstner, Jacob A Dalluge, Elliott L Paine, Omar Davulcu, Chi-Lun Chang, Adam Frost, Wesley I Sundquist.
      Different inositol phospholipids (PIPs) distribute to distinct subcellular organelles, creating an addressing system that dictates the sites of action of PIP-binding proteins, including components of the Endosomal Sorting Complexes Required for Transport (ESCRT). The ESCRT machinery is recruited to remodel many different cellular membranes through combinatorial binding interactions made by the early-acting ESCRT-I and ESCRT-II complexes with PIPs, ubiquitin modifications, and membrane-specific adaptors. Membrane remodeling, constriction, and fission are then mediated by membrane-associated filaments formed by subunits of the late-acting ESCRT-III complexes, together with their associated VPS4 AAA ATPases. Here, we describe two different classes of helical ESCRT-III filaments that can surround and tubulate membranes containing PIP2 lipids. Cryo-EM reconstructions revealed that protofilaments comprising closed IST1 subunits formed 8-stranded nanotubes that encase membrane monolayers. The nanotube coordinates exposed PI(4,5)P2 or PI(3,5)P2 headgroups within a basic pocket formed at the junction of three IST1 subunits, and our structures reveal how the pocket can accommodate either PIP2 isomer with minimal adjustment. In contrast, protofilaments comprising open CHMP1A subunits formed one start helices that encase membrane bilayers and bind exposed PI(4,5)P2 headgroups across a basic surface that spans adjacent subunits of the CHMP1A protofilament. These two different structures extend the known plasticity of ESCRT-III polymers, reveal how PIP2 lipids can promote ESCRT-III filament assembly and membrane remodeling, and define the molecular contacts that underlie specific ESCRT-III/PIP2 interactions.
    Keywords:  ESCRT-III filaments; Endosomal Sorting Complexes Required for Transport (ESCRT); membrane remodeling; phosphatidylinositols
    DOI:  https://doi.org/10.1073/pnas.2616668123
  21. Nat Commun. 2026 Jun 30.
    Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response.
    Anne-Sophie M C Marques, Ludwig G Bauer, Tuan-Anh Nguyen, Alejandro Gonzalez Orta, Jan-Lennart Venne, Carol Cheng, Esra Balıkçı, Yusi Liu, Barr Tivon, Alena Kroupova, Alessio Ciulli, Nir London, Stefan Kubicek, Kilian V M Huber.
      6-Thioguanine (6-TG) is an FDA-approved antimetabolite drug that is widely used clinically, including for the treatment of leukemia. Its cellular effects require metabolic activation and are regulated through interactions with various proteins such as NUDT15, which catalyzes the hydrolysis of the active 6-TG metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP. Recent genome-wide CRISPR loss-of-function studies have identified another NUDIX hydrolase, NUDT5, as a crucial mediator of 6-TG toxicity. Here, we develop and validate a selective, cell-active NUDT5 degrader toolkit and orthogonally characterize target engagement, ternary complex formation, degradation kinetics, and proteome-wide selectivity. These degraders, in conjunction with orthogonal CRISPR knock-out and reconstitution experiments, support a non-enzymatic role for NUDT5 in modulating the cellular response to 6-TG. Depletion of NUDT5 protein is antagonistic to NUDT15 inhibition, suggesting a distinct mode-of-action with potential implications for patient therapy.
    DOI:  https://doi.org/10.1038/s41467-026-74489-9
  22. J Proteome Res. 2026 Jun 29.
    Proteomic Analysis Identifies ATE1-Dependent Arginylation Dysregulation across Meningioma Grades.
    Janaina Macedo-da-Silva, Benedito Jamilson Araújo Pereira, Simon Ngao Mule, Sueli Mieko Oba-Shinjo, Livia Rosa-Fernandes, Suely K N Marie, Giuseppe Palmisano.
      Meningiomas are the most common primary brain tumors, yet the molecular pathways that distinguish grade 1 from grade 2 lesions remain insufficiently understood. Among post-translational modifications, N-terminal arginylation─catalyzed by ATE1─regulates protein stability and cellular stress responses, but its role in meningioma biology has not been explored. Here, we integrated mass-spectrometry-based proteomics, immunoblotting, and transcriptomic reanalysis to investigate pathway regulation across tumor grades. Grade 1 meningiomas displayed higher ATE1 expression and increased arginylation of key chaperones, accompanied by activation of the PERK branch of the unfolded protein response (UPR), enhanced autophagy, and greater engagement of apoptotics pathways. In contrast, grade 2 tumors showed reduced ATE1 levels, diminished BIP arginylation, attenuated UPR-PERK signaling, impaired autophagy, and increased proliferative signaling. Proteins predicted to be substrates of ATE1-mediated degradation were upregulated in grade 2 tumors, suggesting that loss of arginylation may stabilize pro-oncogenic factors. Together, these findings reveal grade-specific remodeling of the N-degron/arginylation axis and highlight protein arginylation as a previously unrecognized modulator of meningioma progression, with potential therapeutic relevance.
    Keywords:  ATE1; arginylation; grade comparison; meningiomas; post-translational modifications (PTMs); proteomics
    DOI:  https://doi.org/10.1021/acs.jproteome.5c01173
  23. Nat Commun. 2026 Jul 02. pii: 5789. [Epub ahead of print]17(1):
    VPS13C/PARK23 initiates lipid transfer and membrane remodeling for efficient lysosomal repair.
    Oluwatobi Andrew Adeosun, Christian Schröer, Elisabeth Südhoff, Fabio Bergenthal, Katharina Sommer, Emely Döffinger, Britta Fiedler, Angelika Hilderink, Ann-Katrin Lehmann, Lea Sophie Pohle, Sergei M Korneev, Florian Fröhlich, Kenji Maeda, Rainer Kurre, Michael Holtmannspötter, Bianca M Esch, Joost C M Holthuis.
      Perturbations in lysosome integrity are tightly linked to neurological disorders and ageing, but the underlying pathogenic mechanisms are incompletely understood. Using an unbiased proteomic approach, we here identified the bridge-like lipid transport protein VPS13C/PARK23 as a key component of a global early response pathway to lysosome damage. VPS13C readily binds lysosomes under mechanical or osmotic tension in anticipation of membrane lesions. The latter trigger a conformational change in the protein's C-terminus, involving its ATG2C domain acting as sensor of damage-induced lipid packing defects. We show that ER-lysosome contacts formed by VPS13C provide critical binding platforms for OSBP/ORPs to enable efficient ER wrapping of damaged lysosomes. A chemical approach to assess directional ER-to-lysosome lipid transport revealed that VPS13C is essential for large-scale lipid delivery to acutely damaged lysosomes to facilitate their repair. Our findings offer new mechanistic insights into how loss-of-function mutations in VPS13C may enhance the risk of Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-026-75145-y
  24. ACS Omega. 2026 Jun 30. 11(25): 37332-37345
    Cannabidiol Activates Integrated Stress Response Signaling and Immune Trafficking Programs in an A375 Melanoma-Jurkat T Cell Coculture Model: A Multi-Omics Analysis.
    Ni Deng, Huifang Li, Ang Cai, Christopher L Hemme, Jonghae Youn, Ryan Janis, Matthew D Stone, Hang Ma, Chang Liu.
      Cannabidiol (CBD) is a nonpsychoactive cannabinoid with emerging anticancer and immunomodulatory properties; however, its systems-level mechanisms in tumor-associated immune cells remain incompletely defined. Here, we investigated CBD in a melanoma-T cell coculture model using integrated transcriptomic and proteomic analyses. At a subcytotoxic concentration (10 μM), CBD selectively induced apoptosis in melanoma while preserving T-cell viability and enhancing IL-2 secretion. RNA sequencing revealed coordinated activation of stress-adaptive, immune activation, and trafficking programs, including modulation of T-cell receptor signaling and cytokine networks. Data-independent acquisition proteomics identified activation of eukaryotic initiation factor 2 (EIF2) signaling, a central node of the integrated stress response (ISR) linking redox and endoplasmic reticulum stress to translational control. Multiomics integration converged on immune cell trafficking as a consistent outcome, with upregulation of ICAM1, ITGB1, and associated adhesion-related proteins. These findings suggest ISR-dependent translational reprogramming as a putative mechanistic axis by which CBD reshapes T-cell function in the melanoma microenvironment. Our study provides pharmacological insight into how CBD modulates tumor-immune interactions and suggests potential utility as an adjunct immunomodulatory agent in melanoma.
    DOI:  https://doi.org/10.1021/acsomega.6c01965
  25. J Cell Sci. 2026 Jul 01. pii: jcs264806. [Epub ahead of print]139(13):
    Disentangling the response to lysosomal damage.
    Hemmo Meyer, Akiko Kuma, Shuhei Nakamura.
      The limiting membrane of lysosomes is prone to damage that can have deleterious consequences for cellular homeostasis. Cells respond to this damage with an array of molecular countermeasures, ranging from membrane repair mechanisms to elimination of terminally damaged lysosomes by selective macroautophagy. The various elements of this response therefore need to be carefully assessed in the context of the specific pathological or experimental conditions being studied. Emerging evidence has revealed further complexity within the lysosomal damage response, such as processes that contribute to initial membrane resealing as well as lysosome regeneration required to restore the lysosomal system. These mechanisms involve unusual ubiquitylation, non-canonical ATG8 lipidation, or modifications that govern lysosome tubulation or microlysophagy pathways. Therefore, caution is advised when using previously established lysosome damage reporters that might confound interpretation of the underlying events and outcomes. This Opinion article seeks to shed light on the emerging regulatory mechanisms of lysosomal regeneration and evaluate the appropriateness of various reporters and assays for studying the lysosomal damage response.
    Keywords:  ATG8; ESCRT; Lysosomes; Membrane permeabilization; Microautophagy; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.264806
  26. EMBO Mol Med. 2026 Jun 29.
    Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma.
    Julien P Gigan, Paulina Garcia-Gonzalez, Angelo Pilotti, Lou Galliot, Alexandre Reynaud, Yoan Ghaffar, Felipe Flores-Santibáñez, Sara Ghafoori, Eve Seillier, Rosario Lavignolle-Heguy, Daniela Barros, Caroline Bret, Sharon Fichaux, Alexis Combes, Alessandro Bani, Rejane Rua, Evelina Gatti, Béatrice Nal-Rogier, Stéphane Rocchi, Jérôme Moreaux, Philippe Pierre, Rafael J Argüello.
      The unfolded protein response (UPR) is a stress-adaptation pathway and therapeutic target in cancer, yet its pro-survival versus pro-death outcome is difficult to predict because the three ER sensors, PERK, IRE1α, and ATF6, are highly interconnected. Transcriptomic analyses identified sensor-specific gene signatures associated with patient survival across malignancies, and indicated that low IRE1α activity (low XBP1 signature or higher expression of RIDD targets) correlates with improved outcome. We developed SNUPR (single nuclei analysis of the unfolded protein response), an accessible flow cytometry approach that profiles all three branches in nuclear suspensions. SNUPR reveals marked heterogeneity of UPR activation across cancer cell lines that cannot be inferred from sensor expression. This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.
    DOI:  https://doi.org/10.1038/s44321-026-00469-7
  27. Adv Sci (Weinh). 2026 Jun 29. e76290
    Functional Suppression of SCAP Triggers Endoplasmic Reticulum Stress-Dependent Ferroptosis by Impairing Cholesterol Metabolism in Gastric Cancer.
    Qianqian Xu, Guangzhao Pan, Lele Zhang, Xiangliu Chen, Kui Zhang, Yang Lu, Zibo Duan, Aiping Chen, Hailong Shen, Yuxi Zhang, Xiaowu Dong, Jinzhou Huang, Xing Huang, Kai Miao, Qian Hua, Fangfang Tao, Weidong Zhang, Jiang-Jiang Qin.
      Cholesterol metabolic reprogramming is an emerging vulnerability in cancer, yet clinical progress has been limited by a lack of druggable targets. Here, we identify the sterol-sensing domain (SSD) of SCAP as a target in gastric cancer (GC), with multi-omics confirming tumor-specific SCAP overexpression, poor prognosis, and hyperactivated synthesis. Using SSD structure-based high-throughput screening, we discovered that the natural compound Platycodin D (PD) is a small-molecule inhibitor of SCAP. PD sustains SREBP2 activation yet paradoxically blocks cholesterol efflux. The underlying mechanism is that PD specifically disrupts SCAP's sterol-sensing function, thereby permitting unrestrained SREBP2-mediated biosynthesis. This critical dysfunction leads to pathological cholesterol overload in the endoplasmic reticulum (ER), inducing proteotoxic stress. Consequently, this stress disrupts Nrf1 ER retention and forces nuclear translocation, thereby compromising LXR-mediated efflux. We further demonstrate that this SCAP targeting initiates GPX4 cascade-mediated ferroptosis, which was reversible by inhibiting cholesterol synthesis or the stress response. PD demonstrated potent tumor suppression with a significantly improved safety profile compared to cisplatin in vivo. Our work establishes a causal link between SSD disruption and ferroptotic death via cholesterol dysregulation, introducing a novel paradigm for exploiting metabolic vulnerabilities in GC therapy.
    Keywords:  SCAP; cholesterol metabolism; endoplasmic reticulum stress; ferroptosis; gastric cancer; sterol‐sensing domain
    DOI:  https://doi.org/10.1002/advs.76290
  28. Cell. 2026 Jul 01. pii: S0092-8674(26)00701-4. [Epub ahead of print]
    Co-option of lysosomal machinery shapes the evolution of the intracellular photosymbiosis supporting coral reefs.
    Shumpei Maruyama, Catherine F Henderson, Natalie Swinhoe, Griffin P Kowalewski, Emily K Meier, Ty R Engelke, Phillip A Cleves.
      Endosymbiosis has spurred the evolution of new organelles across life. Corals and other cnidarians have repeatedly evolved an organelle, called the symbiosome, which houses intracellular algal symbionts. However, the molecular mechanisms enabling this repeated evolution remain unclear. Using the sea anemone Aiptasia, we generated a high-quality proteome of the symbiosome, revealing protein trafficking mechanisms and the types of biomolecules exchanged during symbiosis. Symbiosomal enrichment of lysosomal proteins, visualization of lysosomal fusion, and reduced symbiosis following knockdown of lysosomal genes indicate that the symbiosome functions through extensive co-option of lysosomal proteins. We identified a symbiosomal bicarbonate/sulfate transporter, SLC26A11, and showed through CRISPR/Cas9 mutagenesis that this lysosomal transporter is required for symbiosis in Aiptasia and a reef-building coral. Together, these findings reveal that corals and anemones have repeatedly co-opted lysosomal proteins to concentrate carbon and shuttle metabolites to support photosymbiosis, providing a relatively simple path for the repeated evolution of new photosymbioses.
    Keywords:  coral; endosymbiosis; evolution; lysosome; phagosome; photosymbiosis; symbiosis; symbiosome
    DOI:  https://doi.org/10.1016/j.cell.2026.06.015
  29. Autophagy. 2026 Jun 28. 1-17
    RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis.
    Yujia Liu, Guofang Xia, Huaiying Shi, Simeng Zhu, Hailong Li, Yifan Shi, Wanling Ouyang, Congfeng Xu, Ailian Du.
      Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Although CHRN internalization is well established in MG pathogenesis, the downstream cellular events, especially those related to autophagy, remain poorly described. Here, we report that RAPSN/rapsyn, an intracellular CHRN-binding protein essential for its clustering, accumulates as aggregates in experimental autoimmune myasthenia gravis (EAMG) mice. In CHRN antibody-treated myotubes, RAPSN dissociates from internalized CHRN and forms aggregates due to exposure of its hydrophobic domains. These aggregates in turn impair the trafficking and membrane incorporation of newly synthesized CHRN, thereby exacerbating CHRN loss. Notably, the accumulation of RAPSN aggregates facilitates formation of HSPA/HSP70-BAG3 complex, which recognizes and transports the aggregates along microtubules to form perinuclear aggresomes for subsequent lysosomal degradation. Accordingly, pharmacological inhibition or knockdown of HSPA-BAG3 complex increases RAPSN aggregation, which participates in enhanced CHRN loss and worsened muscle weakness in EAMG mice. This study identifies HSPA-BAG3 aggrephagy as a protective mechanism that clears RAPSN aggregates to maintain CHRN integrity and suggests a potential therapeutic strategy for MG.Abbreviation: 3-MA: 3-methyladenine; AAV: adeno-associated virus; CASA: chaperone-assisted selective autophagy; CHRN/nicotinic acetylcholine receptor: cholinergic receptor nicotinic; CHRN-ab: CHRN antibodies; CHX: cycloheximide; CMAP: compound muscle action potential; CQ: chloroquine; EAMG: experimental autoimmune myasthenia gravis; ER: endoplasmic reticulum; GAS: gastrocnemius; MAP1LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MG: myasthenia gravis; NMJ: neuromuscular junction; Rapa: rapamycin; RAPSN/rapsyn: receptor associated protein of the synapse; SQSTM1: sequestosome 1; TA: tibialis anterior; αBTX-A594: α-bungarotoxin-Alexa-594.
    Keywords:  Aggregate; CHRN; HSPA; RAPSN; autophagy; myasthenia gravis
    DOI:  https://doi.org/10.1080/15548627.2026.2693778
  30. Nat Commun. 2026 Jul 01.
    Two-pore channel-2 controls calmodulin-dependent STIM1 inactivation.
    Subo Lee, Raphael Néré, Kyoung Sun Park, Vincent Jaquet, Nicolas Demaurex, Kyu-Sang Park.
      Lysosomal two-pore channels (TPC) trigger Ca2+ release from the endoplasmic reticulum (ER). The ensuing ER Ca2+ depletion activates STIM1-gated store-operated Ca2+ entry (SOCE) channels that sustain Ca2+ signals regulating fundamental cellular processes. How TPC channels and STIM1 integrate distinct intra and extracellular cues is unclear. Here, we show that TPC2 activation inhibits SOCE by enforcing rapid and persistent Ca2+-CaM-dependent inactivation of the STIM-Orai activating region (SOAR). The TPC2 activators NAADP and TPC2-A1-N abrogated SOCE in multiple cell lines and enhanced the slow Ca2+ dependent inactivation (SCDI) of STIM1-gated Orai1 channels. TPC2 engagement triggered lysosomal Ca2+ release and mobilized ER Ca2+ stores but prevented RFP-STIM1 recruitment to the TIRF plane by thapsigargin and disassembled RFP-STIM1 clusters forming after store depletion, preventing and acutely reversing SOCE. These effects persisted in STIM1 mutants truncated after the SOAR and were prevented by TPC2 genetic or pharmacological invalidation, Calmodulin (CaM) inhibition, and cytosolic Ca2+ chelation. We conclude that Ca2+ ions released by TPC2 channels on lysosomes regulate CaM-dependent STIM1 inactivation.
    DOI:  https://doi.org/10.1038/s41467-026-75158-7
  31. Nat Rev Mol Cell Biol. 2026 Jun 30.
    COPII meets autophagy at the ER membrane.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-026-00997-7
  32. ACS Chem Biol. 2026 Jun 29.
    A Systematic Direct-to-Biology Approach Identified Potent Cereblon HaloPROTACs.
    Rebecca Stevens, Kwok-Ho Chan, Alice Moore, Sam Hardie, Glenn A Burley, Jennifer J Knickelbine, Kristin M Riching, Agnieszka Konopacka, Markus A Queisser, Afjal H Miah.
      HaloTags have emerged as versatile tools for protein labeling, investigating target biology, and facilitating targeting protein degradation using synthetic ligands called HaloPROTACs. These chemical tools are heterobifunctional molecules consisting of a chloroalkane derivative linked to E3 ubiquitin ligase-recruiting moieties to artificially induce proximity between the ligase and target protein of interest fused to the HaloTag construct. Through this induced proximity, HaloPROTACs can facilitate temporal- and dose-dependent degradation of target proteins, enabling efficient cellular protein knockdown without the need for target-specific ligands. In this study, we developed cereblon (CRBN)-recruiting HaloPROTACs through the use of plate-based high-throughput synthesis and direct-to-biology screening. We evaluated over 100 structurally diverse CRBN HaloPROTACs in an FAK-tagged cell line, resulting in the identification of highly potent tools. Notably, HaloPROTACs incorporating dihydrouracil CRBN binders exhibited superior potency and selectivity compared with their IMiD-based counterparts. These newly developed CRBN-based HaloPROTACs represent a valuable addition to the existing HaloPROTAC toolkit, offering enhanced capabilities for advancing research on targeted protein degradation.
    DOI:  https://doi.org/10.1021/acschembio.6c00377
  33. FASEB J. 2026 Jul 15. 40(13): e72042
    Blockade of FGFR1 Trafficking to the Cell Surface Results in the Partial Mistargeting of the Receptor to Peroxisomes.
    Paulina Działek, Aleksandra Chorążewska, Martyna Biaduń, Jian Qiu, Natalia Porębska, Łukasz Opaliński.
      Fibroblast growth factor receptor 1 (FGFR1) is a cell surface receptor tyrosine kinase implicated in cellular signaling and homeostasis. Several reports indicate that N-glycosylation of FGFR1 is critical for the FGFR1 trafficking to the cell surface, as glycosylation-deficient mutant of FGFR1 (FGFR1.GF) is trapped inside the cell, in the endoplasmic reticulum (ER), and in the nuclear envelope. Our recent mass spectrometry analyses revealed dehydrogenase/reductase 2 (DHRS2) as a putative binding partner of the intracellular FGFR1.GF. Here, we identified a peroxisomal targeting signal 1 (PTS1) at the C-terminus of DHRS2 and demonstrated that DHRS2 is dually targeted to peroxisomes and mitochondria. Furthermore, we determined that knockdown of DHRS2 results in increased number of peroxisomes, implicating the role of DHRS2 in peroxisome biogenesis. Using proximity ligation assay (PLA), we confirmed the interaction between FGFR1.GF and DHRS2 and demonstrated that FGFR1.GF/DHRS2 complexes are predominantly detected in peroxisomes. In agreement, we detected a small fraction of FGFR1.GF in peroxisomes. Taken together our data indicate that accumulation of FGFR1.GF in the ER may result in FGFR1.GF targeting to peroxisomes. Furthermore, we reveal interconnection between FGFR1 and DHRS2 and their role in peroxisome biogenesis.
    Keywords:  DHRS2; ER; FGFR1; glycosylation; peroxisomes; protein transport
    DOI:  https://doi.org/10.1096/fj.202600529RR
  34. Autophagy. 2026 Jun 29.
    Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
    Gayatri Mohanan, Kumkum Nag, Harsh Singh Senger, Parvathy J, Purusharth I Rajyaguru.
      The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes ATG1, ATG2, and ATG9. Consistent with these translational changes, sbp1∆ cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.Abbreviations: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.
    Keywords:  Autophagy; DNA repair; Sbp1; hydroxyurea; mrnps; translation regulation; yeast
    DOI:  https://doi.org/10.1080/15548627.2026.2694657
  35. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 102979
    Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
    Tristan N Samuels, Jenica H Kakadia, Cian Ward, Fatema Abdullatif, Marisa I Mendes, Desiree E Smith, Rachel Heilmann, Fanqi Wu, Jakub M Swiercz, Gajja S Salamons, Kyle Hoffman, Teklab Gebregiworgis, Patrick O'Donoghue, Ilka U Heinemann.
      Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.
    Keywords:  ARS disease; MT: non-coding RNAs; NARS1; amino acid supplementation; aminoacyl-tRNA synthetase; integrated stress response; premature termination codon; tRNA
    DOI:  https://doi.org/10.1016/j.omtn.2026.102979
  36. bioRxiv. 2026 Jun 19. pii: 2026.06.19.733470. [Epub ahead of print]
    Remodeling of mRNA by eIF4F in human translation initiation.
    Carlos Alvarado, Christopher P Lapointe, Jinfan Wang, Masaaki Sokabe, Rosslyn Grosely, Ajinkya A Dhepe, Crystal I Stackhouse, Michael Z Palo, Adam Mamot, Jacek Jemielity, Christopher S Fraser, Joseph D Puglisi.
      For the ribosome to load onto an mRNA during the early steps of translation initiation, the mRNA must be activated by the eIF4F complex. The mechanism of this activation step has remained elusive. Here we employ multi-perspective real-time single-molecule assays to observe directly mRNA-eIF4F binding near the 5' end, mRNA conformational remodeling, and 40S ribosomal subunit loading. eIFs 4E, 4G, and 4B play distinct roles in promoting eIF4F association and stabilizing eIF4A binding. Binding of eIF4F is the rate-limiting step in mRNA activation: once bound, mRNA conformation is rapidly extended in an ATP-dependent manner. The mRNA extended state is the necessary substrate for 43S PIC loading and perturbations to extension delay loading. Features of the mRNA, such as the 7-methylguanosine cap at the 5' end and secondary structures, modulate these steps and regulate ribosome loading. Our results establish a kinetic and mechanistic framework for the early steps in translation initiation.
    DOI:  https://doi.org/10.64898/2026.06.19.733470
  37. J Cell Sci. 2026 Jun 15. pii: jcs264845. [Epub ahead of print]139(12):
    The nucleus-vacuole junction at a glance.
    Pascal Höhne, Marie Hugenroth, Maria Bohnert.
      The nucleus-vacuole junction (NVJ) is a central membrane contact site in yeast that connects the nuclear endoplasmic reticulum and the vacuole. This organelle interface is heavily involved in the handling of lipids: it houses numerous lipid metabolism enzymes and lipid transfer proteins, and acts as a hotspot for lipid droplet biogenesis. The NVJ shows plastic responses to metabolic cues, adapting both its architecture and its proteome. Many NVJ-resident proteins display alternative, metabolically controlled localizations at other contact sites. This close-knit communication with diverse cellular structures makes the NVJ an important model for understanding general principles of contact site regulation. In this Cell Science at a Glance article and the accompanying poster, we highlight the multifunctionality and metabolic plasticity of the NVJ, as well as its integration into the cellular contact site network.
    Keywords:  Contact site; Lipid droplet; Lipid transfer protein; NVJ; Nvj1; Vac8
    DOI:  https://doi.org/10.1242/jcs.264845
  38. bioRxiv. 2026 Jun 24. pii: 2026.06.19.733273. [Epub ahead of print]
    ESCRT-0 regulates AMPA receptor currents and Ca 2+ - dependent signaling.
    Mahsa Pourhamzeh, Lara Dozier, Amanda Wilpitz, Yixing Du, Daniel B McClatchy, Mariel K B Micael, Joshua E Mayfield, Stephen K Gilmore-Hall, Josephina E Ronson, Katrin Soldau, Donald P Pizzo, Brent Aulston, Erin E Sullivan, Timothy F Shay, Jin Wang, Subhojit Roy, Viviana Gradinaru, Justin H Trotter, Kim Dore, John R Yates, Gentry N Patrick, Christina J Sigurdson.
      Membrane protein trafficking is essential for synaptic growth, maintenance, function, and plasticity, and involves the regulated exocytosis and endocytosis of proteins to and from the pre-and post-synaptic membranes. Defects in the clearance of membrane proteins can lead to the accumulation of ubiquitinated membrane proteins and contribute to neurodegenerative disease. The ESCRT (endosomal sorting complexes required for transport) machinery binds and sorts ubiquitinated membrane proteins into lysosomes for degradation, yet the presence and function of ESCRTs in sorting ubiquitinated AMPA and other receptors at the post-synapse remain unclear. Here we show that the ubiquitin-binding ESCRT-0 protein, Hrs, localizes to both pre- and post-synapses, and levels are modulated by neuronal activity, increasing and decreasing with higher and lower neuronal activity, respectively. Phosphoproteomic profiling of Hrs-depleted post-synaptic membranes revealed a role for Hrs in glutamatergic synaptic transmission, including long-term potentiation. In addition, Hrs-depleted neurons showed faster AMPAR current kinetics and reduced amplitude in whole-cell patch-clamp recordings. Genetic deletion of neuronal Hgs in mice led to reductions in phosphorylated CaMKII-α and -β (T286/T287) and structural proteins, PSD-95 and gephyrin, suggestive of LTD (long-term depression)-like synaptic depression. In contrast, Hrs overexpression led to increases in Ca 2+ -dependent signaling, including protein kinase C (PKC) and PKC substrate, AMPAR subunit GluA1-S831, a site which increases conductance. Together, these findings identify a dynamic, bidirectional role for Hrs at the post-synapse as it both senses and is modulated by neuronal activity, ultimately impacting excitatory synaptic strength.
    Significance Statement: Synaptic plasticity relies on dynamic trafficking and turnover of membrane proteins, including AMPA-type glutamate receptors (AMPARs), yet how receptor trafficking intersects with ubiquitin-mediated sorting pathways at synapses remains unclear. We show that the ubiquitin-binding ESCRT-0 protein, Hrs, localizes to both pre- and post-synapses, and its abundance is bidirectionally regulated by neuronal activity. Genetic depletion of Hrs in mice reduces CaMKII phosphorylation and impacts AMPAR channel surface localization. In contrast, neuronal-specific Hrs overexpression led to enhanced GluA1 and protein kinase C substrate phosphorylation, suggesting altered AMPAR trafficking, subunit composition, and/or function. Thus, Hrs emerges as a modulator of glutamatergic signaling, coupling ubiquitin-mediated receptor sorting to the fine-tuning of synaptic transmission, with direct implications for learning and memory in health and disease.
    DOI:  https://doi.org/10.64898/2026.06.19.733273
  39. Mol Cell. 2026 Jul 02. pii: S1097-2765(26)00388-6. [Epub ahead of print]
    Spliceosomal proofreading factors safeguard 3' splice-site fidelity and prevent proteotoxicity and inflammation.
    Fangshu Li, Mengyang Wang, Shaorui Zhang, Zimeng Yu, Menghui Zhao, Xiajing Zhu, Siyu Zhou, Mingkui San, Shengyun Ma, Fang Zhao, Yong-Zhen Xu, Rui Xiao.
      Precise intron removal by RNA splicing is essential for faithful gene expression, yet the mechanisms ensuring splicing fidelity in mammals remain unclear. Using a systematic knockdown RNA sequencing (RNA-seq) screen, we uncover widespread splicing errors and identify AQR, SYF1, and SYF3 as cooperative safeguards of 3' splice-site (3'ss) fidelity in human and mouse. These factors act during spliceosome assembly to correct U2AF-mediated misrecognition of non-canonical 3'ss bearing AG dinucleotides embedded within pyrimidine-rich sequences and lacking canonical branch points (BPs), likely through kinetic proofreading. Their loss triggers pervasive 3'ss mis-splicing, resulting in the accumulation of misfolded proteins, proteotoxic stress, unfolded protein response activation, and ultimately cell death and intestinal inflammation. Together, our study reveals a previously unrecognized layer of splicing fidelity control in mammals that links aberrant splice-site selection to proteostasis and inflammation.
    Keywords:  3′ splice site; AQR; SYF1; SYF3; U2AF; inflammation; kinetic proofreading; proteotoxic stress; splicing fidelity
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.017
  40. bioRxiv. 2026 Jun 23. pii: 2026.06.21.733607. [Epub ahead of print]
    Dynamic redistribution of eIF4F controls cap-dependent translation initiation.
    Riley C Gentry, Nicholas A Ide, Victoria M Comunale, Colin Echeverría Aitken, Colin D Kinz-Thompson, Ruben L Gonzalez.
      Translation initiation requires messenger RNAs (mRNAs) to be recognized and loaded into ribosomes through a process catalyzed by the heterotrimeric eukaryotic initiation factor eIF4F. During this process, eIF4F engages the 7-methylguanosine cap at the 5' end of the mRNA and promotes productive engagement with the ribosomal pre-initiation complex (PIC) to facilitate PIC loading onto the mRNA. Although eIF4F is central to translation initiation and its regulation, the molecular mechanism by which eIF4F stimulates PIC loading, and the mechanistic role of the essential ATP hydrolysis step catalyzed by eIF4F, have remained unresolved. Here, we use single-molecule fluorescence microscopy to directly visualize the dynamics of eIF4F during cap recognition and PIC engagement. We show that ATP binding, but not ATP hydrolysis, promotes productive assembly of eIF4F on mRNA and enables dynamic redistribution of eIF4F along the transcript. In contrast, ATP hydrolysis is specifically required for recycling of cap-stalled eIF4F during productive PIC engagement. Furthermore, we identify eIF3 and eIF4B as the minimal PIC-associated factors required to stimulate ATP-hydrolysis-dependent recycling of eIF4F during PIC loading. Together, our results support a model in which productive PIC engagement stimulates ATP-hydrolysis-dependent recycling of eIF4F, thereby coupling eIF4F recycling to PIC loading during translation initiation. This mechanism provides a framework for understanding how mRNA topology, RNA-binding proteins, and the availability of initiation factors can control translational efficiency.
    DOI:  https://doi.org/10.64898/2026.06.21.733607
  41. Autophagy. 2026 Jul 01.
    AARS2-mediated lactylation of ULK1 promotes autophagy-dependent progression of clear cell renal cell carcinoma.
    Xiangbo Zeng, Yuanchao Zhu, Yongyuan Xiao, Zhiyong Zhang, Xiaoliang Chen, Daqiang Wei, Can Huang, Kaizheng Liu, Xianghua Shi, Fei Luo, Qiong Wang, Zhe Lin, Wenfeng Xu, Wanlong Tan, Zaosong Zheng.
      Macroautophagy/autophagy is an evolutionarily conserved degradation pathway wherein cytoplasmic components are sequestered within double-membrane autophagosomes for lysosomal delivery. The initiation of autophagy is governed by autophagy-related (ATG) proteins, with the ULK1 kinase complex serving as the most upstream regulator. However, how ULK1 senses and integrates metabolic signals via post-translational modifications remains poorly understood. Here, we discover that ULK1 undergoes lactylation at lysine 46, catalyzed by the mitochondrial aminoacyl-tRNA synthetase AARS2, in response to autophagic stimuli. This modification promotes ULK1 kinase activity, leading to enhanced and selective phosphorylation of its downstream substrate ATG14 at Ser29, thereby activating the class III PtdIns3K complex and facilitating autophagosome biogenesis. Furthermore, we demonstrate that AARS2-mediated ULK1 lactylation drives autophagic flux and promotes tumor metastasis in clear cell renal cell carcinoma (ccRCC), and that a cell-penetrating peptide targeting K46 lactylation suppresses ccRCC progression in vitro and in vivo. Our study identifies lactylation as a novel regulatory mechanism controlling autophagy initiation and suggests that targeting AARS2-mediated ULK1 lactylation could be a potential strategy for treating ccRCC.
    Keywords:  AARS2; ULK1; autophagy; clear cell renal cell carcinoma; lactylation; post-translational modification
    DOI:  https://doi.org/10.1080/15548627.2026.2694660
  42. ACS Macro Lett. 2026 Jul 03.
    Multitargeted Degradation of Cell Surface Receptors by Modular Glyco-Nanosheets.
    Yiwei Shi, Xin Liang, Xiangyun Xu, Long Li, Guosong Chen.
      Targeted protein degradation mediated by antibodies represents a powerful approach for eliminating cell surface proteins. However, most existing systems require the customized conjugation of antibodies to functional groups that mediate cellular endocytosis, thereby lacking structural universality and expandability. Herein, we developed a modular glyco-nanosheet platform for GLUT1-facilitated lysosomal degradation of cell-surface immune checkpoints, integrating a glucosyl polymer module for tumor-specific endocytosis and a protein A (ProA) module for universal antibody loading. By programming the spatial distribution of functional modules, we constructed three nanostructures with tunable antibody density and distribution. These nanosheets enabled efficient GLUT1-facilitated internalization and lysosomal trafficking, resulting in an effective single-target degradation of PD-L1 and simultaneous dual-target degradation of PD-L1/CD47. Under IFN-γ cotreatment, the dual-target nanosheets reduced the relative viability of cancer cells to ∼30%, significantly outperforming single-target systems. This modular, target-expandable glyco-nanosheet provides a universal strategy for multitargeted TPD and shows great potential for precision immunotherapy.
    DOI:  https://doi.org/10.1021/acsmacrolett.6c00229
  43. J Med Chem. 2026 Jun 29.
    Dual Targeting of Nucleotidase-Dependent and -Independent Functions via PROTAC-Mediated CD73 Degradation.
    Ping Xie, Jie Fan, Longzhen Song, Jing Cao, Arabela A Grigorescu, Yong Wan, Timothy M Kuzel, Gary E Schiltz, Bin Zhang.
      CD73 (ecto-5'-nucleotidase) drives immunosuppressive and tumor progression through both enzymatic adenosine production and nonenzymatic mechanisms, limiting the efficacy of current CD73-targeted therapies, including small-molecule enzymatic inhibitors and antibodies. Here, we reported NUCC-0227579 (C79), a first-in-class proteolysis-targeting chimera (PROTAC) that degraded CD73 via the VHL E3 ligase-dependent proteasomal and lysosomal pathways. C79 eliminated CD73 at the cell surface and intracellular compartments across multiple human cancer cell lines, abolishing nucleotidase activity and more effectively reversing adenosine-mediated immunosuppression than enzymatic inhibitors. C79 enhanced NF-κB/NFAT signaling, increased IFN-γ and TNF-α production, and promoted human CD8+ T cell activation and proliferation. In addition, C79 impaired tumor cell metabolic fitness, proliferation, migration, and adhesion through non-nucleotidase-dependent mechanisms. In humanized NSG mouse models of triple-negative breast cancer, C79 significantly suppressed tumor growth while enhancing antitumor immune responses, highlighting CD73 degradation as a mechanistically distinct strategy to overcome the limitations of existing CD73-targeted therapies.
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c00746
  44. Chem Biol Interact. 2026 Jul 01. pii: S0009-2797(26)00338-8. [Epub ahead of print] 112230
    Arsenic Promotes Nonalcoholic Steatohepatitis via MCFD2-Induced PERK/eIF2α-Mediated Integrated Stress Response.
    Yingyue Yuan, Tianming Qiu, Huilin Luo, Wenjuan Tan, Jingyuan Zhang, Ningning Wang, Jie Bai, Xiaofeng Yao, Xiance Sun.
      Arsenic exposure, a typical environmental stressor, is closely associated with nonalcoholic steatohepatitis (NASH), but the definite mechanism remains elusive. The integrated stress response (ISR) acts as a core signaling cascade that mediates cellular stress responses and is implicated in the development of multiple metabolic disorders. Nevertheless, the critical regulatory role of ISR in the progression of arsenic-associated NASH has not been definitively clarified. In the present study, we verified the activation of ISR in arsenic-induced NASH by detecting the expression of ISR-related markers through in vivo and in vitro. Notably, the majority of the downstream impacts of the ISR were modified after arsenic exposure. However, of the four upstream ISR signaling initiators, only Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) was influenced, as evidenced by a marked elevation in PERK phosphorylation levels following arsenic treatment. Furthermore, we demonstrated that NaAsO2 downregulated the protein levels of multiple coagulation factor deficiency protein 2 (MCFD2), which is localized on the endoplasmic reticulum and Golgi apparatus, in vivo and in vitro. Notably, overexpression of MCFD2 markedly attenuated PERK-eIF2α-mediated ISR, inflammation and lipid accumulation caused by arsenic in vitro. In conclusion, our findings reveal that arsenic exposure triggers the activation of PERK-eIF2α-mediated ISR and NASH by suppressing MCFD2. These findings may provide insights into the underlying mechanisms of NASH.
    Keywords:  Integrated stress response; MCFD2; NASH; NaAsO(2)
    DOI:  https://doi.org/10.1016/j.cbi.2026.112230
  45. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2514112123
    A genome-wide screen identifies that PLCG2 restrains lysosomal GCase activity.
    Jessica Lawrence, Vineet Vinay Kulkarni, Chan Lek Tan, Marinella Callow, Yves Juste, Dewakar Sangaraju, Mike Costa, Baris Bingol.
      Mutations in the GBA1 gene, which encodes the lysosomal glucocerebrosidase enzyme GCase, cause the lysosomal storage disorder Gaucher disease and represent the most common genetic risk factor for Parkinson's disease (PD). These mutations deplete lysosomal GCase activity and cause accumulation of GCase substrate, glucosylceramide, and its pathological metabolite, glucosylsphingosine. Impaired GCase activity then drives immune and neuronal dysfunction in Gaucher disease and promotes pathogenic aggregation of α-Synuclein in PD. As such, boosting the lysosomal activity of GCase is a therapeutic strategy to ameliorate substrate accumulation and prevent associated neurotoxicity. To identify the regulators of GCase activity in lysosomes, we conducted a genome-wide screen in primary mouse macrophages using a fluorescent enzyme activity reporter. By validating the screen hits in cellular biochemical and profiling assays, we identified pathways that promote or inhibit lysosomal GCase activity. Our screen identified PLCG2 as a regulator of lysosomal GCase activity. Mechanistically, PLCG2 depletion accumulates Golgi-associated phosphatidylinositols, promoting the transport of mutant GCase into lysosomes while reducing its Golgi-associated pool. Functionally, PLCG2 depletion boosts the activity of lysosomal mutant GCase, the cellular flux of glucosylceramide, and the clearance of pathogenic GCase substrates. In summary, our screen has uncovered the regulators of GCase abundance and trafficking at a whole-genome scale and identified potential pathways for future therapeutic interventions in Gaucher and Parkinson's to boost the activity of this enzyme in lysosomes.
    Keywords:  Gaucher disease; Parkinson’s disease; functional genomics; lipid homeostasis; lysosomes
    DOI:  https://doi.org/10.1073/pnas.2514112123
  46. Science. 2026 Jul 02. 393(6806): eadr3817
    Membrane protein solubilization and structure determination using de novo-designed proteins.
    Ljubica Mihaljević, David E Kim, Pooja D Bandawane, Helen E Eisenach, Andrew J Borst, Alexis Courbet, Connor Weidle, Kenneth D Carr, Everton Bettin, Qiushi Liu, Aldo T Trejos, Sagardip Majumder, Surabhi Kokane, Alexander Stevens, Edin Muratspahić, Thomas Schlichthaerle, Marc Expòsit, Xinting Li, Mila Lamb, Analisa Nicole Azcárraga Murray, Rashmi Ravichandran, Elizabeth C Williams, Shuyuan Hu, Lynda Stuart, Linda Grillová, Nicholas R Thomson, Michael Landreh, Pengxiang Chang, Lorenzo Giacani, Melissa J Caimano, Kelly L Hawley, Neil P King, David Baker.
      Developing therapies and vaccines against integral membrane proteins is hindered by their extensive hydrophobic surfaces, which complicate production and structural analysis. Here, we describe a general deep learning-based design approach for solubilizing native membrane proteins while preserving their sequence, fold, active-site, and ligand-binding properties. Genetically encoded de novo protein WRAPs [water-soluble RFdiffused amphipathic proteins] surround the lipid-interacting hydrophobic surfaces, rendering them thermostable and water-soluble without the need for detergents. We design WRAPs for both monomeric and oligomeric beta-barrel outer membrane proteins and helical multipass transmembrane proteins. A 2.95-angstrom-resolution cryo-electron microscopy structure of WRAPed mycobacterial porin demonstrates that WRAPs can be used for the structural determination of membrane proteins in solution. As a step toward syphilis vaccine development, we generated soluble versions of Treponema pallidum antigens.
    DOI:  https://doi.org/10.1126/science.adr3817
  47. J Immunol. 2026 Jun 07. pii: vkag151. [Epub ahead of print]215(6):
    ER stress amplifies inflammation via a dual mechanism involving IκBζ-XBP1s synergism and Regnase-1 degradation.
    Yuri Nakaminami, Lerdluck Ruengsinpinya, Riko Sakihara, Yoshifumi Takahata, Kenji Hata, Takao Iwawaki, Riko Nishimura, Tomohiko Murakami.
      Inflammatory diseases arise from complex interactions between immune signaling and cellular stress. Although endoplasmic reticulum (ER) stress is a key modulator of immunity, the mechanisms by which it promotes inflammatory pathology remain incompletely understood. Notably, ER stress-induced NF-κB activation alone is insufficient to account for robust IL-6 production, thus suggesting the involvement of additional regulators. Using bone marrow-derived macrophages and sepsis model mice, we identified the inducible transcription factor IκBζ as a critical mediator of this response, with ER stress synergizing with TLR signaling to markedly upregulate IκBζ. Mechanistically, ER stress triggered calcium-dependent signaling that led to IκB kinase-mediated degradation of the RNase Regnase-1, likely stabilizing Nfkbiz mRNA and promoting the accumulation of IκBζ, which was found to cooperate with the ER stress factor XBP1s to drive transcription of selected secondary-response genes, particularly Il6 and Nos2. Importantly, this synergy was required for excessive IL-6 production in septic mice, highlighting a gene-specific amplification pathway. Together, these findings identify a dual mechanism in which transcriptional synergy between IκBζ and XBP1s is coupled to posttranscriptional mRNA stabilization via Regnase-1 degradation, thereby linking proteotoxic stress to hyperinflammatory responses. Our results establish ER stress-mediated IκBζ accumulation as a key driver of inflammatory pathogenesis and a potential therapeutic target in ER stress-associated inflammatory disorders.
    Keywords:  ER stress; IκBζ; Regnase-1; XBP1; inflammation
    DOI:  https://doi.org/10.1093/jimmun/vkag151
  48. Nat Commun. 2026 Jun 30. pii: 5552. [Epub ahead of print]17(1):
    Gravitational and mechanical forces shape mitochondrial translation.
    Taisei Wakigawa, Yusuke Kimura, Mari Mito, Toshiya Tsubaki, Muhoon Lee, Koki Nakamura, Abdul Haseeb Khan, Hironori Saito, Tohru Yamamori, Tomokazu Yamazaki, Akira Higashibata, Tatsuhisa Tsuboi, Yusuke Hirabayashi, Nono Takeuchi-Tomita, Taku Saito, Atsushi Higashitani, Yuichi Shichino, Shintaro Iwasaki.
      Life on Earth has evolved in a form suitable for the gravitational force. Although the pivotal role of gravity in gene expression has been suggested, the molecular details remain unclear. Here, we show that mitochondria utilize gravity to activate protein synthesis within the organelle. Genome-wide ribosome profiling reveals reduced mitochondrial translation in mammalian cells and Caenorhabditis elegans under microgravity. We found that attenuation of cell adhesion through laminin-integrin interactions caused the phenotype. Mitochondrial translation is activated by a signal relayed by FAK, RAC1, PAK1, BAD, and Bcl-2 family proteins in the cytosol, and the mitochondrial fatty acid synthesis (mtFAS) pathway in the matrix. Consumption of mitochondrial malonyl-CoA by mtFAS reduces the malonylation of the translational machinery and accelerates the rates of translational initiation and elongation. Physiologically, this system operates in mechano-response of skeletal muscles. Our work provides mechanistic insights into how cells convert gravitational and mechanical forces into translation in mitochondria.
    DOI:  https://doi.org/10.1038/s41467-026-74493-z
  49. Bioessays. 2026 Jun;48(6): e70157
    The Temporal Architecture of Human Cells: Organelle Clocks and Distributed Circadian Time.
    Jhommara Bautista, Andrés López-Cortés.
      For decades, eukaryotic circadian timing has been framed mainly through nuclear transcription-translation feedback loops (TTFLs). Here, we synthesize evidence supporting a broader organelle-centered model in which cellular time emerges from dynamic coupling between TTFL clocks, post-translational feedback loop (PTFL) oscillators, and entrained rhythmic modules across mitochondria, endoplasmic reticulum, lysosomes, peroxisomes, Golgi apparatus, plasma membrane, and cytoskeleton. Metabolic flux, redox cycling, proteostasis, ion handling, membrane excitability, trafficking, and mechanotransduction act as temporal currencies that either sustain selected transcription-independent rhythms or transmit phase information within a TTFL-coordinated network. In this layered architecture, the TTFL remains a central integrator that stabilizes inter-organelle phase relationships, aligns intracellular rhythms with environmental Zeitgebers, and links biochemical state to epigenetic and RNA-based regulation. We propose that circadian dysfunction reflects progressive intracellular desynchronization rather than isolated clock-gene failure, opening diagnostic and therapeutic opportunities aimed at restoring subcellular temporal coherence.
    Keywords:  biology; cell biology; circadian rhythm; cytoskeleton; endoplasmic reticulum; epigenetics; mechanotransduction; neuroscience; proteostasis
    DOI:  https://doi.org/10.1002/bies.70157
  50. STAR Protoc. 2026 Jul 02. pii: S2666-1667(26)00335-7. [Epub ahead of print]7(3): 104682
    Protocol for integrated ubiquitination analysis of in vitro E3 ligase-DUB regulation and in vivo ubiquitin chain linkage characterization.
    Daniela Mennerich, Carlos Vela-Rodriguez, Lari Lehtiö, Thomas Kietzmann.
      Here, we present a protocol for the recombinant production of DTX3L and USP28, along with in vitro and in vivo procedures for examining their regulatory functions. We describe steps for reconstituting DTX3L-dependent ubiquitination in vitro with purified UBA1, UbE2D1, ubiquitin, and DTX3L and assessing USP28-mediated deubiquitination. We then detail procedures for the in vivo detection of ubiquitin chain linkage-type through co-immunoprecipitation and Western blotting. This adaptable approach enables analysis of regulatory crosstalk between E3 ligases and deubiquitinases within the ubiquitin system. For complete details on the use and execution of this protocol, please refer to Mennerich et al.1.
    Keywords:  Cell Biology; Molecular Biology; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2026.104682
  51. Science. 2026 Jul 02. eaeh1834
    A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis.
    Geylani Can, Maksym Shyian, Archana Krishnamoorthy, Samreen Ahmed, Yang Lim, Alex Wu, Raphael Pavani, Manal S Zaher, André Nussenzweig, Markus Räschle, Thomas E Wilson, Thomas W Glover, Johannes C Walter, David Pellman.
      Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its noncatalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
    DOI:  https://doi.org/10.1126/science.aeh1834
  52. Nature. 2026 Jul 01.
    N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity.
    Sarah Schiffers, Blake W Nelson, Maria Prigge, Shriya Krishna, Leslie Watkins, Yining Zhu, Nishu Tyagi, Hamid Beiki, Sudipto Das, Ayush Raman, Jingyao Ma, Thorkell Andresson, Hai-Quan Mao, Bin Wu, Shalini Oberdoerffer.
      Synthetic mRNA therapeutics offer a versatile platform for treating diverse conditions, including cancer and infectious diseases. For delivery into cells, these mRNAs are encapsulated in lipid nanoparticles and commonly incorporate modified ribonucleotides to improve stability, enhance translation and mitigate immune recognition1. N1-Methylpseudouridine (m1Ψ) has become the industry standard for synthetic mRNAs owing to its effectiveness in promoting translation and reducing immunogenicity2. However, recent studies have shown that m1Ψ can compromise translational fidelity, leading to errors such as premature termination and ribosomal frameshifting3-5. Here we reveal N4-acetylcytidine (ac4C) as a functionally distinct alternative to m1Ψ. Across cultured cell lines, primary human monocyte-derived dendritic cells and mouse liver, ac4C suppressed inflammatory responses as effectively as m1Ψ while driving higher protein yields. Single-molecule imaging of translation revealed broadly similar ribosome densities per mRNA for ac4C-modified and m1Ψ-modified transcripts. However, translation elongation with m1Ψ-modified mRNA was nearly twofold slower than with ac4C, which resulted in reduced protein output and increased ribosome collisions that further limited protein production through the engagement of quality-control pathways and +1 frameshifting. These findings underscore the importance of context in designing therapeutic mRNAs and position the translation elongation rate as a key determinant of the efficacy of modified ribonucleotides.
    DOI:  https://doi.org/10.1038/s41586-026-10729-8
  53. NAR Genom Bioinform. 2026 Sep;8(3): lqag069
    The role of ATF4 in neurons under mitochondrial stress.
    Maria Bilen, Yubing Liu, Imane Chakroun, Mohamed Ariff Iqbal, Bensun C Fong, Jingwei Chen, Smitha Paul, Alexandre Blais, Ruth S Slack.
      Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.
    DOI:  https://doi.org/10.1093/nargab/lqag069
  54. iScience. 2026 Jul 17. 29(7): 116464
    A NACHT domain-containing protein Ncp is required for appendage-associated unconventional protein secretion in the fungus Penicillium herquei.
    Luwen Yan, Wei Deng, Penglei Qiu, Tongyao Liu, Kaiwen Deng, Liao Zhang, Xiaojing Liu, Jie Fan, Penglin Wei, Dongsheng Wei, Xingzhong Liu.
      Unconventional protein secretion (UcPS) enables leaderless proteins to bypass the ER-Golgi pathway, yet its regulation in fungi is not fully characterized. Here, we identify an appendage-associated secretion route in the symbiotic fungus Penicillium herquei Ph506 that mediates the extracellular accumulation of leaderless proteins. Functional analyses reveal that Ncp, a highly upregulated NACHT domain-containing protein, is dispensable for appendage formation but required for the efficient secretion of leaderless proteins into these specialized structures under tested conditions. Notably, Ncp depletion suppresses programmed cell death (PCD) features and reduces ionic stress tolerance, suggesting a potential link between NACHT-mediated processes and stress-associated cellular states. Together, this work provides evidence of a specific regulatory mechanism for protein secretion in symbiotic fungi, offering insights into how PCD-related pathways and UcPS may be co-regulated to maintain cellular homeostasis.
    Keywords:  Cell biology; Molecular biology; Mycology
    DOI:  https://doi.org/10.1016/j.isci.2026.116464
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