bims-proteo Biomed News
on Proteostasis
Issue of 2026–10–18
fifty-nine papers selected by
Eric Chevet, INSERM
  1. USP9X promotes the degradation of trapped translation factors on collided ribosomes.
  2. Ribosome-associated chaperone DNAJC2 titrates translation flux to alleviate the burden of co-translational quality control.
  3. Stress granules at the crossroads of the proteostasis network.
  4. Subcellular spatiotemporal proteomics delineates distinct phases of ER stress proteostatic response.
  5. Failure to release from the ER translocon induces 60S ribosome degradation.
  6. Location, location, deUFMylation: Coordinating ribosome quality control at the ER.
  7. Structural basis of an endoplasmic reticulum EMC:Spf1 insertase-dislocase complex.
  8. Sugar on the Coat: Site-Specific O-GlcNAc and Myoferlin Adapt COPII for Collagen Export.
  9. RING E3 ligase TRIM8 is structurally selective for UBE2N-mediated ubiquitination.
  10. Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes.
  11. Multivalent weak contacts shape chaperone-nascent protein interactions.
  12. Ribosome roadblocks and traffic controllers in bacteria.
  13. Proximity-Induced Protein Deglycosylation by Endogenous O-GlcNAcase.
  14. TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.
  15. Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.
  16. Computational design of metalloproteases.
  17. Proteasomal surveillance of exposed cysteines.
  18. Mammalian MemPrep establishes the lipid composition of ER membranes in HEK293T cells.
  19. Rank Normalization Enables Cross Pathway Comparison in Degradation Resolved Proteome Turnover Analysis.
  20. Methyltransferase RsmB chaperones E. coli ribosome assembly by orchestrating the recruitment of ribosomal proteins.
  21. Chemogenetic ubiquitin E1 inhibitor TAK-243 CRISPR screen uncovers HAPSTR1/HUWE1 axis in chromatin proteostasis and cell cycle control.
  22. CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma.
  23. Functional diversification of the cephalopod proteome by RNA editing.
  24. Declining ribosome function limits oocyte longevity.
  25. Rho GTPase-driven stress granules enable anchorage-independent survival under adhesion stress.
  26. Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.
  27. Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder.
  28. De novo design of cysteine proteases.
  29. RiboBA: a bias-aware probabilistic framework for robust ORF identification across diverse ribosome profiling protocols.
  30. A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.
  31. Stress-induced membrane insertion at the β-barrel assembly machinery complex regulates BepA metalloprotease activity.
  32. A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.
  33. Co-opted CHIP E3 Ub-ligase provides protein quality control by regulating molecular properties of condensates formed by a positive-strand RNA virus.
  34. A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity.
  35. TM6SF2 is a cholesterol-bound homomultimeric ER membrane protein that binds ApoB and is required for bulk lipidation of VLDL.
  36. Untranslated region rewiring defines a novel class of oncogene fusions.
  37. A B1 SINE element within the mouse Malat1 long noncoding RNA acts as an internal ribosome entry site mediating micropeptide translation.
  38. Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
  39. PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
  40. EPG5 orchestrates iron compartmentalization through dual regulation in macroferritinophagy.
  41. Computational design of a versatile, zero-radius proximity labeling enzyme.
  42. Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming.
  43. NEURL1-mediated K63-ubiquitination of SLC40A1 drives ferroptosis resistance in pathological scars: Therapeutic targeting via autophagy-activating microneedles.
  44. Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
  45. Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.
  46. Dynamic partitioning shapes the in vivo organization of the Escherichia coli RNA degradosome.
  47. BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING.
  48. Defects in ribosomes and translational control in lymphoid leukemia and lymphoma.
  49. TXNDC11 is associated with poor prognosis and promotes stress-associated survival in acute myeloid leukemia.
  50. The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology.
  51. A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.
  52. Small-molecule activators of the Staphylococcus aureus ClpC/ClpP AAA+ protease.
  53. The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
  54. Beyond the binding site: PROTAC-mediated protein degradation assists the therapeutic paradigm of hematological malignancies.
  55. RAISE quantifies RNA binding protein activity via transcriptomic profiling.
  56. RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
  57. Degradation-coupled antibody conjugates for precision cancer therapy.
  58. P-body sequestration of clock transcripts delays repressor synthesis to set circadian period in Drosophila.
  59. An ALLO-1-associated network links mitochondrial quality control to functional recovery in structurally compromised muscle.
  1. Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01204-0. [Epub ahead of print]45(10): 118125
    USP9X promotes the degradation of trapped translation factors on collided ribosomes.
    Wojciech Teodorowicz, Lukas-Adrian Gurzeler, Oliver Mühlemann.
      Various ribosome-associated quality control pathways safeguard translation fidelity by detecting and resolving aberrant translation events. Recently, a pathway that senses stalled ribosomes with an occluded A-site has been described. The small molecules NVS1.1 and ternatin-4 induce ribosome stalling by trapping eukaryotic release factor 1 (eRF1) and elongation factor 1A1 (eEF1A1), respectively, within the ribosomal A-site, thereby promoting their ubiquitination and proteasomal degradation. Additionally to the previously identified factors GCN1, RNF14, and RNF25, we identify here the deubiquitinase USP9X as a regulator of this pathway. In the absence of USP9X deubiquitinase activity, eRF1 is still ubiquitinated but fails to undergo efficient degradation. However, compared with wild-type cells, K6-linked ubiquitin chains accumulate on eRF1 in cells lacking USP9X activity, suggesting that USP9X trims K6-linked ubiquitin chains during a late step of substrate processing. Furthermore, clearance of trapped eRF1 engages a feedback mechanism involving 4EHP and the integrated stress response (ISR) to suppress translation, whereas impaired degradation prevents translational shutdown.
    Keywords:  CP: molecular biology; K6-linked ubiquitination; USP9X; deubiquitination; eEF1A1; eRF1; proteasomal degradation; ribosome; ribosome quality control; translation; ubiquitination
    DOI:  https://doi.org/10.1016/j.celrep.2026.118125
  2. Mol Cells. 2026 Oct 14. pii: S1016-8478(26)00098-1. [Epub ahead of print] 100407
    Ribosome-associated chaperone DNAJC2 titrates translation flux to alleviate the burden of co-translational quality control.
    Jongmin Park, Youngim Yu, Heeju Park, Hyunwoo Bang, Jongbin Lee, Chunghun Lim.
      Ribosome collisions during aberrant translation activate ribosome-associated quality control (RQC) to resolve stalled ribosome complexes and triage incomplete nascent chains. How this co-translational surveillance is coordinated with other ribosome-associated activities remains unclear. Here, we identify the ribosome-associated Hsp40 chaperone DNAJC2 that restrains translational flux and limits RQC engagement during collision-prone translation. Genetic epistasis analysis revealed that DNAJC2 titrates the flux of aberrant translation intermediates through the canonical RQC pathway, from the collision-sensing RQC factor ZNF598 to the downstream NEMF-LTN1 E3 ligase complex for proteasomal degradation. DNAJC2 depletion further sensitized cells to collision-induced ribotoxic stress response (RSR), indicating increased vulnerability to global translation stress. Mechanistically, loss of DNAJC2 accelerated translation elongation, thereby promoting ribosome collisions and ZNF598-dependent ribosome disassembly. Accordingly, reducing translational flux with the translation inhibitor homoharringtonine or a huntingtin upstream ORF rescued DNAJC2-depletion phenotypes during RQC-sensitive poly(A)-mediated translational stalling. Together, we propose that DNAJC2 acts as a translational rheostat to buffer ribosome collisions, prevent RQC overload, and set the threshold for RSR activation.
    Keywords:  DNAJC2; Ribosome-associated quality control (RQC); ribosome-associated complex (RAC); ribotoxic stress response (RSR); translational flux
    DOI:  https://doi.org/10.1016/j.mocell.2026.100407
  3. RNA Biol. 2026 Dec;23(1): 1-22
    Stress granules at the crossroads of the proteostasis network.
    Rachel Kim, Erika N Calle Urgiles, Stephanie L Moon.
      The proteostasis network maintains cell function by safeguarding the proteome through the coordinated actions of protein synthesis, quality control, and degradation machinery including chaperones and the ubiquitin-proteasome system. Proteostasis collapse and activation of the integrated stress response (ISR) occur in ageing and neurodegeneration. Upon proteotoxic stress, translation suppression during the ISR drives the assembly of non-translating mRNAs into biomolecular condensates called stress granules. Stress granules act as a double-edged sword in the proteostasis network, serving beneficial or detrimental roles through their effects on translation, protein quality control, and protein aggregation. In this review, we discuss how protein synthesis, quality control, and degradation factors regulate stress granule dynamics, and conversely how stress granules impact proteostasis. While stress granules may initially protect cells by sequestering misfolded, aggregation-prone proteins and regulating translation, they may evolve into sites of pathological aggregation. Clarifying these intersections may reveal therapeutic strategies for neurodegeneration and other disease processes.
    Keywords:  Proteostasis; integrated stress response; protein quality control; stress granules; translation
    DOI:  https://doi.org/10.1080/15476286.2026.2731904
  4. bioRxiv. 2026 Sep 28. pii: 2026.09.25.754245. [Epub ahead of print]
    Subcellular spatiotemporal proteomics delineates distinct phases of ER stress proteostatic response.
    Lorena Alamillo, Thalia Paiz, Alexander Black, Matthew C Juber, Ethan M Arends, Jacob G Cox, Dominic C M Ng, Timothy A McKinsey, Maggie P Y Lam, Edward Lau.
      Endoplasmic reticulum (ER) stress is associated with many human diseases, but current understanding of how ER stress responses reshape the stressed proteome over time is still emerging. Specifically, how organellar protein quality control and clearance pathways coordinate to maintain proteostasis in early and prolonged ER stress is unclear. Here we describe a spatiotemporal proteomic strategy termed simultaneous proteome localization and turnover analysis with time resolution (SPLAT-TR) to interrogate the synthesis, degradation, and localization changes of over 4,000 proteins in early (1-4 hours) and prolonged (16-24 hours) ER stress. As ER stress progresses, each time point is distinguished by distinct protein translocation and clearance regulations, coupled to differential organellar proteostasis and usage of protein degradation pathways. Mitochondria show a bimodal response, with a shift from early activation of respiratory protein towards protein quality control pathways in prolonged stress, coinciding with energetics decline. In the Golgi, the increased clearance of collagen proteins is paradoxically coupled to an increased synthesis of secretory pathway components, suggesting removal by secretion. In the ER, the proteome remodels under prolonged stress via increased synthesis of UFMylation and ER-phagy-related proteins coupled to the selective degradation of ER membrane and microdomain proteins. Inhibition of UFMylation alters ER-phagy receptor usage and synergistically induces stress-induced cell death. These results present a systematic delineation of cell compartment proteostasis under unfolded protein response and highlight the utility of SPLAT-TR to investigate time-dependent cellular events.
    DOI:  https://doi.org/10.64898/2026.09.25.754245
  5. bioRxiv. 2026 Sep 28. pii: 2026.09.26.754687. [Epub ahead of print]
    Failure to release from the ER translocon induces 60S ribosome degradation.
    Zebulon G Levine, Stuti Khandwala, Christina J Zhang, Kelsey L Hickey, Julia Joung, Jingjie Hu, Yi Hua Chen-Neumann, Jingchuan Luo, Anders S Hansen, J Wade Harper, Gavin Schlissel, Jonathan S Weissman.
      Ribosome malfunction has toxic consequences, but how mammalian cells select ribosomal subunits for degradation remains poorly understood. Here, we develop a pulse-chase CRISPR screening strategy to identify regulators of ribosome turnover and uncover that loss of protein UFMylation promotes ribosome degradation. Normal UFMylation releases the 60S subunit from the endoplasmic reticulum (ER) translocon. Without UFMylation, single-molecule tracking and optogenetic proximity labeling reveal accumulation of ER-associated 60S subunits and their specific degradation. This translocon-associated large subunit degradation (TLSD) is independent of the lysosome and, in our human cell model, is only active in nondividing, contact-inhibited cells. Degradation requires the poorly characterized protein R3HDM4, which we term TLSD1. Upon UFMylation loss, TLSD1 redistributes to the ER and promotes 60S degradation. These findings identify a cell-state-dependent pathway for clearing ER-retained 60S subunits. We propose translocon release acts as a checkpoint for ribosome function, explaining TLSD1's genetic links to neuronal health and erythropoiesis.
    DOI:  https://doi.org/10.64898/2026.09.26.754687
  6. Cell Chem Biol. 2026 Oct 15. pii: S2451-9456(26)00325-9. [Epub ahead of print]33(10): 1353-1355
    Location, location, deUFMylation: Coordinating ribosome quality control at the ER.
    Alexander R Mikesell, Zachary T Campbell.
      Endoplasmic-reticulum-associated ribosome quality control (ER-RQC) requires ubiquitin-fold modifier 1 (UFM1) for UFMylation of the ribosomal protein RPL26. In the August 6 issue of Molecular Cell, Mao et al.1 identify an ER-associated complex (UFSP2/ODR4) as critical for deUFMylation of RPL26 and uncover a critical physiologic role for UFSP2 in neuronal proteostasis.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.015
  7. Nat Struct Mol Biol. 2026 Oct;33(10): 1548-1560
    Structural basis of an endoplasmic reticulum EMC:Spf1 insertase-dislocase complex.
    Carolin J Klose, J Rajan Prabu, Emma J Fenech, Bastian Bräuning, Ida Baydar, Barbara Steigenberger, Susanne von Gronau, Sivan Arad, Christine R Langlois, Maya Schuldiner, Brenda A Schulman, Matthias J Feige.
      Most eukaryotic membrane proteins are inserted into the membrane at the endoplasmic reticulum (ER). This essential process relies on molecular quality control machineries to prevent mistargeting and incorrect structure formation. Here, we show that the ER membrane protein complex (EMC) forms an evolutionarily conserved supercomplex with the P5A-ATPase Spf1/ATP13A1. Biochemical, structural and cellular analyses demonstrate that the EMC and Spf1 associate in a stoichiometric manner and retain their individual catalytic activities, the transmembrane domain (TMD) insertase function of the EMC and the TMD dislocase activity of Spf1. Our cryo-electron microscopy structures show that the EMC insertase cavity and the Spf1 dislocase cleft are positioned in close proximity within the membrane and reveal that the ATPase cycle of Spf1 remodels the interface between the two machineries and alters cytoplasmic accessibility of both substrate-binding cavities. Together, our study provides structural insights into how membrane protein insertion and extraction machineries can be spatially coordinated at the ER membrane, suggesting that functionally distinct proteostasis factors can assemble into hubs to support membrane protein biogenesis and quality control.
    DOI:  https://doi.org/10.1038/s41594-026-01883-8
  8. Traffic. 2026 Dec;27(4): e70055
    Sugar on the Coat: Site-Specific O-GlcNAc and Myoferlin Adapt COPII for Collagen Export.
    Miharu Maeda, Kota Saito.
      Recent work by Hirata and colleagues identifies site-specific O-GlcNAc modification of the cargo-selecting COPII subunit Sec24D as a dynamic regulatory switch that promotes collagen export from the endoplasmic reticulum (ER), providing new insight into how COPII accommodates cargoes far larger than canonical transport vesicles. Two glycosites in the poorly characterized N-terminal intrinsically disordered region (IDR) of Sec24D, T9 and S13, display strikingly different dynamics: S13 is constitutively glycosylated, whereas T9 is rapidly modified following a synchronized burst of collagen transport and returns to baseline within minutes. Both sites are required for collagen I trafficking and rescue of Sec24D-deficient bulldog zebrafish, while T9 is also required for efficient transport of the smaller cargo E-cadherin, suggesting that a single intrinsically disordered region can encode cargo-selective information. Crosslinking proteomics further reveals distinct glycosylation-dependent changes in the Sec24D interactome and identifies myoferlin (MYOF) as a partner proposed to promote fusion of ER exit sites (ERES) with ER-Golgi intermediate compartment (ERGIC) membranes. In this commentary, we discuss how these findings recast the COPII inner coat as a signal-integrating platform, intersect with TANGO1-dependent ERGIC recruitment and competing models of large collagen carriers, and raise key mechanistic questions concerning signal transmission across the ER membrane, glycan stoichiometry, and how the recruitment or tethering function proposed for MYOF is coupled to membrane fusion.
    DOI:  https://doi.org/10.1111/tra.70055
  9. J Biol Chem. 2026 Oct 13. pii: S0021-9258(26)02514-7. [Epub ahead of print] 113642
    RING E3 ligase TRIM8 is structurally selective for UBE2N-mediated ubiquitination.
    Jane Dudley-Fraser, Diego Esposito, Katrin Rittinger.
      RING domains catalyse ubiquitination by stabilising a closed conformation of E2-ubiquitin (Ub) conjugates, with TRIpartite Motif (TRIM) proteins representing the largest subfamily of RING-type E3 ligases. TRIM proteins are implicated in many physiological processes and diseases. For example, TRIM8 perturbation has been variously linked to neurodevelopmental defects and several cancer types, attributed to its ubiquitination of a myriad of putative substrates. However, the molecular mechanisms behind these modifications are not yet clear. Here we show that TRIM8 has preferential functionality with the E2 enzyme UBE2N to generate K63-linked poly-ubiquitin chains. By solving the crystal structure of TRIM8 RING bound to a UBE2N-Ub conjugate, we discover that its non-canonical asparagine 'linchpin' residue belies this selectivity by failing to form key contacts required to stabilise the closed conformation of other E2 enzymes. These findings not only open the door to exploring the impact of TRIM8-mediated K63 chain formation in health and disease, but also add to a growing appreciation of the specificities of RING domain catalytic activity.
    Keywords:  E3 ubiquitin ligase; NMR; RING; TRIM protein; X-ray crystallography; ubiquitin; ubiquitination
    DOI:  https://doi.org/10.1016/j.jbc.2026.113642
  10. bioRxiv. 2026 Sep 30. pii: 2026.09.29.755516. [Epub ahead of print]
    Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes.
    Evan N Whitford, Joshua D Gilbert, Marius M Kostelic, Michelle A Estrada, Aaron C Ehlinger, Tiffany A Thibaudeau, Shaun M McLoughlin, Vicki H Wysocki.
      Proteolysis-targeting chimeras (PROTACs) promote targeted protein degradation by inducing a transient ternary complex between a protein of interest and an E3 ubiquitin ligase. Despite the clinical promise of these event-driven therapeutics, defining the conformational landscape and interfacial organization of these complexes remains challenging. Here, we use an integrated native mass spectrometry (nMS) approach combining ion mobility, surface-induced dissociation (SID), and variable-temperature electrospray ionization (vT-ESI) to determine how small-molecule architecture shapes the structural and thermodynamic landscapes of bromodomain-containing protein 4 (BRD4) with the VCB E3 ligase complex. Using a set of PROTACs that differ in targeting ligand identity (JQ1 versus I-BET726) and PEG linker length, ion mobility measurements show that shorter linkers constrain the ternary complex into more extended topologies, whereas longer, more flexible linkers allow dynamic sampling of relaxed, native-like conformations. SID directly probes noncovalent interfaces and shows that JQ1 complexes favor prompt PROTAC ejection, whereas tighter-binding I-BET726 complexes are more likely to retain the PROTAC at the interface. Complementing these kinetically-controlled gas-phase measurements, vT-ESI reveals a monophasic melting transition for a JQ1-mediated complex and a distinct biphasic melting profile for an I-BET726-mediated complex. The gas-phase activation measurements revealed targeting-ligand-driven differences in PROTAC ejection and retention, whereas vT-ESI uncovered distinct temperature-dependent disassembly pathways for the matched-linker-length JQ10L and IBET10L complexes. Together, these complementary techniques show how PROTAC architecture influences ternary-complex conformation, interfacial connectivity, and disassembly.
    Synopsis: Proteolysis-targeting chimeras (PROTACs) offer a promising therapeutic strategy by selectively directing disease-related proteins for intracellular degradation. Here, we employ a systematic native mass spectrometry approach to investigate how PROTAC design impacts the conformation and stability of the resulting ternary complexes. Integrating gas- and solution-phase data provides critical insights to inform rational PROTAC optimization.
    DOI:  https://doi.org/10.64898/2026.09.29.755516
  11. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2607201123
    Multivalent weak contacts shape chaperone-nascent protein interactions.
    Nandakumar Rajasekaran, Dmitri Toptygin, Ting-Wei Liao, Vincent J Hilser, Taekjip Ha, Christian M Kaiser.
      Molecular chaperones interact with non-native proteins, playing crucial roles in preventing misfolding and in enabling efficient folding in the cellular environment. Trigger factor is a bacterial chaperone that binds to ribosomes, interacting with nascent polypeptides emerging from the ribosome and guiding their early folding steps. In contrast to the central role of the chaperone in promoting folding of newly synthesized proteins, its dynamic interactions with nascent chains emerging from the ribosome remain poorly understood. Here, we use single-molecule fluorescence and optical tweezers approaches to directly observe and characterize trigger factor interactions with a ribosome-bound client protein at increasing chain lengths. We find that trigger factor dwell times on ribosome-nascent chain complexes increase non-monotonically with nascent chain length, and that binding to nascent proteins is best described by a combination of multiple weak, dynamic interactions that are established after the chaperone docks onto the ribosome and evolve during polypeptide elongation. Application of mechanical force perturbs trigger factor binding, supporting a multivalent interaction model. This binding mode may help to stabilize nascent proteins against misfolding while allowing them to dynamically sample conformational space in search of their native structures.
    Keywords:  molecular chaperones; protein synthesis; ribosome; single-molecule fluorescence; single-molecule spectroscopy
    DOI:  https://doi.org/10.1073/pnas.2607201123
  12. Microbiol Mol Biol Rev. 2026 Oct 14. e0034625
    Ribosome roadblocks and traffic controllers in bacteria.
    Mahmoud Shoman, Mee-Ngan Frances Yap.
      SUMMARYProtein synthesis by ribosomes proceeds through the sequential stages of initiation, elongation, termination, and ribosome recycling. In most bacteria, coupled transcription-translation enhances the efficiency of transcription but limits opportunities to repair or eliminate faulty mRNAs, thereby increasing the likelihood that ribosomes encounter incomplete or damaged transcripts. Furthermore, mRNA integrity can be compromised by transcriptional errors, abortive transcription, nucleolytic cleavage, or chemical damage. Translation of such defective transcripts, as well as other hard-to-translate mRNAs, can impede elongation or termination, resulting in stalled ribosome complexes that sequester ribosomes and tRNAs, thereby reducing their availability for subsequent rounds of translation. To maintain translation capacity, bacteria employ dedicated ribosome rescue and quality control pathways that resolve stalled complexes and promote the turnover of aberrant mRNAs and nascent polypeptides. Here, we summarize the molecular mechanisms underlying bacterial ribosome stalling, describe the pathways that rescue stalled ribosomes, and discuss current technologies for detecting ribosome stalling. We also highlight the physiological roles of programmed ribosome stalling and explore the potential of ribosome rescue pathways as druggable sites.
    Keywords:  ABCF; RQC; Ribo-seq; antibiotic; ribosome collision; ribosome profiling; ribosome stalling; tmRNA; translation arrest
    DOI:  https://doi.org/10.1128/mmbr.00346-25
  13. Angew Chem Int Ed Engl. 2026 Oct 15. e1827729
    Proximity-Induced Protein Deglycosylation by Endogenous O-GlcNAcase.
    Haixing Xu, Bowen Ma, Yunpeng Huang, Jialin Liu, Billy Wai-Lung Ng.
      O-GlcNAcylation is an important post-translational modification that regulates numerous cellular processes, yet tools enabling selective removal of O-GlcNAc from individual proteins via endogenous O-GlcNAcase (OGA) in living cells remain limited. Here, we report De-O-GlcNAcylation-targeting chimeras (DOGTACs), a chemically induced proximity strategy that selectively reduces O-GlcNAc from target proteins by recruiting endogenous OGA. Initial designs incorporating potent competitive OGA inhibitors efficiently engaged OGA but failed to induce de-O-GlcNAcylation, revealing that catalytic competence is essential for productive proximity-driven editing. By attenuating inhibitor potency while retaining OGA engagement, we developed optimized DOGTACs that promote concentration- and time-dependent, target-specific de-O-GlcNAcylation in living cells without perturbing global O-GlcNAc levels. Furthermore, we successfully applied DOGTAC to additional target proteins including FKBP12F36V fused proteins and endogenous CK2α across different cell lines. Besides, we found DOGTAC (R)-C4 treatment could reduce the stability of FKBP12F36V fused-NUP98-KDM5A in cells. Collectively, this work established attenuated competitive inhibitors as recruitment modules for catalytic enzyme engagement and a novel strategy, DOGTAC, for targeted de-O-GlcNAcylation via endogenous OGA recruitment in living cells.
    Keywords:  O‐GlcNAcylation; bifunctional molecules; enzymes; inhibitors; protein modification
    DOI:  https://doi.org/10.1002/anie.1827729
  14. Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01195-2. [Epub ahead of print]45(10): 118116
    TM6SF2 acts at ER membrane contact sites to enable RAB7-dependent endolysosomal VLDL secretion and maintain Golgi structure.
    Emad Heidary Arash, Marko Groeger, James P Grenert, Torsten Wittmann, Robert L Raffai, Jacquelyn J Maher, Holger Willenbring.
      Although a loss-of-function variant of TM6SF2 is a highly penetrant risk factor for steatotic liver disease, including progression to cirrhosis and cancer, its normal function is largely unknown. Here we show that endoplasmic reticulum (ER)-localized TM6SF2 forms membrane contact sites (MCSs) with late endosomes/lysosomes, where it activates the small GTPase RAB7 to enable an endolysosomal route for selective secretion of lipid-rich very low-density lipoprotein (VLDL) particles. In accord, TM6SF2 and RAB7 deficiency similarly cause endolysosomal VLDL retention and accumulation of enlarged late endosomes/lysosomes. TM6SF2 further binds to VAMP-associated protein (VAP) ER-anchor proteins to maintain MCSs between the ER, endosomes, and the trans-Golgi network, with TM6SF2 deficiency causing Golgi fragmentation and disruption of cGAS-STING signaling known to prevent cirrhosis and cancer by clearing senescent hepatocytes. Our findings establish TM6SF2 as an ER-MCS component that enables endolysosomal VLDL secretion and maintains Golgi structure, which suggests that TM6SF2 loss of function causes liver disease through steatosis-dependent and independent mechanisms.
    Keywords:  CP: cell biology; Golgi; RAB7; TM6SF2; VAP; cGAS-STING; endoplasmic reticulum; late endosomes/lysosomes; membrane contact sites; steatotic liver disease
    DOI:  https://doi.org/10.1016/j.celrep.2026.118116
  15. Microb Cell. 2026 ;13 358-377
    Scp160 deletion suppresses TDP-43 aggregation and toxicity in Saccharomyces cerevisiae.
    Joan Castells-Ballester, Natalia Shcherbik.
      Protein misfolding and aberrant protein aggregation are central features of neurodegenerative disorders, including amyotrophic lateral sclerosis, where the RNA-binding protein TDP-43 accumulates in abnormal intracellular assemblies. Although yeast models have identified multiple modifiers of TDP-43 toxicity, the cellular factors that determine how aggregation-prone proteins are organized remain incompletely understood. Here, we investigated whether the ribosome- and mRNP-associated proteins Scp160 and Bfr1 influence TDP-43 proteotoxicity and aggregate formation. We report that deletion of SCP160 or BFR1 improves growth during TDP43-GFP induction without reducing steady-state reporter abundance and decreases formation of prominent TDP43-GFP foci. Deletion of BFR1 produced an intermediate TDP-43 phenotype, with a weaker effect than SCP160 deletion on severe foci formation and toxicity. Importantly, the effect of SCP160 or BFR1 deletion on visible protein aggregation was not specific to TDP-43: severe Htt103Q-GFP aggregation was strongly reduced, and formation of VHL-GFP foci was suppressed, including under conditions of proteasome inhibition. Despite these shared effects, the two mutants were not phenotypically identical. Deletion of SCP160 produced a distinct spatial phenotype in which residual TDP43-GFP foci showed markedly increased association with Sec63-positive ER structures and reduced distance to these regions, whereas bfr1 Δ cells did not show the same Sec63-associated shift. Together, these findings uncouple TDP43-GFP abundance from toxicity and prominent foci formation and identify Scp160 and Bfr1 as factors that influence the intracellular partitioning of aggregation-prone and misfolded proteins, with an additional role for Scp160 in the spatial organization of TDP43 relative to the ER.
    Keywords:  Bfr1; Saccharomyces cerevisiae; Scp160/Vigilin; TDP-43; endoplasmic reticulum; protein aggregation; proteostasis; proteotoxicity
    DOI:  https://doi.org/10.15698/mic2026.10.888
  16. Nature. 2026 Oct 14.
    Computational design of metalloproteases.
    Anqi Chen, Kejia Wu, Hojae Choi, Preetham Venkatesh, Samuel J Pellock, Nikita Hanikel, Hojeong Shin, Declan Evans, Kieran Didi, Lars L Schaaf, Cristina Díaz-Perlas, Brian Coventry, Donghyo Kim, Seth M Woodbury, Pengfei Ji, Shingo Honda, Asim K Bera, Hannah Nguyen, Alex Kang, Yanqing Wang, Xinting Li, Stacey Gerben, Lemuel Chang, Xiao Yan, Benjamí Oller-Salvia, Anthony A Hyman, Donald Hilvert, David Baker.
      De novo design of enzymes that cleave amide bonds represents a major challenge1,2. Here we use RFdiffusion methods3,4 to de novo design proteins with water-activating zinc-based active sites adjacent to a peptide substrate binding pocket. Of 135 designs tested, 36% catalyse cleavage of their cognate peptide substrates at the targeted scissile bond. The best design accelerates peptide-bond hydrolysis by more than 108-fold relative to the uncatalysed reaction; four substitutions increase this acceleration to more than 1010-fold by improving active-site preorganization5. We use this approach to design metalloproteases that selectively cleave the human disease-associated proteins TDP-43, amyloid-β and serum amyloid A, with rate enhancements of up to 109-fold. We further design caged cytokines and receptor antagonists that are selectively activated by the designed proteases, enabling bioorthogonal control of cell state. Thus, de novo design can yield highly active, programmable proteases with applications in therapeutics, biotechnology and bioremediation.
    DOI:  https://doi.org/10.1038/s41586-026-11167-2
  17. bioRxiv. 2026 Sep 30. pii: 2026.09.29.755535. [Epub ahead of print]
    Proteasomal surveillance of exposed cysteines.
    Elijah L Mena, Ken C Dong, Anthony Kairouz, Katherine A Donovan, Mostafa A Soliman, Hai-Tsang Huang, Bercin Yildiran, Eric S Fischer, Richard I Sherwood, Richard T Timms, Andreas Martin, Stephen J Elledge.
      Cysteine residues are critical for both the catalytic activity and structural stability of many proteins, yet their high chemical reactivity threatens proteome integrity. Whether cells have specialized mechanisms to recognize and eliminate proteins with aberrant or exposed cysteines is unknown. By systematically analyzing the stability of thousands of cysteine-containing peptides, here we identify two complementary surveillance mechanisms targeting proteins with exposed cysteine residues. First, a set of E3 ubiquitin ligases - including AMBRA1, TRPC4AP, FBXO3, and FBXO21 - detects double cysteines and targets proteins for ubiquitin-dependent proteasomal degradation. Second, the PSMD14/Rpn11 subunit of the 26S proteasome recognizes exposed cysteines in a ubiquitin-independent manner. Both pathways function in quality control to clear misfolded proteins exposing cysteine residues, including zinc finger-containing proteins. Mutational escape from the ubiquitin-independent pathway through dysregulation of ornithine decarboxylase or FOS levels is responsible for two human diseases, Bachmann-Bupp Syndrome and osteoblastoma, respectively. Our findings reveal conserved mechanisms for degrading proteins with exposed cysteines and uncover an alternative mode of substrate recognition by the 26S proteasome.
    Keywords:  26S proteasome; FOS; UPS; cysteine; ornithine decarboxylase (ODC); proteostasis; ubiquitin-independent degradation; zinc
    DOI:  https://doi.org/10.64898/2026.09.29.755535
  18. EMBO Rep. 2026 Oct 14.
    Mammalian MemPrep establishes the lipid composition of ER membranes in HEK293T cells.
    Aamna Jain, Alexander von der Malsburg, Cynthia Alsayyah, Claudia Götz, Mohamed Elmofty, John Reinhard, Per Haberkant, Volkhard Helms, Joseph H Lorent, Robert Ernst.
      The endoplasmic reticulum (ER) forms a dynamic network of sheets and tubules, whose lipid composition remains incompletely defined. Using an optimized MemPrep workflow, we establish a high‑confidence lipidome of the mammalian ER and selectively enrich membrane vesicles originating from ER tubules as a major ER subdomain. Quantitative lipidomics show ER membranes are dominated by phosphatidylcholine and monounsaturated glycerophospholipids, consistent with a highly compressible bilayer. Although proteomics suggests a functional specialization of ER tubules and an enrichment of tubule-associated proteins, the lipidome of an ER tubule-enriched isolate is indistinguishable from the general ER, indicating that principal ER architectures share a common lipid composition. Integration of lipidomic data with bioinformatic analyses of transmembrane helices demonstrates that the physicochemical features of ER lipids mirror those of ER-resident membrane proteins, including reduced hydrophobicity and increased polarity compared to plasma membrane proteins. These findings support a coordinated evolution of ER proteins and lipids based on shared biophysical constraints. Together, this work provides a definitive characterization of the mammalian ER lipidome and suggests that membrane properties are maintained across the ER.
    DOI:  https://doi.org/10.1038/s44319-026-00952-9
  19. bioRxiv. 2026 Oct 01. pii: 2026.09.30.755414. [Epub ahead of print]
    Rank Normalization Enables Cross Pathway Comparison in Degradation Resolved Proteome Turnover Analysis.
    Zi Gao, Qiang Xiao, Jeffery W Kelly, Evan T Powers.
      Protein homeostasis, or proteostasis, is essential for cellular health, and its disruption contributes to cancer, aging, and neurodegenerative disease. Proteostasis is maintained largely by two intracellular degradation systems: the ubiquitin proteasome system (UPS) and the autophagy lysosomal pathway (ALP). Here, we combine pulse stable isotope labeling by amino acids in cell culture (pSILAC) with selective inhibition of the UPS or ALP to quantify pathway-dependent protein turnover and identify substrates that are preferentially cleared through each route. Direct comparison of these perturbations is complicated by their markedly different response distributions. To address the mismatch in dynamic range, we developed a normalization strategy based on within-condition ranks. Protein stabilization values are converted to percentile scores before comparison across pathways, placing both perturbations on a common relative response scale. Across two independent pSILAC experiments, 5,518 proteins were quantified in at least one condition, and 3,814 yielded high confidence half-life measurements in control, proteasome-inhibited, and lysosome-inhibited conditions. Rank normalization resolved pathway sensitivities that were obscured by direct comparison of absolute half-life changes. Importantly, the method reports relative pathway preference rather than absolute pathway contribution, exchanging effect size magnitude for comparability across perturbations with unequal response distributions. Integration with a curated proteostasis network annotation revealed coherent pathway preferences, including coordinated stabilization of proteasome core and regulatory subunits following lysosomal inhibition. This finding provides proteome-wide quantitative evidence for proteaphagy that complements previous targeted observations. Together, these results establish rank normalization as a practical strategy for comparing degradation resolved proteome turnover across perturbations with different dynamic ranges.
    DOI:  https://doi.org/10.64898/2026.09.30.755414
  20. Sci Adv. 2026 Oct 16. 12(42): eaef7741
    Methyltransferase RsmB chaperones E. coli ribosome assembly by orchestrating the recruitment of ribosomal proteins.
    Qilan Wei, Sarah A Woodson.
      Ribosomal RNA modification enzymes increase cellular fitness, but it's little known whether this benefit arises from rRNA modification or a chaperone function of the modification enzyme. Here, we show that E. coli methyltransferase RsmB chaperones the initial recruitment of ribosomal proteins to the 16S 3' domain rRNA, a key step in assembly of the 30S subunit. Real-time single-molecule assembly experiments show that the RsmB product, 16S m5C967, has little effect on the rRNA affinity for ribosomal proteins. Instead, RsmB facilitates stable recruitment of primary protein uS7 during transcription while blocking the addition of secondary protein uS19. Completion of the methyltransferase cycle promotes RsmB release, allowing assembly to continue. Dimethyl sulfate footprinting of trapped RsmB-rRNA complexes revealed that RsmB restructures a critical rRNA helix junction. Our results illustrate how an RNA modification enzyme favors the proper sequence of protein addition by temporarily reshaping the energy landscape of co-transcriptional rRNA folding.
    DOI:  https://doi.org/10.1126/sciadv.aef7741
  21. Sci Adv. 2026 Oct 16. 12(42): eaea3388
    Chemogenetic ubiquitin E1 inhibitor TAK-243 CRISPR screen uncovers HAPSTR1/HUWE1 axis in chromatin proteostasis and cell cycle control.
    Nila K van Overbeek, Linda Clijsters, Martina Wirth, Ilona J de Graaf, Klaas de Lint, Sidrit Uruci, Amina F A S Teunisse, Vyacheslav Akimov, Arnoud H de Ru, Maja Vukic, Idil Kirdök, Lucia Daxinger, Peter A van Veelen, Blagoy Blagoev, Martijn S Luijsterburg, Rob M F Wolthuis, Ilana Berlin, Alfred C O Vertegaal.
      In this study, we sought to comprehensively map ubiquitin signaling networks at the crossroads of cellular proliferation and proteostasis, both crucial in cancer. Genome-wide CRISPR knockout screening in the presence of the ubiquitin E1 inhibitor TAK-243 identified 239 genes whose ablation sensitizes cells to ubiquitination blockade. Follow-up studies reveal a role for the nuclear protein, C16orf72/HECT, UBA, and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1)-Associated Protein modifying Stress Responses (HAPSTR1), in chromatin proteostasis and DNA replication. We show that HAPSTR1 recruits the E3 ligase HUWE1 to the chromatin, keeping the chromatin-associated proteome in check, and is itself turned over by HUWE1 during cell cycle progression. Structural modeling of the HAPSTR1/HUWE1 complex, supported by mutational analysis, demonstrates that loss of HUWE1 binding renders HAPSTR1 unable to support cellular proliferation when ubiquitin signaling is suppressed. Consequently, HAPSTR1 ablation impairs clearance of chromatin-associated proteins, triggering global transcriptional and proteostatic adaptations. Under diminished ubiquitin signaling, these adaptive mechanisms give way to replication stress and premature S phase entry, culminating in cell cycle collapse and DNA damage. Our findings uncover protein networks exhibiting synthetic lethality with ubiquitin signaling blockade and highlight vulnerabilities of actively proliferating cells to proteostatic imbalance at the chromatin.
    DOI:  https://doi.org/10.1126/sciadv.aea3388
  22. Nat Commun. 2026 Sep 11. pii: 10714. [Epub ahead of print]17(1):
    CReP-mediated control of eIF2α phosphorylation is a critical node in MYC-driven medulloblastoma.
    Liliana Mirabal-Ortega, Sandra Majo, Lucie J Taunay, Magalie Larcher, Dave Yong Xiang Ng, Sara Chabi, Marion Le Grand, Kevin Muller, Jacob Torrejon, Laure Lagaye, Sofia Gaid, Coline Kerbaj, Moustapha Ka, Cristèle Gilbert, Véronique Marsaud, Bertrand Duvillié, Marine Blanchard, Boris Julien, Sophie Leboucher, Florent Dingli, Damarys Loew, Franck Griscelli, Annelise Bennaceur-Griscelli, Franck Bourdeaut, François Doz, Olivier Ayrault, Florence M Cavalli, Michael D Taylor, Alain Eychène, Rachid Benhida, Eric Chevet, Eddy Pasquier, Sabine Druillennec, Celio Pouponnot.
      Medulloblastoma (MB) is the most common malignant pediatric brain tumor. The MYC‑amplified group 3 (G3) MB represents a high‑risk disease lacking effective therapies. A genetic screen identified the endoplasmic reticulum chaperone HSPA5 (BiP/GRP78) as a critical dependency in G3 MB. Its silencing induces apoptosis and suppresses tumor growth, with strong activation of the unfolded protein response (UPR). The UPR includes three branches, including the PERK-eIF2α axis, which transiently reduces global protein synthesis while enabling selective translation of stress‑responsive factors such as ATF4. We show that G3 MB requires sustained eIF2α activity for survival. Its inhibition triggers cell death through ATF4‑dependent and ‑independent transcriptional programs and translational reprogramming that deplete essential proteins and promote accumulation of detrimental factors. The eIF2α phosphatase PPP1R15B (CReP) maintains basal eIF2α activity and prevents apoptosis. These findings identify the eIF2α axis and its regulators as a crucial node and a targetable vulnerability in G3 MB.
    DOI:  https://doi.org/10.1038/s41467-026-77565-2
  23. Cell. 2026 Oct 15. pii: S0092-8674(26)01184-0. [Epub ahead of print]
    Functional diversification of the cephalopod proteome by RNA editing.
    Jack M Moen, Alicia L Richards, Einar K Krogsaeter, Benjamin J Polacco, Martin Gordon, Erica Stevenson, Rhiana Boyles, Maximilien Burq, Dejan Stepec, Bryan Crampton, Nathaniel Sin, Zachary Gale-Day, Jason E Gestwicki, Peter Cimermancic, Joshua J C Rosenthal, Nevan J Krogan, Danielle L Swaney.
      Coleoid cephalopods exhibit the highest levels of adenosine deaminases acting on RNA (ADAR)-mediated RNA editing of any known taxon, yet the functional consequences of most recoding events remain unclear. Here, we integrated proteomics with biochemical and cellular assays to characterize recoding across the Doryteuthis pealeii proteome. This confirmed the translation of 7,997 recoded sites at the protein level and revealed how recoding reshapes the proteome by altering protein stability, subcellular localization, post-translational modifications, and enzymatic activity. We find that recoding also creates or ablates post-translational modification sites, with direct effects on protein function and protein-protein interactions. Recoding the E3 ligase MARCHF5 drives widespread changes in substrate ubiquitylation and perturbs mitochondrial homeostasis, illustrating how RNA editing can influence organelle function. Together, these data give a proteome-scale view of how extensive RNA recoding diversifies protein function in coleoid cephalopods and offer a framework for understanding how RNA-level plasticity shapes protein function and cellular physiology.
    Keywords:  ADAR; MARCHF5; RNA editing; cephalopods; coleoids; post-translational modifications; protein recoding; proteomics; solvent shift; subcellular localization
    DOI:  https://doi.org/10.1016/j.cell.2026.09.043
  24. bioRxiv. 2026 Sep 30. pii: 2026.09.29.755503. [Epub ahead of print]
    Declining ribosome function limits oocyte longevity.
    Kayla Judson, Katie J Danielson, Shuang Tang, Sahil Chandhok, Elizabeth Hui, Fiona Wong, Thibault Mayor, Karen Schindler, Ethan J Greenblatt.
      Protein synthesis declines with age across many tissues, but whether this decline actively contributes to physiological aging remains unclear. Oocytes may be particularly vulnerable because they rely on ribosomes synthesized during growth and maintained for prolonged periods without continual replacement. Here we show that declining translational capacity is a causal component of oocyte aging. An unbiased genetic screen identified ribosome dosage as a major determinant of oocyte longevity, and experimentally reducing ribosome abundance was sufficient to accelerate the loss of developmental competence and prematurely recapitulate meiotic defects that arise during natural aging, while also producing defects in early embryonic development. Ribosomes isolated from aged Drosophila oocytes exhibit ~50% lower translational activity despite only a modest reduction in ribosome abundance and preserved gross structure and composition, with both ribosomal subunits contributing to this functional decline. Protein synthesis also declines markedly in aged metaphase-I mouse oocytes. Together, these findings identify long-lived translational machinery as an intrinsic vulnerability of the oocyte and establish declining ribosome function as a mechanistic contributor to reproductive aging.
    Keywords:  Fertility; aging; meiotic spindle; oocyte; ribosome; translation
    DOI:  https://doi.org/10.64898/2026.09.29.755503
  25. Res Sq. 2026 Oct 01. pii: rs.3.rs-10284597. [Epub ahead of print]
    Rho GTPase-driven stress granules enable anchorage-independent survival under adhesion stress.
    Pavel Ivanov, Seungwon Yang, Anais Aulas, Paul Anderson.
      Cells that lose adhesion to their native extracellular matrix must either adapt to impaired adhesion signaling or undergo anoikis. How cells convert loss of adhesion into translational stress responses and survival signaling remains incompletely understood. Here, we define adhesion stress as a cellular stress state triggered by impaired adhesion signaling and show that this state induces stress granule (SG) assembly as an adaptive survival mechanism. We modeled adhesion stress through cell detachment, reduced adhesion strength, and pharmacologic inhibition of focal adhesion kinase (FAK). Across these models, adhesion stress activated a RhoA-ROCK-PERK-eIF2α signaling pathway that drove SG assembly. PERK was the principal eIF2α kinase required for this adhesion-stress response. Proteomic profiling further showed that adhesion-stress SGs represent a previously unrecognized SG subtype characterized by a Rho GTPase-associated protein signature and selective enrichment of CASP4, an inflammatory caspase linked to cell-death signaling. Functionally, SG assembly limited CASP4 activation and reduced apoptotic signaling during FAK inhibitor-induced adhesion stress. In parallel, PERK contributed to sustained AKT-mTOR survival signaling during anoikis. Genetic loss of SG assembly or pharmacologic inhibition of G3BP-dependent SG formation increased anoikis sensitivity and sensitized cancer cells to multiple FAK inhibitors. SGs were also enriched in invading cancer cells in human breast tumors, consistent with a role for adhesion-stress adaptation in invasive tumor contexts. Together, these findings identify adhesion-stress SGs as a RhoA-ROCK-PERK-driven survival program that limits anoikis and enables anchorage-independent cancer cell survival.
    DOI:  https://doi.org/10.21203/rs.3.rs-10284597/v1
  26. Nat Chem Biol. 2026 Oct 16.
    Tryptoline stereoprobe elaboration identifies inhibitors of the GRPEL1-HSPA9 complex.
    Rachel E Hayward, Raymond F Berkeley, Zijian Gao, Maximilian Garhammer, Marc A Morizono, Evert Njomen, Haoxin Li, Kristen E DeMeester, Victor Cociorva, Mark A Herzik, F Ulrich Hartl, Bruno Melillo, Benjamin F Cravatt.
      Activity-based protein profiling has identified hundreds of human proteins from diverse classes that react at cysteine residues with stereochemically defined electrophilic compounds (stereoprobes). The structure-activity relationships underlying these stereoprobe-protein interactions, however, remain poorly understood. Here, we show that the protein interaction landscape of tryptoline acrylamide stereoprobes can be profoundly altered by structural modifications distal to the acrylamide reactive group. Most stereoprobe liganding events occurred at nonorthosteric sites and evaded assignment by the machine learning-based cofolding model Boltz-2, which instead tended to misplace stereoprobes in orthosteric pockets (an outcome we term 'orthostery burnout'). We found that stereoprobes reacting with C124 in the nucleotide exchange factor GRPEL1 disrupt interactions with the mitochondrial HSP70 chaperone HSPA9/mortalin, leading to impairments in mitochondrial protein import and mitophagy induction. Our results highlight tryptoline acrylamides as a versatile source of covalent ligands targeting nonorthosteric sites on proteins, including tool compounds that perturb the mitochondrial HSP70 chaperone system.
    DOI:  https://doi.org/10.1038/s41589-026-02348-1
  27. J Clin Invest. 2026 Oct 13. pii: e199882. [Epub ahead of print]
    Bi-allelic variants in the secretory pathway gene SEC16A are associated with a neurodevelopmental disorder.
    Mengqi Ma, Xiaowei Lei, Juan Li, Yiming Zheng, Yu Yuan, Yohei Nitta, Xiao Mao, Zhenming Guo, Shenzhao Lu, Mingxi Deng, Xueyang Pan, Oguz Kanca, Shiyi Liu, Hua Wang, Bo Xiao, Rachel Schot, Serwet Demirdas, Yolande van Bever, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Shan Bian, Hugo J Bellen, Lili Long.
      SEC16A encodes a scaffold protein that organizes the endoplasmic reticulum (ER) exit sites, specialized ER subdomains that mediate export of newly synthesized proteins and regulate early secretory pathway steps. The role of SEC16A in human nervous system diseases has not been established yet. Here, we report six individuals with bi-allelic SEC16A variants who presented with early-onset neurological symptoms, including cognitive impairment, motor delays, and seizures. Using Drosophila, we show the Sec16 ortholog is essential for normal development and that its loss causes early lethality. Neuron-specific knockdown of Sec16 causes neurological phenotypes including locomotor defects, seizure-like bang sensitivity, and impaired synaptic transmission, which can be associated with the clinical features observed in affected individuals. Neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) carrying SEC16A variants display reduced SEC16A protein, impaired neurite outgrowth and increased excitability, which are rescued in isogenic control neurons when the variants are corrected, consistent with a loss-of-function mechanism. Increased ER stress was observed in both patient iPSC-derived neurons and fly models. In summary, our findings indicate a conserved requirement for SEC16A in neurodevelopment and neuronal function and implicate ER stress as a key cellular phenotype underlying the SEC16A-associated neurodevelopmental disorder.
    Keywords:  Genetics; Neurodevelopment; Neuroscience; Protein traffic
    DOI:  https://doi.org/10.1172/JCI199882
  28. Nature. 2026 Oct 14.
    De novo design of cysteine proteases.
    Hojae Choi, Magnus S Bauer, Brian Coventry, Preetham Venkatesh, Anqi Chen, Donghyo Kim, Asim K Bera, Alex Kang, Hannah Nguyen, Shayan Sadre, Justin Decarreau, Emily Joyce, Bhanumathi Shankaran, Tuscan Rock Thompson, Gabriel Greenstein, Kieran Didi, Lars L Schaaf, Jacob Merle Gershon, Alexander F Shida, Gyu Rie Lee, Donald Hilvert, Samuel J Pellock, David Baker.
      Despite advances in de novo enzyme design, success has been largely limited to low-energy-barrier model reactions. Amide bonds such as those linking amino acids along the peptide backbone are stable for hundreds of years in neutral aqueous solution because of the high energy barrier to hydrolysis1. Here we describe the de novo design of enzymes that use an activated cysteine nucleophile to hydrolyse the polypeptide backbone in a sequence-dependent manner, with a success rate of 13/69 = 19% and rate enhancements over the background reaction (kcat/kuncat) of up to 3 × 107. The designed proteases have folds that are very different from proteases in nature (TM score < 0.50), and six crystal structures are very close to the design models (Cα root mean squared deviation of <1.2 Å), highlighting the capacity for generalization and the accuracy of the design methodology. Experimental and computational analyses suggest that the remaining gap in activity to the most active native cysteine proteases arises from imperfections in active-site preorganization and substrate positioning. The designed proteases efficiently cleave their targets in mammalian cells, opening the door to a wide range of synthetic biology applications.
    DOI:  https://doi.org/10.1038/s41586-026-11143-w
  29. Nucleic Acids Res. 2026 Oct 13. pii: gkag969. [Epub ahead of print]54(19):
    RiboBA: a bias-aware probabilistic framework for robust ORF identification across diverse ribosome profiling protocols.
    Junyu Bai, Ruolin Yang.
      By mapping ribosome-protected fragments genome-wide, ribosome profiling (Ribo-seq) has uncovered extensive translation beyond conventional coding sequences, revealing non-canonical ORFs (ncORFs) with roles in diverse biological processes. However, robust ncORF identification remains challenging when Ribo-seq datasets exhibit attenuated periodicity. Protocol-induced biases during library construction is an important contributor to this loss, yet most ORF callers do not explicitly model these distortions. Here, we present RiboBA, a bias-aware probabilistic framework for robust ORF identification from Ribo-seq data. RiboBA combines a generative module that jointly infers protocol-induced biases and codon-level ribosome occupancy with a supervised module that identifies translated ORFs and initiation sites from the bias-adjusted profiles. In simulations with known P-site positions, RiboBA improved exact nucleotide- and codon-level P-site assignment relative to a conventional fixed-offset approach. Across simulations and diverse empirical Ribo-seq datasets, together with orthogonal immunopeptidomics evidence, RiboBA accurately recovers protocol-induced parameters and improves ncORF identification, with pronounced advantages for RNase I libraries with attenuated periodicity, and for MNase and nuclease P1 datasets, while maintaining competitive runtimes. In a Drosophila case study, RiboBA identified candidate ncORFs with coding potential, including recurrent upstream translation in ThrRS and Mettl2, linking ncORF translation to threonine-related translational regulation.
    DOI:  https://doi.org/10.1093/nar/gkag969
  30. Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01215-5. [Epub ahead of print]45(10): 118136
    A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.
    Ivan Vlassakev, Christina Savva, Liying Zhou, Danilo Ritz, Alexander Schmidt, Cholsoon Jang, Amir Ata Saei, Paul Petrus.
      Daily light-dark cycles impose environmental fluctuations that require coordinated regulation of physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the signals that convey circadian information between organs remain incompletely defined. We identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In adipocytes and neuronal cells, NaR engages the unfolded protein response (UPR). Proteome-wide stability profiling implicates the prefoldin complex as a target of NaR, linking NaR exposure to altered proteostasis. In adipocytes, NaR-induced UPR signaling converges on the transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). Sustained NaR exposure suppresses adipocyte lipid deposition, whereas temporally restricted NaR stimulation enhances adipogenesis. Together, these findings identify NaR as a liver clock-controlled circulating metabolite that couples systemic circadian metabolism to proteostasis and tissue remodeling, revealing a mechanism by which temporal metabolic signals shape tissue-specific physiological outcomes.
    Keywords:  CP: metabolism; CP: molecular biology; adipocyte; circadian rhythms; metabolism; organ communication; systems biology; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.118136
  31. Nat Commun. 2026 Sep 09. pii: 10665. [Epub ahead of print]17(1):
    Stress-induced membrane insertion at the β-barrel assembly machinery complex regulates BepA metalloprotease activity.
    Henri Voedts, Phuong Chi Nguyen, Van Son Nguyen, Pauline Leverrier, Bogdan I Iorga, Seung Hyun Cho, Han Remaut, Jean-François Collet.
      Proteases must be tightly regulated to prevent uncontrolled degradation, yet the mechanisms ensuring such control remain poorly understood. Members of the widespread M48 metalloprotease family are kept inactive by an autoinhibitory plug that blocks catalytic water activation, but how this plug is released remained elusive. Here, using genetic, biochemical and cryo-EM approaches, we discover the activation mechanism of BepA, a quality-control protease that preserves outer membrane integrity by surveilling the β-barrel assembly machinery (BAM) in Gram-negative bacteria. Our cryo-EM analysis of BepA engaged with a stalled BAM-substrate assembly complex revealed that a flexible, unstructured α6-lid covering the active site in the latent protein functions as a molecular harpoon, inserting into the outer membrane when a substrate stalls at BAM and thereby docking BepA at the complex. This membrane anchoring promotes displacement of the autoinhibitory plug and unlocks protease activity precisely where and when it is needed. Thus, a dual enzyme activation mechanism is coupled to membrane association under stress, ensuring that BepA remains inactive until properly localized. Our findings reveal how membranes themselves can license protease activation, a principle that may extend beyond M48 metalloproteases.
    DOI:  https://doi.org/10.1038/s41467-026-77559-0
  32. Mol Cell. 2026 Oct 12. pii: S1097-2765(26)00666-0. [Epub ahead of print]
    A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.
    Alina S Thielen, Bastian Bräuning, Karthik V Gottemukkala, Judith Müller, J Rajan Prabu, Pooja Verma, Simon Klaessens, Benoit J Van den Eynde, Gary Kleiger, Peter J Murray, Brenda A Schulman.
      Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation, yet how endogenous ligands gate UPS decisions remains poorly understood. Here, we define control of UPS access to human tryptophan 2,3-dioxygenase (TDO2), which converts the amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert hypotryptophanemia. We discovered that a CK2-β-TrCP kinase-E3 ligase cascade generates and recognizes phosphodegrons in TDO2 unless they are shielded by Trp binding at an exosite distal from the catalytic site. Effects of Trp analogs on CK2-β-TrCP-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups collectively protect TDO2. Cryo-EM reveals that these moieties organize a Trp-ordered flap that covers the exosite and thereby restricts generation of adjacent phosphodegrons. In the absence of Trp, the flap is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule conformationally stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade.
    Keywords:  BTRC; CK2; CUL1; E3 ligase; FBXW11; feedback regulation; kinase; metabolism; phosphodegron; tryptophan; ubiquitin; ubiquitin-proteasome system; ubiquitylation; β-TrCP
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.023
  33. Sci Adv. 2026 Oct 16. 12(42): eaeh7253
    Co-opted CHIP E3 Ub-ligase provides protein quality control by regulating molecular properties of condensates formed by a positive-strand RNA virus.
    Wenwu Lin, Yuyan Liu, Peter D Nagy.
      Positive-strand RNA viruses are important pathogens that built viral replication organelles (VROs) via exploiting co-opted host proteins and intracellular membranes in infected cells. Tomato bushy stunt virus (TBSV) membranous VROs are associated with dynamic virus-induced replication (vir)-condensate substructures driven by TBSV p33 replication protein. We targeted micropeptide "killswitch" to VROs to enhance p33 self-association and remodel vir-condensates. Recruitment of killswitch induced p33 aggregations, reduced mobility of co-opted glycolytic enzymes in vir-condensate, limited ATP production within VROs, and inhibited TBSV replication. We discovered that TBSV co-opts CHIP/STUB1 E3 ubiquitin ligase involved in protein quality control to limit detrimental effect of protein aggregations in VROs. Expression of CHIP reduced accumulation of aggregated TBSV p33. Knockdown of CHIP resulted in inhibition of TBSV replication, enhanced accumulation of aggregation-prone p33 mutants, and inhibited mobility of co-opted client host proteins in vir-condensate. Subverted CHIP plays critical role in regulating protein interactions, stability, and maintenance of dynamic vir-condensate. Hijacking protein quality control mechanism is a previously unknown phenomenon during (+)RNA virus replication.
    DOI:  https://doi.org/10.1126/sciadv.aeh7253
  34. bioRxiv. 2026 Sep 29. pii: 2026.09.28.755091. [Epub ahead of print]
    A PPARγ-like signalling axis integrates lipid homeostasis and mitochondrial quality control to preserve neuronal integrity.
    Dikaia Tsagkari, Maria Markaki, Tao Zhang, Ellen Nollen, Nektarios Tavernarakis.
      Peroxisome proliferator-activated receptor gamma (PPARγ) is a central regulator of lipid metabolism and a critical mediator of neuroprotection, yet the mechanisms linking these functions remain unclear. Here, we identify the Caenorhabditis elegans nuclear receptor SEX-1 as a functional PPARγ-like regulator and define a pathway that coordinates lipid metabolism with mitochondrial homeostasis to preserve neuronal function. Integrating comparative genomics, multi-omics profiling, meta-analysis, and experimental validation, we show that SEX-1 orchestrates membrane sphingolipid metabolism, lipid droplet (LD) dynamics, and mitochondrial quality control through interconnected lipogenic and autophagic programs. Loss of sex-1 disrupts this metabolic network, resulting in aberrant LD accumulation, mitochondrial dysfunction, and widespread alterations in sphingolipid metabolism. These defects compromise the structural integrity and thermosensory function of amphid neurons during early adulthood, while the capacity of SEX-1 to restrict neuronal lipid droplet accumulation declines with age. Notably, genetic modulation of sphingolipid metabolic pathways rescues neuronal defects, establishing a causal link between lipid metabolic homeostasis and neuronal maintenance. Together, our findings identify a PPARγ-like signalling axis that integrates sphingolipid metabolism, organelle quality control, and neuronal homeostasis, providing a mechanistic framework for understanding how metabolic regulation promotes neuroprotection.
    DOI:  https://doi.org/10.64898/2026.09.28.755091
  35. bioRxiv. 2026 Sep 28. pii: 2026.08.17.745233. [Epub ahead of print]
    TM6SF2 is a cholesterol-bound homomultimeric ER membrane protein that binds ApoB and is required for bulk lipidation of VLDL.
    Sen Hong, Jin Wang, Matthew A Mitsche, Jonathan C Cohen, Xiaochun Li, Helen H Hobbs.
      A missense variant in TM6SF2 (transmembrane 6 superfamily member 2, TM6SF2 E167K ) is a major risk factor for steatotic liver disease 1 , while protecting against coronary artery disease 2 . TM6SF2 is a polytopic resident protein of the smooth endoplasmic reticulum (ER) and ER-Golgi intermediate compartment that promotes lipidation of hepatic ApoB-containing lipoproteins before secretion into the circulation. Here, we used cryo-electron microscopy (cryo-EM) to determine the structures of TM6SF2 and TM6SF2 E167K . TM6SF2 comprises 10 transmembrane helices that bind a single cholesterol molecule within a transmembrane cavity. The protein assembles into homodimers and homotetramers that interact with ApoB. Structural and biochemical analyses show that the E167K substitution reduces cholesterol binding and ApoB interaction without disrupting overall protein structure. Expression of wild-type, but not mutant, TM6SF2 restores hepatic triglyceride secretion in TM6SF2-deficient hepatocytes. Together, these findings establish the structural framework for the bulk lipidation step in hepatic lipoprotein biogenesis, the principal pathway for hepatic triglyceride and cholesterol export into the circulation.
    DOI:  https://doi.org/10.64898/2026.08.17.745233
  36. Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01224-6. [Epub ahead of print]45(10): 118145
    Untranslated region rewiring defines a novel class of oncogene fusions.
    Marina Cerqua, Estelle Bigot, Cédric Chaveroux, Paolo M Comoglio, Dogus M Altintas.
      Gene fusions in cancer are traditionally understood to generate hybrid proteins with altered functions that promote malignancy. Here, we define a previously unrecognized class of oncogenic fusions that preserve protein structure but replace the 5' untranslated region (5' UTR), thereby rewiring translational regulation. Using the MET oncogene as a paradigm, we show that 5' UTR-replacing fusions, identified across >200,000 cancer samples, increase MET protein abundance 5- to 10-fold without corresponding changes in mRNA levels. The resulting receptor remains correctly localized, ligand-responsive, and active, thereby promoting cell survival and motility. These fusion transcripts are detected following irradiation, documenting UTR rewiring in a post-treatment context. Beyond MET, similar 5' UTR-replacing fusions occur in FGFR1, JAK2, and NTRK2, where partner-derived 5 'UTRs are associated with reduced regulatory complexity and enhanced protein output. Together, our findings establish UTR rewiring as an overlooked mechanism of oncogene overexpression with implications for cancer genome annotation and precision oncology.
    Keywords:  5′ untranslated regions; CP: molecular biology; cancer genomics; gene fusions; oncogene regulation; translational control; untranslated region rewiring
    DOI:  https://doi.org/10.1016/j.celrep.2026.118145
  37. Sci Adv. 2026 Oct 16. 12(42): eaee5884
    A B1 SINE element within the mouse Malat1 long noncoding RNA acts as an internal ribosome entry site mediating micropeptide translation.
    Wen Xiao, Tanja Hann, Zion Perry, Vijaya Pandey, Jeffrey Cheng, James Wohlschlegel, Anna Marie Pyle, Douglas L Black.
      In most cells, Malat1 long noncoding RNA localizes to the nucleus where it affects splicing and chromatin function. In mouse neurons, Malat1 is exported to the cytoplasm where it is translated to generate the M1 micropeptide. Here, we characterize an internal ribosome entry site (IRES) required for M1 translation that is sufficient to induce cap-independent expression of a downstream open reading frame. In vivo chemical probing and structural modeling defined a three-stem-loop RNA secondary structure that encompasses the active IRES segment and coincides with a mouse B1 SINE (short interspersed element) repetitive element. In affinity purification experiments, a minimal IRES/B1 RNA selectively bound ribosomal subunits, translation factors, and the known IRES cofactors Rack1 and hnRNP A2/B1. Depletion of Rack1 and hnRNP A2/B1 inhibited IRES-dependent translation of the reporter and expression of the endogenous M1 peptide. Our study identifies an unexpected functional unit hidden within a widely studied long noncoding RNA.
    DOI:  https://doi.org/10.1126/sciadv.aee5884
  38. bioRxiv. 2026 Oct 03. pii: 2026.01.16.700014. [Epub ahead of print]
    Local ROS and inefficient autophagosome formation limit Optineurin-mediated mitophagy in neurons.
    Jordan R Green, Anne E Ojo, Molly K Gooden, Lillian D Papell, Titilola D Kalejaiye, Chantell S Evans.
      Mitophagy is a quality control mechanism that maintains neuronal health by removing damaged mitochondria. In neurons, mitophagy can be driven by Optineurin (OPTN), a selective autophagy receptor recruited in response to oxidative stress. However, mechanistic studies of mitophagy have relied mainly on non-neuronal cell lines and acute damage paradigms. It remains unknown whether these findings translate to neurons under physiological stress conditions. Here, we investigated the temporal dynamics of OPTN-dependent mitophagy under mild oxidative stress using live-cell imaging in primary rat hippocampal neurons. We found that autophagosomes failed to readily engulf OPTN-positive (OPTN+) mitochondria, revealing a previously unidentified rate-limiting step in neuronal OPTN-mediated mitophagy. Additionally, OPTN+ mitochondria colocalized with acidified lysosomes over timescales significantly longer than previously reported. These OPTN+ mitochondria displayed locally elevated reactive oxygen species (ROS). Scavenging mitochondrial ROS increased lysosomal colocalization with damaged mitochondria and accelerated mitophagy progression. Together, these findings indicate that redox signaling contributes to the slow timescale of OPTN-mediated mitophagy in neurons.
    DOI:  https://doi.org/10.64898/2026.01.16.700014
  39. Sci Adv. 2026 Oct 16. 12(42): eaef8820
    PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
    Diogo Gonçalves, Emma Guilbaud, Léa Di Mascio, Camille Guerrier, Linda Mejri, Sonia Núñez-Vázquez, Lucie Levasseur, Rachel Paul, Corinne Menigot, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Paul Hofman, Marin Truchi, Bernard Mari, Laurent Yvan-Charvet, Johanna Chiche, Sandrine Marchetti, Jean-Ehrland Ricci.
      Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of KRAS-targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in KRAS-driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aef8820
  40. J Biol Chem. 2026 Oct 14. pii: S0021-9258(26)02518-4. [Epub ahead of print] 113646
    EPG5 orchestrates iron compartmentalization through dual regulation in macroferritinophagy.
    Yilun Chen, Yi Yang, Rui Wang, Hanyu Wang, Chunyan Wu, Qun Lu.
      Intracellular iron is distributed across functionally distinct pools though the mechanisms regulating its compartmentalization remain unclear. Here we show that EPG5, a tethering factor required for autophagosome-lysosome fusion, governs iron compartmentalization through dual mechanisms: direct involvement in autophagy and indirect regulation of ferritinophagy initiation. A systematic comparison of autophagy genes indicates that EPG5 deficiency uniquely decreases hemosiderin and increases the labile iron pool, a profile distinct from ATG5, ATG14, FIP200, or WDR45 deficiencies. Mechanistically, EPG5 loss disrupts autophagosome maturation and endocytic trafficking, causing ferritin condensates and iron transporters to accumulate in aberrant autophagosomes and endosomes. This blockade triggers compensatory TBK1 activation. TBK1 subsequently phosphorylates TAX1BP1 and interacts with the ferritinophagy receptors NCOA4, inhibiting receptor homo-oligomerization and modulating ferritinophagic flux. These findings position EPG5 as a novel orchestrator of iron compartmentalization and highlight the role of TBK1-NCOA4/TAX1BP1 axis in iron homeostasis and related stress response.
    Keywords:  EPG5; NCOA4; TBK1; ferritinophagy; iron compartmentalization
    DOI:  https://doi.org/10.1016/j.jbc.2026.113646
  41. bioRxiv. 2026 Sep 28. pii: 2026.09.24.754223. [Epub ahead of print]
    Computational design of a versatile, zero-radius proximity labeling enzyme.
    Shizhong A Dai, Peter E Cavanagh, Albert Qiang, Zijuan Zhang, Qixiang Geng, Maribel Anguiano, Andrew G Xue, Tsutomu Matsui, Khanh Nguyen, Namrata D Udeshi, Sam Pellock, Brian Hie, Steven A Carr, Christina Kim, Nathanael S Gray, Wei Qin, Alice Y Ting.
      The ability to map protein interactomes and organelle proteomes is foundational for achieving a molecular understanding of living cells. Proximity labeling (PL) provides a powerful strategy for this, but existing enzymes and photocatalysts are limited by their spatial resolution, reliance on biotin, and/or in vivo compatibility. Here we report FlexID, an engineered promiscuous ligase that catalyzes the rapid attachment of diverse small-molecule probes to proximal endogenous proteins. Critically, FlexID operates through a zero-radius, direct-contact mechanism, offering superior spatial precision compared to existing PL tools. We engineered FlexID by combining the strengths of sequence-and structure-trained computational models to enhance its catalytic activity and structural stability. Biophysical analysis revealed that specific conformational changes in FlexID improve its ability to recognize diverse target proteins while simultaneously preventing the premature release of the reactive intermediate. We demonstrate FlexID's versatility through in vivo proximity labeling, comprehensive organelle proteome mapping, and a high-throughput, fluorescence-based screen for molecular glues. Our work shows that computational methods can be harnessed to create mechanistically distinct PL enzymes and establishes FlexID as a flexible, high-resolution tool for mapping protein interactions and proteomes in living cells.
    DOI:  https://doi.org/10.64898/2026.09.24.754223
  42. bioRxiv. 2026 Oct 02. pii: 2026.09.29.755403. [Epub ahead of print]
    Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming.
    Ping Ren, Shao-Yu Fang, Shushu Zhao, Hanbing Cao, Kaiyuan Tang, Xingbo Shang, Cole W Christopher, Yunfei Jiao, Medha Majety, Andre Levchenko, David B Weiner, Sidi Chen, Xiaoyu Zhou.
      Despite the success of immune checkpoint blockade in cancer therapy, overcoming the immunosuppressive tumor microenvironment remains a major barrier to durable responses. Here, we introduce cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)-targeting chimeras (cTACs), a class of synthetic molecules that harness CTLA-4-mediated trans-endocytosis (TE) for targeted protein degradation across cellular boundaries. The lead candidate, cTAC4.0, is composed of the extracellular domain of CD80 fused to an anti-programmed death-ligand 1 (PD-L1) fragment via a human immunoglobulin G4 (IgG4) heavy chain. Unlike existing protein degraders that function within cancer cells via house-keeping pathways, cTAC4.0 operates in trans between immune and tumor cells. It redirects the natural CD80-CTLA-4 internalization to capture and degrade PD-L1 from tumor cells into T cells, while simultaneously converting PD-L1-mediated suppression into CD28-driven co-stimulation, depending on the relative availability of CTLA-4 or CD28. Mechanistically, we demonstrate that cTAC4.0 promotes CTLA-4-dependent internalization and lysosomal degradation of both membrane-bound and soluble PD-L1, reduces surface PD-L1 levels on target cells, and activates T cells in a CD28-dependent manner. Functionally, cTAC4.0 enhances the cytotoxicity of both bispecific T cell engagers and T cell receptor (TCR)-engineered T cells in vitro, and when combined with these engineered T cells, it suppresses tumor growth in vivo in a glioblastoma xenograft model. By coupling immune checkpoint degradation with T cell activation in an immune synapse-enriched manner, cTACs establish a paradigm for intercellular protein degradation systems that simultaneously deplete suppressive ligands and enhance T cell function to overcome resistance in cancer immunotherapy.
    Keywords:  CTLA-4; PD-L1; Protein degrader; co-inhibition; co-stimulation; immune synapse; trans-endocytosis
    DOI:  https://doi.org/10.64898/2026.09.29.755403
  43. Redox Biol. 2026 Sep 29. pii: S2213-2317(26)00419-2. [Epub ahead of print]97 104420
    NEURL1-mediated K63-ubiquitination of SLC40A1 drives ferroptosis resistance in pathological scars: Therapeutic targeting via autophagy-activating microneedles.
    Mengzhu Lv, Jiamei Liu, Qi Dong, Zibo Guo, Qianlong Wu, Simeng Zhang, Shengye Liu.
      Ferroptosis resistance contributes to pathological skin scarring, but the underlying regulatory mechanisms remain unclear. Here, we identified a novel selective autophagy pathway NEURL1-SQSTM1/p62-SLC40A1 that controls fibroblast ferroptosis and scar formation. SLC40A1 is upregulated in human scars, conferring ferroptosis resistance by promoting iron efflux. Mechanistically, NEURL1 mediates K63-linked ubiquitination of SLC40A1, enabling its recognition by SQSTM1 for lysosomal degradation. A microneedle system co-delivering curcumin (autophagy activator) and siSLC40A1 effectively activates this axis, induces ferroptosis, and alleviates scarring in vivo. Our findings reveal a new therapeutic target and strategy for pathological scars.
    Keywords:  Autophagy; Ferroptosis; Microneedles; Pathological scars; SLC40A1
    DOI:  https://doi.org/10.1016/j.redox.2026.104420
  44. J Inherit Metab Dis. 2026 Nov;49(6): e70259
    Revisiting Inherited Metabolic Diseases (IMDs) Through the Lens of Selective Autophagy.
    Marianna Maddaluno, Laura Cinque, Viviana Cetrangolo, Chiara De Leonibus.
      Selective autophagy is increasingly recognized as a fundamental quality-control mechanism that complements bulk autophagy by enabling the targeted degradation of specific intracellular cargos, including mitochondria, endoplasmic reticulum (ER), lipid droplets, glycogen, peroxisomes, ferritin, ribosomes, and protein aggregates. Cargo selectivity is mediated by selective autophagy receptors (SARs), which link damaged or superfluous substrates to the autophagic machinery through LC3/GABARAP interactions, thereby coordinating cargo sequestration. Recent studies have revealed substantial mechanistic differences between bulk and selective autophagy, highlighting the specialized signaling pathways, receptor networks, and transcriptional programs that regulate selective cargo clearance. Dysregulation of these pathways has emerged as a key contributor to the pathogenesis of inherited metabolic diseases (IMDs), a heterogeneous group of genetic disorders characterized by defective metabolism and multisystem involvement. This review summarizes the molecular mechanisms underlying major forms of selective autophagy, including mitophagy, pexophagy, glycophagy, lipophagy, ER-phagy, and ferritinophagy. It also discusses their relevance across IMD classes, such as mitochondrial disorders, lysosomal storage disorders, and peroxisomal diseases, among many others. Furthermore, selective autophagy is highlighted as a potential therapeutic target, with modulation of autophagy receptors and signaling pathways offering promising strategies to restore cellular homeostasis and improve disease manifestations in IMDs.
    Keywords:  bulk autophagy; inherited metabolic diseases (IMDs); selective autophagy; selective autophagy cargos (SACs); selective autophagy receptors (SARs)
    DOI:  https://doi.org/10.1002/jimd.70259
  45. Nat Commun. 2026 09 10. pii: 10711. [Epub ahead of print]17(1):
    Mapping high resolution, multidimensional phase diagrams of near-physiological protein condensates.
    Tanushree Agarwal, Tomas Sneideris, Fabian Svara, Klavs Jermakovs, Helena Coyle, Seema Qamar, Emanuel Kava, Rob Scrutton, Nicole Pleschka, Priyanka Peres, Gea Cereghetti, Ewa Andrzejewska, Alejandro Diaz-Barreiro, Gaby Palmer, Antonio J Costa-Filho, Georg Krainer, Tuomas Pj Knowles, Jonathon Nixon-Abell.
      Biomolecular condensates are membraneless compartments, crucial for organising and regulating diverse cellular processes. Current approaches to study condensate biology either use simplified recombinant protein systems with limited physiological relevance, or complex live-cell models with restricted experimental control and scalability. Here, we present ExVivo PhaseScan, a droplet microfluidics platform that couples mammalian lysate-based reconstitution with scalable analysis to generate high-resolution phase diagrams of compositionally complex protein condensates. We apply this approach to study two multicomponent condensate systems, stress granules and nucleoli, and dissect the physicochemical interactions that influence their stability. We further developed a machine learning pipeline to analyse condensate morphology which we use to reveal how mutations in the amyotrophic lateral sclerosis (ALS)-linked protein Fused in Sarcoma (FUS) remodels condensate properties. We identify liquid-to-solid transitions of mutant FUS within stress granules and nucleoli, and show that these transitions can be reversed by RNA aptamer-based interventions. Together, these findings establish ExVivo PhaseScan as a versatile tool for dissecting the physicochemical and pathological regulation of condensates, with potential to inform therapeutic strategies for diseases driven by aberrant phase transitions.
    DOI:  https://doi.org/10.1038/s41467-026-77696-6
  46. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2621525123
    Dynamic partitioning shapes the in vivo organization of the Escherichia coli RNA degradosome.
    Laura Troyer, Yu-Huan Wang, Kevin Wu, Seunghyeon Kim, Sangjin Kim.
      The bacterial RNA degradosome is a central mediator of RNA turnover, yet how its components are organized and regulated in living cells remains unclear. Using live-cell single-molecule imaging, we quantified the spatial distribution and dynamics of the four major Escherichia coli degradosome components: RNase E, RhlB, PNPase, and enolase. These proteins occupied distinct membrane-associated and cytoplasmic pools whose relative abundance varied among proteins and changed with physiological state. In particular, PNPase underwent pronounced redistribution between membrane-associated and cytoplasmic states in response to altered RNA availability and growth conditions, whereas RNase E and RhlB remained largely membrane associated. To determine the functional consequences of this organization, we examined the degradation of lacZ reporter transcripts with different translation initiation strengths. PNPase and RhlB preferentially promoted degradation of weakly translated transcripts, whereas strongly translated transcripts were largely insensitive to their loss. Together, these results reveal that the bacterial RNA degradosome is not a static, uniformly assembled molecular machine. Instead, RNA decay is organized through dynamic intracellular partitioning of degradosome components, linking physiological state and translation status to transcript degradation.
    Keywords:  RNA degradation; biomolecular stoichiometry; post-transcriptional gene regulation; single-molecule microscopy
    DOI:  https://doi.org/10.1073/pnas.2621525123
  47. bioRxiv. 2026 Sep 28. pii: 2026.09.25.752224. [Epub ahead of print]
    BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING.
    Elaheh S Hosseini, Steven Wang, Mona Arabzadeh, Kristen E Warrington, Maria T Søgaard, Amartya Singh, Wenjin Chen, Lomaani Ranasinghe, Rinkee Kumari, Christopher K Alcott, Adam Robinson, Shreya Yadav, Wenwei Hu, Jian Cao, Eugenia Girda, Eileen P White, Christian S Hinrichs, Kyle Kristopher Payne.
      High-grade serous ovarian cancer progresses within a lipid-rich ascites microenvironment that engages stress-adaptation programs supporting malignant growth, yet how failed stress resolution influences tumor progression remains incompletely defined. Here, we show that unresolved lysosomal stress restrains tumor progression by sustaining tumor cell-intrinsic STING activity and reorganizing antitumor immunity. We identify BLTP3A as a lysosomal stress-resolution factor in ovarian cancer and show that the common germline missense variant BLTP3A M1098T increases stress-induced lysosomal damage. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or orthologous variant expression delayed progression and generated Cxcl9 + antigen-presenting macrophage niches; M1098T-expressing human tumors similarly promoted interferon-responsive myeloid and T-cell enrichment in humanized mice. Mechanistically, ascites-induced lysosomal stress activated a STING-ATF4-BLTP3A feedback program. BLTP3A dysfunction disrupted CASM-associated lysosomal stress resolution, resulting in prolonged STING activity and sustained tumor-derived IFN-λ without increased cGAMP. Tumor-cell STING and IFN-λ were required for immune remodeling and tumor control. Thus, BLTP3A-dependent lysosomal stress resolution constrains the persistence of stress-induced STING signaling, whereas failure of this response sustains a tumor-intrinsic inflammatory program that organizes protective antitumor immunity.
    DOI:  https://doi.org/10.64898/2026.09.25.752224
  48. Semin Hematol. 2026 Sep 16. pii: S0037-1963(26)00087-9. [Epub ahead of print]
    Defects in ribosomes and translational control in lymphoid leukemia and lymphoma.
    Marino Caruso, Naomy Pasau, Óscar Herranz, Kim De Keersmaecker.
      Translational control has emerged as a critical layer of gene expression reprogramming in cancer, with the ribosome functioning as a central regulatory node rather than a passive protein synthesis machinery. This review provides an integrated overview of how defects in ribosomes and translational regulation contribute to the pathogenesis of lymphoid leukemias and lymphomas. We focus on 3 major axes: mutations in ribosomal proteins, alterations in ribosomal RNA, and dysregulation of translation initiation mediated by the eukaryotic initiation factor 4F complex. Recurrent mutations in ribosomal proteins, such as RPL10 in T-cell acute lymphoblastic leukemia and RPS15 in chronic lymphocytic leukemia, alter ribosome function, leading to selective changes in mRNA translation, impaired translational fidelity, and increased oxidative stress that promotes genomic instability. In parallel, emerging evidence indicates that alterations in ribosomal RNA, including changes in ribosomal DNA copy number, biogenesis, and epigenetic modifications, contribute to ribosome heterogeneity and oncogenic transformation, although their precise roles in hematologic malignancies remain incompletely understood. Furthermore, aberrant activation of translation initiation pathways-often driven by the AKT/mTOR/MYC signaling axis-enhances both global protein synthesis and selective translation of oncogenic transcripts, reinforcing malignant phenotypes. Together, these ribosome-intrinsic and -extrinsic defects converge to reprogram the translatome, promote tumor progression, and create therapeutic vulnerabilities. Targeting translational control mechanisms therefore represents a promising strategy for the treatment of lymphoid malignancies.
    Keywords:  Chronic lymphocytic leukemia; Ribosomal protein mutations; Ribosome biogenesis; T-cell acute lymphoblastic leukemia; eIF4F; rRNA
    DOI:  https://doi.org/10.1053/j.seminhematol.2026.09.002
  49. Hum Cell. 2026 Oct 11. pii: 148. [Epub ahead of print]39(10):
    TXNDC11 is associated with poor prognosis and promotes stress-associated survival in acute myeloid leukemia.
    Shisi Huang, Chengyun Pan, Weili Wang, Tianzhen Hu, Wei Cheng, Ying Chen, Ming Ni, Peng Zhao, Qian Kang, Mei Zhao, Mei Li, Fengqi Zhang, Li Wang, Aoshuang Huang, Yanju Li.
      TXNDC11 is an endoplasmic reticulum-associated redox protein involved in protein quality control, but its relevance in acute myeloid leukemia remains incompletely understood. This study examined the expression pattern, prognostic value, and stress-related functional role of TXNDC11 in acute myeloid leukemia using public transcriptomic datasets and experimental validation. Bioinformatic analyses were used to evaluate TXNDC11 expression, survival association, protein interaction networks and pathway enrichment. Loss-of-function experiments were performed in acute myeloid leukemia cell lines to assess cell viability, oxidative stress status, endoplasmic reticulum stress signaling, and responses to the chemical chaperone 4-phenylbutyric acid. TXNDC11 expression was relatively elevated in acute myeloid leukemia samples and higher expression was associated with shorter overall survival. Protein interaction and enrichment analyses connected TXNDC11-associated networks with endoplasmic reticulum-associated degradation, unfolded protein response, endomembrane organization, and apoptosis-related pathways. In THP-1 and HL-60 cells, TXNDC11 knockdown reduced cellular viability and was accompanied by increased reactive oxygen species and malondialdehyde levels, decreased ATP content, reduced glutathione availability, and a lower GSH/GSSG ratio, indicating disruption of redox homeostasis. At the molecular level, TXNDC11 depletion increased GRP78/BiP, p-eIF2α/eIF2α, ATF4, p-IRE1α/IRE1α, cleaved ATF6 p50/full-length ATF6, DDIT3/CHOP mRNA, XBP1s mRNA, HSPA5/BiP mRNA, and cleaved caspase-3, supporting activation of multiple UPR-associated signals and apoptosis-associated marker expression. Treatment with 4-phenylbutyric acid partially attenuated these stress-related molecular and redox changes. Repeated local si-TXNDC11 administration suppressed AML xenograft growth and reduced TXNDC11 expression in endpoint tumor tissues. These findings suggest that TXNDC11 is linked to adverse prognosis in acute myeloid leukemia and may support leukemic cell stress adaptation by limiting endoplasmic reticulum stress-associated redox imbalance and apoptotic signaling.
    Keywords:  Acute myeloid leukemia; Apoptosis; Endoplasmic reticulum stress; Oxidative stress; TXNDC11
    DOI:  https://doi.org/10.1007/s13577-026-01460-7
  50. Mol Cell. 2026 Oct 15. pii: S1097-2765(26)00704-5. [Epub ahead of print]
    The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology.
    Wenxin Lyu, Berthe Katrine Fiil, John Rizk, Majken Kjær, Max Benjamin Sauerland, Saulė Špokaitė, Biao Ma, Malin Jessen, Hanna Kulvicki, Rune Busk Damgaard, Paul R Elliott, Mads Gyrd-Hansen.
      Met1-linked ubiquitin chains (Met1-Ub), synthesized by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, regulate inflammatory signaling and cell death. OTULIN activity prevents tumor necrosis factor (TNF)-driven autoinflammatory pathology and embryonic lethality, but the role of the direct OTULIN-LUBAC interaction remains unclear. Here, we show that mice harboring a point mutation in the OTULIN peptide:N-glycanase/UBA- or UBX-containing proteins (PUB)-interacting motif (OTULINY56A), which disrupts LUBAC binding, are viable without spontaneous pathology but are highly sensitive to TNF-induced toxicity and TNF-mediated immunopathology during Listeria monocytogenes infection. Mechanistically, the OTULIN-LUBAC interaction prevents Met1-linked autoubiquitination, thereby limiting LUBAC activity and Met1-Ub conjugation on non-LUBAC substrates. Disrupting the OTULIN-LUBAC interaction increased Met1-Ub accumulation at the TNF receptor signaling complex, which stabilized the signaling complex, increased nuclear factor-kappa B (NF-κB) signaling, and, unlike loss of OTULIN or its activity, protected from TNF-induced apoptosis. Collectively, we identify the OTULIN-LUBAC interaction as a critical brake restricting LUBAC function and Met1-Ub-dependent signaling.
    Keywords:  LUBAC; LUBAC autoubiquitination; Met1-Ub; NF-κB activation; OTULIN; PIM-PUB interaction; TNF signaling; cell death; immune pathology; inflammation
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.039
  51. Nat Chem Biol. 2026 Oct 13.
    A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.
    Holly H Guo, Ye Tao, Victor E Cruz, Divya Reddy, Min Fang, Vishal Khivansara, Shanhai Xie, Ashley Leach, Johann Peterson, Garrett C Kimble, Michael Buszczak, Jiwoong Kim, Noelle S Williams, Arin B Aurora, Jan P Erzberger, Jef K De Brabander, Deepak Nijhawan.
      Ribosome biogenesis is highly upregulated in cancer and essential for malignant growth, yet efforts to selectively target this process pharmacologically have been unsuccessful. Here we identify nuclear valosin-containing protein-like (NVL), a hexameric AAA+ ATPase required for large ribosomal subunit (60S) assembly, as a druggable target in this pathway. Using forward genetics, we discovered that the cytotoxic dibenzothiazepinone MM17 inhibits NVL. Mutations conferring resistance to MM17 in cancer cells also rendered recombinant NVL refractory to enzymatic inhibition in vitro, providing convergent genetic and biochemical evidence of target engagement. Cryo-electron microscopy structures revealed two MM17-binding sites within the NVL hexamer, with resistance mutations clustering around the ligand pocket. NVL inhibition disrupts 60S biogenesis and activates p53 without inducing DNA damage. A more potent, bioavailable analog, MM927, recapitulates these effects and suppresses tumor growth in vivo without detectable toxicity. These findings establish NVL inhibitors as first-in-class therapeutics targeting ribosome biogenesis in cancer.
    DOI:  https://doi.org/10.1038/s41589-026-02324-9
  52. iScience. 2026 Oct 16. 29(10): 117738
    Small-molecule activators of the Staphylococcus aureus ClpC/ClpP AAA+ protease.
    Timo Jenne, Vsevolod Viliuga, Ulrike Uhrig, Britta Jehle, Merlin Schwan, Jürgen Kopp, Dirk Flemming, Elisabeth Seebach, Irmgard Sinning, Bernd Bukau, Axel Mogk.
      The central AAA+ ClpC/ClpP protease in Gram-positive bacteria is crucial for virulence and stress resistance and has been recognized as drug target. Natural cyclic peptides deregulate the essential Mycobacterium tuberculosis ClpC1 and cause cell death. Similarly, overactivated mutants of the non-essential Staphylococcus aureus ClpC homolog cause uncontrolled proteolysis and severe toxicity in vivo. However, no chemical modulators of S. aureus ClpC have been described. Here, using a biochemical high-throughput screen, we identify eight distinct bona fide small molecules that stimulate ClpC ATPase and proteolytic activity in vitro. Structural, computational, and mutational analyses define two ligandable regulatory sites within the ClpC N-terminal domain (NTD) as compound targets: a conserved hydrophobic groove and an allosteric pArg1 pocket, both engaged in substrate recognition. These findings establish S. aureus ClpC as chemically targetable and provide mechanistic insight into its regulatory architecture, enabling future development and optimization of chemical probes to deregulate AAA+ protease control.
    Keywords:  AAA protein; ClpP; Hsp100; MoA; SAR; bacteria; chaperone; protease; protein degradation; protein quality control
    DOI:  https://doi.org/10.1016/j.isci.2026.117738
  53. Cell Rep. 2026 Oct 16. pii: S2211-1247(26)01233-7. [Epub ahead of print]45(10): 118154
    The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Juliette A Bokor, Vasiliya Kril, Cara Schiavon, Scott B Biering, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind.
      The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE2-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE2 acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE2 signaling and mtDNA-dependent STING activation and identify the COX2-PGE2-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.
    Keywords:  CP: immunology; EP4; STING signaling; antiviral innate immunity; cyclooxygenase-2; herpes simplex virus type 1; mitochondrial DNA; mitophagy; prostaglandin E2; protein kinase A; type I interferons
    DOI:  https://doi.org/10.1016/j.celrep.2026.118154
  54. Leuk Res. 2026 Oct 08. pii: S0145-2126(26)00180-3. [Epub ahead of print]170 108336
    Beyond the binding site: PROTAC-mediated protein degradation assists the therapeutic paradigm of hematological malignancies.
    Mahsa Fatahichegeni, Mohammad Amin Ansarian, Yuqi Wang, Tongxin Zhang, Ruimin Liu, Juan Ren, Xiaoning Wang.
      Hematological malignancies represent a growing global health burden, with conventional therapies limited by systemic toxicity and resistance mechanisms. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack cellular degradation machinery to eliminate, rather than merely inhibit, target proteins, enabling engagement of previously undruggable oncogenic drivers. This review synthesizes PROTAC applications across acute myeloid leukemia, lymphoid malignancies, and multiple myeloma, addressing targets including BRD4, FLT3, BCL-XL, BTK, and epigenetic regulators. Clinical advancement has been notable, with Bruton tyrosine kinase (BTK) degraders achieving response rates exceeding 75% in heavily pretreated patients and progressing to Phase 3 trials, while cereblon-targeting degraders in multiple myeloma represent the most clinically mature application. Mechanistically, PROTACs offer catalytic, substoichiometric activity, elimination of non-catalytic protein functions, and retention of efficacy against certain resistance mutations. Significant challenges persist, however, including poor drug-like properties, limited oral bioavailability, complex ternary-complex optimization, and degrader-specific resistance mechanisms such as E3 ligase loss or impaired proteasomal capacity, necessitating expanded biomarker surveillance frameworks. Emerging innovations, including degrader-antibody conjugates, novel E3 ligase recruiters, and artificial intelligence-driven design, aim to address these limitations. Integration with precision medicine and rational combination strategies positions targeted protein degradation as a potentially transformative approach for addressing longstanding unmet needs in blood cancer therapy, although substantial translational hurdles remain.
    Keywords:  BTK degrader; Hematological malignancies; PROTAC; Protein degradation; Targeted therapy
    DOI:  https://doi.org/10.1016/j.leukres.2026.108336
  55. Nat Commun. 2026 Sep 11. pii: 10718. [Epub ahead of print]17(1):
    RAISE quantifies RNA binding protein activity via transcriptomic profiling.
    Yilei Liu, Yingtung Lo, Youqi Zheng, Pinxin Xiong, Jianzhong Lu, Zhixing Feng, Huijuan Feng.
      Alternative splicing (AS) greatly expands proteomic diversity and is tightly regulated by RNA-binding proteins (RBPs), whose activities reflect both the direction and the strength of their regulatory influence. However, inferring RBP activity remains challenging owing to the incomplete characterization of RBP-splicing regulatory relationships and the lack of experimental approaches for direct activity measurement. Here, we present RAISE, a computational framework that integrates multimodal evidence including CLIP-seq, sequence motifs, and splicing alterations derived from RNA-seq data to identify RBP targets, construct RBP-exon regulatory networks and quantitatively infer RBP activity across conditions. The targets identified by RAISE recapitulate the known functions and characteristic regulatory patterns of RBPs. RAISE accurately inferred the activity of diverse RBPs across multiple cell lines and perturbation experiments, and effectively captured activity changes independent of RBP expression levels. When applied to The Cancer Genome Atlas (TCGA) datasets, RAISE revealed RBPs with altered activity in cancer, underscoring its potential for large-scale analyses of splicing regulation. Furthermore, we provide RAISEDB, a database of predicted RBP-exon interactions. Collectively, RAISE enables systematic quantification of RBP activity and illuminates splicing regulatory networks across biological and disease contexts.
    DOI:  https://doi.org/10.1038/s41467-026-77620-y
  56. EMBO Mol Med. 2026 Oct 14.
    RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
    Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii.
      Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s44321-026-00534-1
  57. Trends Mol Med. 2026 Oct 16. pii: S1471-4914(26)00230-3. [Epub ahead of print]
    Degradation-coupled antibody conjugates for precision cancer therapy.
    Xinlei Zhuang, Li Lin, Yiyi Zhang, Yifan Wang, Liqiang Pan.
      Antibody-drug conjugates (ADCs) are an important class of targeted cancer therapeutics that selectively deliver potent cytotoxic payloads to tumor cells through antibody-mediated targeting. However, the efficacy of some ADCs can be limited by inefficient target protein (e.g., membrane receptor) internalization and lysosomal trafficking, which determine intracellular payload release. In addition, persistent disease-driving proteins sustain oncogenic signaling, promoting tumor progression and therapeutic resistance. Recent advances in targeted protein degradation (TPD) offer a strategy to overcome these limitations by controlling the trafficking and degradation fate of target proteins. Building on the limitations of ADCs and the capabilities of TPD, we propose degradation-coupled antibody conjugates, a conceptual framework that integrates degradation-driven programmable protein fate control with antibody conjugates to enhance payload delivery and expand therapeutic functionality.
    Keywords:  antibody–drug conjugates; degradation-coupled antibody conjugates; degrader–degrader conjugates; degrader–drug conjugates; protein fate control; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.molmed.2026.09.014
  58. bioRxiv. 2026 Sep 28. pii: 2026.09.28.754909. [Epub ahead of print]
    P-body sequestration of clock transcripts delays repressor synthesis to set circadian period in Drosophila.
    Yangbo Xiao, Ye Yuan, Shrabastee Chakraborty, David Brooks, Swathi Yadlapalli.
      Negative-feedback oscillators require a delay between the accumulation of a repressor's mRNA and the action of its protein. In the circadian clock, this delay has been attributed largely to post-translational control of PERIOD (PER) stability and nuclear entry. The RNA-binding proteins shown to regulate per translation, ATAXIN-2 and its partners, promote it, leaving open whether any step holds clock transcripts back before they are translated. Here, using time-resolved miniTurbo proximity labeling of endogenous PER across four phases of the circadian cycle in Drosophila clock neurons, we define a 252-protein PER proximitome that partitions into a nuclear arm and a cytoplasmic RNA-metabolism arm. A behavioral RNAi screen identified two P-body components, the DEAD-box helicase Me31B (DDX6) and the 5'-3' exonuclease Pacman (Pcm; XRN1), as strong regulators of circadian rhythms. Using single-molecule RNA-FISH, proximity RNA editing and ribosome profiling, we show that as per and tim transcripts accumulate, they localize to Me31B-labeled P-bodies and are poorly translated, most prominently at ZT12. Me31B knockdown disrupts P-bodies and releases per mRNA from them, causing PER to accumulate earlier and to ∼2-fold higher levels, whereas Me31B overexpression delays PER accumulation and lengthens the free-running period by ∼2 h. Knockdown of Pcm, in contrast, impairs clearance of per mRNA, sustaining PER and TIM accumulation, prolonging the repression phase and abolishing cycling of ∼89% of rhythmic transcripts. Together, these findings identify P-body sequestration as a repressive step that delays repressor synthesis, and Pcm-dependent decay as required to end repression on time. Given the deep conservation of DDX6 and XRN1, RNP compartments may provide a conserved means of generating delay in circadian and other negative-feedback circuits.
    DOI:  https://doi.org/10.64898/2026.09.28.754909
  59. Commun Biol. 2026 Oct 06. pii: 1348. [Epub ahead of print]9(1):
    An ALLO-1-associated network links mitochondrial quality control to functional recovery in structurally compromised muscle.
    Anwesha Sarkar, Lilla Biriczová, Natalia A Szulc, Pankaj Thapa, Remigiusz Serwa, Wojciech Pokrzywa.
      Muscle function can recover before damaged contractile structures are fully repaired, but the mechanisms enabling this recovery remain poorly understood. Using a temperature-sensitive Caenorhabditis elegans model of UNC-45 dysfunction, in which impaired myosin chaperoning triggers muscle proteotoxic stress and reversible paralysis, we show that coordinated movement recovers while sarcomere disorganisation persists. Quantitative proteomics identified ALLO-1, a selective-autophagy receptor previously characterised for paternal organelle clearance during embryogenesis, as induced during recovery from UNC-45dependent muscle stress. Functional and proteomic analyses revealed an ALLO-1-associated regulatory network comprising IKKE-1, SIP-1, DIM-1 and CAR-1 that modulates mitochondrial stress responses and muscle recovery. Loss of ALLO-1 or its associated factors altered mitochondrial homoeostasis and delayed functional recovery, whereas muscle-specific ALLO-1a restoration improved recovery, preserved mitochondrial network integrity, and modulated mitochondrial turnover despite reduced respiratory capacity. These findings identify ALLO-1 as a regulator of mitochondrial stress adaptation that enables functional recovery before completing structural repair.
    DOI:  https://doi.org/10.1038/s42003-026-11093-z
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