bims-proteo Biomed News
on Proteostasis
Issue of 2026–04–05
fifty-six papers selected by
Eric Chevet, INSERM
  1. Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
  2. A neuropeptide regulates cell non-autonomous protein homeostasis.
  3. An interactome-based framework for DDB1- and CUL4-associated factor prioritization in targeted protein degradation.
  4. Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
  5. Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
  6. Small-molecule binding and sensing with a designed protein family.
  7. Lysosomal homeostasis at the crossroads of neurodegeneration.
  8. Signal peptide-directed proteins generated in the endoplasmic reticulum are secreted or degraded via the autophagic pathway.
  9. Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins.
  10. Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.
  11. A protein disulfide isomerase coordinates redox homeostasis and ER calcium regulation for optimal lytic cycle progression in Toxoplasma gondii.
  12. Single-molecule dissection of CFTR folding defects and pharmacological rescue.
  13. A current view on molecular mechanisms and machineries driving unconventional pathways of protein secretion.
  14. Structures of ZYG11B-EloB-EloC-substrate complex reveal mechanisms of CRL2ZYG11B assembly and function.
  15. Hippocampal BiP Overexpression Rescues Cognitive Performance and Increases REM theta in 3xTg Mouse Model of Alzheimer's Disease.
  16. Ligand-Induced Conformational Plasticity of the CTLH E3 Ligase Receptor GID4.
  17. STING is the scaffold protein for stress granule pre-condensation at the ER.
  18. A Deep-Learning Atlas of XPO1-Mediated Nuclear Export at Proteome Scale.
  19. Membrane Protein Insertion in Mammalian Cells.
  20. Intercompartmental communication in senescence.
  21. Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response.
  22. Extracellular Vesicle-Mediated Nucleolin Transfer in Glioblastoma: A Targetable Axis Driving Blood-Tumour Barrier Formation.
  23. Structures of folding intermediates on BAM show diverse substrates fold by a conserved mechanism.
  24. A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway.
  25. Assessing the suitability of deubiquitylases as substrates for targeted protein degradation.
  26. RNase L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA.
  27. Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
  28. SMURF2 attenuates NRF2-driven tumor progression by acting as a nuclear brake on NRF2 during cellular stress.
  29. Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System.
  30. Unexpected role of the integrated stress response in cancer immune evasion.
  31. Regulatory dynamics of monosomes and polysomes in cellular adaptation.
  32. Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion.
  33. PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion.
  34. A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.
  35. ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
  36. The ribosome-associated N-terminal acetyltransferase B coordinates global proteostasis and autophagy in plants by creating Ac/N-degrons.
  37. Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.
  38. Transcriptomic reprogramming of the medial amygdala in chronic stress: Implications of ER proteostasis and neuropeptide signaling for anxiety-like behaviors.
  39. Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation.
  40. Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation.
  41. Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer.
  42. Recent Advances in Small-Molecule Modulators Targeting IRE1α.
  43. ER-localized ceramide accumulation contributes to replicative senescence.
  44. Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome.
  45. TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.
  46. G/C-ending and synonymous codon bias define functional translational programs that shape human tissue and cancer proteomes.
  47. 2'-O-Methylation maintains ribosome structural and translation integrity.
  48. New PROTAC Designs for Targeted Protein Degradation in 2021-2025: Novel E3 Ligases and Pre-PROTACs.
  49. Ubiquitin ligases in plant immunity: structural mechanisms and signaling.
  50. A Novel Eukaryotic Ribosome Factor Enables Translation Restart Following Cellular Dormancy.
  51. BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia.
  52. AhR inhibition promotes axon regeneration via a stress-growth switch.
  53. Exploration of the proxiOME of large subunit ribosomal proteins reveals Acl1 and Bcl1 as cooperating dedicated chaperones of Rpl1.
  54. Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.
  55. Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
  56. Deltex E3 ubiquitin ligase 2 potentiates STING-mediated type I interferon response by K63-linked ubiquitination.
  1. bioRxiv. 2026 Mar 28. pii: 2026.03.27.714830. [Epub ahead of print]
    Dynamic UFMylation governs cellular fitness by coordinating multi-organelle proteostasis.
    Guy B Kunzmann, William E Leiter, Sophie E Durn, Amy M Weeks, Jason R Cantor.
      Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like protein (UBL) covalently attached to substrates through a dedicated enzymatic cascade (UFMylation) and removed by specific proteases. Despite a key role in endoplasmic reticulum (ER)-ribosome homeostasis, the basis by which this UBL supports cell fitness remains elusive, as the essentiality of UFMylation machinery varies widely across hundreds of cancer lines. Here, we trace a conditional dependence on the UFMylation pathway to the availability of alanine, an amino acid provided by human plasma-like medium but absent from most conventional synthetic media. We show that by facilitating the clearance of stalled ribosomes at the ER, dynamic UFMylation maintains cellular levels of glutamic-pyruvic transaminase 2 (GPT2), the primary enzyme responsible for de novo alanine synthesis in most human cancer lines. This buffering preserves the alanine pools required to sustain protein synthesis under alanine-restricted conditions. Beyond GPT2, UFM1 deficiency leads to widespread proteomic remodeling that spans diverse processes, including mitochondrial translation. Our results reveal that despite primarily targeting ER-localized ribosomes, the UFMylation system orchestrates a multi-organelle proteostasis network whose client composition and contributions to cell fitness are shaped by intrinsic factors and nutrient conditions.
    DOI:  https://doi.org/10.64898/2026.03.27.714830
  2. Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00285-8. [Epub ahead of print]45(4): 117207
    A neuropeptide regulates cell non-autonomous protein homeostasis.
    Carrie A Sheeler, Jacqueline Y Lo, Areebah Rahman, Saebom Kwon, Daviana Menendez Escalera, Emmett Griffin-Baldwin, Karmen Mah, Adam Roszczyk, Jennifer L Garrison, Ashley E Frakes.
      The coordination of proteostasis between the brain and peripheral tissues is essential for the health and survival of all animals. In C. elegans, glia coordinate organismal proteostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the signaling molecules required remain unknown. Here, we show that glial UPRER activation increases levels of specific neuropeptides. We identify a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER and protect against chronic ER stress. FLP-17 signals partially through the receptor, EGL-6, to activate transcellular UPRER and confer stress resistance. Both XBP-1 and PERK are required for maximal FLP-17-induced UPRER activation, though only XBP-1 is necessary for organismal ER stress resistance. This work reveals a complex neuropeptide network initiated by glial UPRER activation and identifies FLP-17 as a critical mediator that coopts an existing sensory-metabolic circuit to coordinate organismal proteostasis.
    Keywords:  C. elegans; CP: cell biology; ER stress; cell non-autonomous cellular signaling; cellular stress responses; endoplasmic reticulum; glia; neurons; neuropeptides; protein homeostasis; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.117207
  3. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00160-7. [Epub ahead of print]86(7): 1397-1416.e11
    An interactome-based framework for DDB1- and CUL4-associated factor prioritization in targeted protein degradation.
    Satoshi Yamanaka, Koya Nagaoka, Yuki Shoya, Kohei Nishino, Yumi Mikura, Kenshi Tanaka, Keisuke Konishi, Yoshinori Hasegawa, Atsushi Hijikata, Hidetaka Kosako, Tatsuya Sawasaki.
      The DDB1- and CUL4-associated factor (DCAF) family functions as substrate receptors within Cullin4-really interesting new gene (RING) ubiquitin ligases (CRL4s), facilitating proteasomal degradation of targeted substrates. Although CRL4-based targeted protein degradation (TPD) has emerged as a promising strategy to modulate undruggable proteins, the complex formation, substrates, and functional properties of many DCAFs remain poorly defined. In this study, using proximity biotinylation-based interactome analysis in human HEK293T cells, we systematically annotated interactors and functional associations of individual DCAFs. Furthermore, we identified substrates of the model DCAFs COP1 and DCAF3 using proximity biotinylation coupled with multi-omics approaches. By combining biochemical and cell-based analyses, we establish CRL4 complex formation and DCAF autodegradation as experimentally tractable proxy indicators to evaluate DCAF degradation activity and propose a set of high-activity DCAFs. These datasets establish a resource for functional characterization of DCAFs and provide a framework for their prioritization in TPD.
    Keywords:  AirID; BioID; CRL4; DCAF; E3 ligase; interactome; proteomics; proximity labeling; targeted protein degradation; ubiquitination
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.004
  4. Science. 2026 Apr 02. 392(6793): eaea8782
    Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.
    Lucas C Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W Dooling, Yuwei Liu, I-Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A Debeaubien, Tristan Croll, D John Lee, Christopher Arthur, Thomas E Dever, Peter Walter, Jin Chen, Adam Frost, Mauro Costa-Mattioli.
      The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice.
    DOI:  https://doi.org/10.1126/science.aea8782
  5. Mol Cell. 2026 Apr 02. pii: S1097-2765(26)00158-9. [Epub ahead of print]86(7): 1377-1396.e6
    Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains.
    Xiaoli Ma, Zhiyang Cheng, Hongyu Zhao, Huan Zhang, Ke Xiao, Jiali Xie, Yun Feng, Chun Yang, Yujie Feng, Xi Wang, Yaozu Xiang, Junjie Hu, Qiaoxia Zheng, Wei Ji, Hong Zhang.
      ER-phagy involves the selective autophagosomal engulfment of ER fragments, but the signaling events, selection mechanisms, and membrane source of ER-phagic autophagosomes remain elusive. Here, using state-of-the-art super-resolution multi-SIM imaging, we reveal that stresses (prolonged starvation, cholesterol dyshomeostasis, and high-Ca2+ insults) trigger the expansion of sheet ER subdomains containing high levels of luminal Ca2+ in mammalian cells, which are subsequently degraded by ER-phagy. Autophagosome formation and sequestration of ER sheets require the concerted actions of FAM134B and lipidated LC3, whereas the autophagy proteins ATG14 and ATG9 are partially dispensable. Electron microscopy and cryo-electron tomography show that the membranes of autophagosomes enclosing high-Ca2+-containing ER sheets are directly remodeled from the ER. The ER-localized cation channels PIEZO1 and TRPV1 are enriched at and mediate Ca2+ transients from high-Ca2+-containing ER sheets, triggering liquid-liquid phase separation of the autophagosome-initiating FIP200 complex to initiate ER-phagy. Thus, distinct mechanisms are employed for the formation of high-Ca2+-containing ER-enclosing autophagosomes and non-selective autophagosomes.
    Keywords:  Ca(2+); ER-phagy; FAM134B; FIP200; PIEZO1; TRPV1
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.002
  6. Nat Commun. 2026 Mar 28.
    Small-molecule binding and sensing with a designed protein family.
    Gyu Rie Lee, Samuel J Pellock, Christoffer Norn, Doug Tischer, Justas Dauparas, Ivan Anishchenko, Jaron A M Mercer, Alex Kang, Asim K Bera, Hannah Nguyen, Evans Brackenbrough, Banumathi Sankaran, Inna Goreshnik, Dionne Vafeados, Nicole Roullier, Hannah L Han, Brian Coventry, Hugh K Haddox, David R Liu, Andy Hsien-Wei Yeh, David Baker.
      The de novo design of small-molecule-binding proteins holds great promise as a potential tool to develop sensors on-demand for arbitrary small molecules. Here we combine deep learning and physics-based methods to generate a family of proteins with diverse and designable pocket geometries, which we employ to computationally design binders for six small-molecule targets. Biophysical characterization of the designed binders reveals nanomolar to low micromolar binding affinities and atomic-level design accuracy. Additionally, we use a cortisol binder to design a chemically induced dimerization (CID) system that enables the construction of a biosensor for cortisol detection. The approach described here demonstrates the potential of the NTF2 fold and deep learning-based protein design in sensor development, paving the way for future platforms to design binders and sensors for small molecules across analytical, environmental, and biomedical applications.
    DOI:  https://doi.org/10.1038/s41467-026-70953-8
  7. J Clin Invest. 2026 Apr 01. pii: e199845. [Epub ahead of print]136(7):
    Lysosomal homeostasis at the crossroads of neurodegeneration.
    Stefano De Tito, Sharon A Tooze.
      Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.
    DOI:  https://doi.org/10.1172/JCI199845
  8. Biochim Biophys Acta Mol Cell Res. 2026 Mar 27. pii: S0167-4889(26)00037-6. [Epub ahead of print]1873(4): 120140
    Signal peptide-directed proteins generated in the endoplasmic reticulum are secreted or degraded via the autophagic pathway.
    Taek-Yeong Kim, Ye-Jin Cho, Kwon-Yul Ryu.
      Signal peptides (SPs) are short N-terminal sequences that direct proteins to the endoplasmic reticulum (ER). After cleavage of the SP, these proteins are mostly trafficked to the Golgi apparatus for secretion. Lipocalin-2 (LCN2), a neurotoxic secretory protein, was recently identified as a target of autophagy. The presence of an SP is a prerequisite for secretion and autophagic degradation. Based on these observations, we investigated whether the SP of LCN2 is sufficient to enable proteins to be secreted or degraded via autophagy. We fused the SP of LCN2 to a non-secretory green fluorescent protein (GFP) and found that this ER-generated GFP was either secreted or degraded via autophagy. These results indicate that the LCN2-derived SP alone is sufficient to direct proteins to the ER and subsequent secretion or autophagic degradation. This dual regulation was abolished when the SP was deleted from LCN2. Notably, the effect was preserved even when the LCN2 SP was replaced with the SP from brain-derived neurotrophic factor, another secretory protein. These results suggest that SPs with different sequences can similarly direct proteins to the ER and subsequent secretion or autophagic degradation. Furthermore, we found that even when LCN2 reached the Golgi apparatus for secretion, it could also be degraded via autophagy. Thus, we propose that SP-directed and ER-generated secretory proteins can undergo autophagic degradation during ER-Golgi transport, including at the ER, the ER-Golgi intermediate compartment, or the Golgi apparatus. Taken together, degradation of secretory proteins via autophagy suggests implications for the potential control of secretory protein homeostasis.
    Keywords:  Autophagy; Brain-derived neurotrophic factor; Green fluorescent protein; Lipocalin-2; Secretion; Signal peptide
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120140
  9. Cell Chem Biol. 2026 Mar 27. pii: S2451-9456(26)00072-3. [Epub ahead of print]
    Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins.
    Camilla Gustafsen, Joachim Vilstrup, Marianne Kristensen, Ditte Køster, Jonas Lende, Casper Larsen, Amanda Simonsen, Astrid Graversen, Ditte Olsen, Lone T Pallesen, Christian B Vægter, Jean-Claude Kresse, Michael Schou, Kathrin Weyer, Anders Etzerodt, Johan Palmfeldt, Mathias Kaas, Omar Qureshi, Neale Harrison, Jamie Cowley, Nicholas Barnes, Franck Galland, Philippe Naquet, Sofia M M Mazarakis, Daniel Greve, Anna Quattropani, Paul Glossop, Gavin Whitlock, Klaus Th Jensen, Simon F Nielsen, Peder Madsen, Simon Glerup.
      Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a powerful therapeutic strategy for degrading difficult-to-drug cytosolic proteins in the proteasome. Here, we present a strategy for extracellular TPD by reshaping the interaction between the lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation followed by endocytosis and target degradation. SORTAC activity can be genetically encoded, demonstrated by converting an IgG-binding nanobody to an IgG-degrading nanobody or by chemical conjugation, enabling conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, we generated PROTAC-like small molecule SORTACs with nanomolar range potency against two inflammatory proteins, the cytokine TNFa and the membrane protein vanin-1. Our results demonstrate that SORTACs constitute a modular platform for rapid generation of degraders of extracellular targets and with the potential to have wide impact in drug discovery.
    Keywords:  drug discovery; extracellular TPD; lysosome sorting receptor; progranulin; sortilin; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.002
  10. Adv Sci (Weinh). 2026 Mar 31. e21101
    Endoplasmic Reticulum Geometry Dictates Neuronal Bursting via Calcium Store Refill Rates and Exposes Selective Neuronal Vulnerability.
    Valentina Davi, Pierre Parutto, Yuyi Zhang, Tasuku Konno, Cecile Crapart, Raquel Pereira, John P Franklin, Mosab Ali Awadelkareem, Daniel C Maddison, Michael J Devine, Edgar R Gomes, Joseph Chambers, Elena Koslover, Edward Avezov.
      The endoplasmic reticulum (ER)'s continuous morphology is tightly controlled by ER-shaping proteins, whose genetic or expression defects drive a spectrum of neurodegenerative disorders from Hereditary Spastic Paraplegia to Alzheimer's disease. Why perturbations in ER morphology manifest specifically in neurons remains unknown. Here, by coupling visualisation of global sub-Hz firing bursts to ER ultrastructural manipulations in human inducible Pluripotent Stem Cells (hiPSC)-derived cortical neurons, alongside physical simulations, we establish a key ER structure-function principle: neuronal ER architecture dictates Ca2+ replenishment speed. Altering ER structure hinders network ER luminal connectivity and Ca2+ propagation from refill points at plasma membrane contact sites, impairing the ER's capability to supply repetitive Ca2+ bursts. The ER morpho-regulatory control of Ca2+ refill speed thus constitutes a switch on neuronal activity. Further, perturbed ER shape also abolishes Ca2+ firing and contraction in primary skeletal muscle cells. These results expose the selective vulnerability of Ca2+-firing cells to ER structural disruptions, rationalizing ER dysfunction in neurodegeneration and unveiling a new role for the continuous ER morphology that could apply universally to Ca2+-firing cells.
    Keywords:  calcium oscillations; endoplasmic reticulum Ca2+ refill; endoplasmic reticulum morphology; human iPSC‐derived neurons; modelling; neurodegenerative diseases ; neuronal firing
    DOI:  https://doi.org/10.1002/advs.202521101
  11. mBio. 2026 Apr 01. e0312425
    A protein disulfide isomerase coordinates redox homeostasis and ER calcium regulation for optimal lytic cycle progression in Toxoplasma gondii.
    Katherine E Moen, Silvia N J Moreno.
      The endoplasmic reticulum (ER) maintains an oxidative environment that facilitates the formation of disulfide bonds, a critical process for proper protein folding. Protein disulfide isomerases (PDIs) are ER-resident enzymes that facilitate the formation, breakage, and rearrangement of disulfide bonds between cysteine residues, thereby stabilizing protein structures. Although PDIs are functionally diverse, they all contain at least 1 thioredoxin-like domain and most mediate disulfide exchange through their conserved CXXC motifs. The apicomplexan parasite, Toxoplasma gondii, infects approximately one-third of the world population, posing a significant risk to immunosuppressed individuals and unborn fetuses. The fast-replicating tachyzoite form engages in a lytic cycle, causing host tissue damage and contributing to pathogenesis. While approximately 26 PDIs are predicted to be present in T. gondii, their specific roles remain largely unexplored. In this study, we investigate TgPDIA3, a T. gondii PDI localized to the ER, along with several of its interacting protein substrates. We explore its role in ER redox activity and calcium sequestration and assess how these functions contribute to the parasite's lytic cycle.IMPORTANCEThe lytic cycle of Toxoplasma gondii is critical for parasite dissemination and disease progression in the host. Calcium signaling plays a crucial role in driving these processes; however, the molecules that control calcium storage and release remain poorly understood. The endoplasmic reticulum, likely the largest calcium reservoir in T. gondii, has been understudied in the context of calcium signaling. Here, we uncover a direct link between ER redox regulation and calcium homeostasis, showing that ER redox activity can influence calcium signaling events that govern microneme protein maturation and secretion, parasite invasion, and replication. Our findings indicate that redox-dependent calcium regulation in the ER contributes to control of the parasite lytic cycle and reveals a previously unrecognized mechanism that may influence parasite virulence.
    Keywords:  SERCA; Toxoplasma gondii; calcium homeostasis; endoplasmic reticulum; protein disulfide isomerase; redox regulation
    DOI:  https://doi.org/10.1128/mbio.03124-25
  12. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2528216123
    Single-molecule dissection of CFTR folding defects and pharmacological rescue.
    Sang Ah Kim, Jesper Levring, Jue Chen, Tae-Young Yoon.
      Cystic fibrosis is a lethal genetic disorder caused by misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, most commonly due to the ΔF508 mutation. Despite extensive study, CFTR's folding process has remained inaccessible to direct observation. Here, we apply single-molecule magnetic tweezers to resolve the complete folding trajectories of wild-type and ΔF508 CFTR with near-amino acid resolution. We find that CFTR follows a hierarchical, template-guided folding pathway in which N-terminal domains scaffold downstream folding. This mechanism tightly couples the free energy states of intermediates, allowing ΔF508-induced instability to propagate across the folding pathway. Pharmacological correctors, in synergy with ATP, reshape the entire folding energy landscape by catalyzing transitions rather than simply stabilizing end states. These long-range, allosteric effects reveal a folding-embedded regulatory network. Our work provides a quantitative framework for mapping multidomain protein folding and therapeutic rescue, offering a broadly applicable strategy for interrogating rare mutations and accelerating structure-based drug discovery.
    Keywords:  membrane protein folding; pharmacological rescue; single-molecule magnetic tweezers; ΔF508 CFTR
    DOI:  https://doi.org/10.1073/pnas.2528216123
  13. Curr Opin Cell Biol. 2026 Mar 28. pii: S0955-0674(26)00020-7. [Epub ahead of print]100 102632
    A current view on molecular mechanisms and machineries driving unconventional pathways of protein secretion.
    Yifei Pei, Ningning Guo, Min Zhang, Walter Nickel, Liang Ge.
      Unconventional protein secretion (UcPS) has emerged as a major route for exporting proteins that lack signal peptides and cannot enter the classical ER-Golgi pathway. UcPS comprises mechanistically diverse pathways involving either direct membrane translocation or vesicular intermediates. Direct export is exemplified by PI(4,5)P2-dependent FGF2 pore formation and gasdermin pores that release cytokines during pyroptosis. Vesicle-based routes include TMED-mediated translocation at the ER-Golgi intermediate compartment (ERGIC) feeding secretory autophagy carriers, GRASP-dependent CUPS that enable starvation-induced Golgi-bypassing secretion, and MAPS-mediated export of misfolded proteins via late endosomes. These pathways reveal a shared principle: cells deploy multiple, context-specific mechanisms to move proteins across membranes without classical signal peptides.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102632
  14. Nat Commun. 2026 Mar 31.
    Structures of ZYG11B-EloB-EloC-substrate complex reveal mechanisms of CRL2ZYG11B assembly and function.
    Ni Lin, Han Feng, Yushan Geng, Yina Gao, Miao Shi, Songqing Liu, Pu Gao, Yong Wang.
      ZYG11B is a substrate receptor of the Cullin2-RING E3 ligase (CRL2), mediating the Gly/N-degron pathway and contributing to diverse processes including cell cycle control, protein homeostasis, apoptosis, and innate immunity. While previous studies resolved the structure of its truncated ARM domain, how full-length ZYG11B coordinates substrate engagement and CRL2ZYG11B assembly remains unclear. Here, we present cryo-EM structures of full-length human ZYG11B in complex with the EloB-EloC adaptor and a Gly/N-degron peptide, revealing a seahorse-like architecture with distinct interfaces for adaptor and substrate binding. Unexpectedly, ZYG11B adopts both monomeric and dimeric assemblies, with the dimer stabilizing two substrate-binding sites in opposite orientations. Functional assays demonstrate that interfaces mediating adaptor recruitment, substrate binding, and dimerization are essential for substrate degradation, suggesting a dynamic mechanism involving both assembly states. These findings provide a structural framework for understanding CRL2ZYG11B-mediated ubiquitination and offer mechanistic insights that may inform the rational design of ZYG11B-based applications.
    DOI:  https://doi.org/10.1038/s41467-026-71318-x
  15. bioRxiv. 2026 Mar 25. pii: 2026.03.23.713240. [Epub ahead of print]
    Hippocampal BiP Overexpression Rescues Cognitive Performance and Increases REM theta in 3xTg Mouse Model of Alzheimer's Disease.
    William E Duncan, Polina Fenik, Ewa Strus, Sigrid Veasey, Nirinjini Naidoo.
      The accumulation of Aβ plaques and hyperphosphorylation of Tau neuropathologically characterize Alzheimer's disease (AD). Synaptic dysfunction and endoplasmic reticulum (ER) stress precede overt neuropathology. ER stress is characterized by the accumulation of unfolded/misfolded proteins, which leads to activation of the adaptive signaling pathway, the unfolded protein response (UPR). Chronic or unresolved ER stress, as in disease, is maladaptive and triggers the integrated stress response (ISR). We hypothesize that targeted attenuation of ISR activation would mitigate the early cognitive deficits and molecular pathology in the triple transgenic (3xTg) mouse model of AD. To test this hypothesis, we used an adeno-associated viral (AAV) vector to overexpress BiP, the key ER chaperone and UPR regulator, in the hippocampi of young 3xTg mice. BiP overexpression reduced phosphorylated PERK (pPERK), a marker of ISR activation, and increased synaptic proteins BDNF, PSD95, and choline acetyltransferase marker (ChAT). Hippocampal-dependent working memory, social memory, long-term spatial memory, and REM theta power were improved without changes in locomotion. BiP overexpression reduced neuroinflammation, as evidenced by a decrease in the astrocyte marker GFAP. Additionally, Aβ and Aβ42 levels were reduced in the hippocampus and cortex. Collectively, these findings indicate that modulation of ER stress via BiP overexpression ameliorates early cognitive and molecular alterations associated with AD.
    DOI:  https://doi.org/10.64898/2026.03.23.713240
  16. ChemMedChem. 2026 Apr 14. 21(7): e202500849
    Ligand-Induced Conformational Plasticity of the CTLH E3 Ligase Receptor GID4.
    Daria Kotlarek, Katarzyna Dudek, Bartosz Woźniak, Martyna W Pastok, Dmitrii Shishov, Sylvain Cottens, Michał Biśta, Emilia Krzywiecka, Karolina M Górecka-Minakowska, Kinga Jurczak, Tomáš Drmota, Justyna Adamczyk, Szymon Faliński, Daria Gajewska, Marta Klejnot, Aleksandra Król, Monika Cuprych-Belter, Iwona Mames, Arnaud Mathieu, Aleksandra Podkówka, Ziemowit Pokładek, Kamil Przytulski, Alicja N Skowron, Magdalena Sypień, Anna Szlachcic, Toshimitsu Takagi, Weronika Wanat, Igor H Wierzbicki, Janusz Wiśniewski, Michał J Walczak.
      The application of targeted protein degradation is currently constrained by the limited availability of low-molecular-weight molecules that can recruit E3 ligases other than CRBN (Cereblon) or VHL (von Hippel-Lindau ligase). In this study, we present the structure-based drug design of high-affinity ligands that engage E3 ligase GID4 (glucose-induced degradation protein 4) in biophysical and cellular experiments. Through structural studies and molecular modeling, we identified three clusters of compounds that induce distinct conformations of GID4. We characterized potential exit vectors and used the most promising ligand as a building block to prepare bifunctional degraders in the form of proteolysis-targeting chimeras (PROTACs). Although ternary complex formation was successful in vitro, degradation of BRD4 was not observed, highlighting the need for further optimization of the degraders. Finally, we theoretically investigated the likelihood of the identified GID4 conformations participating in protein-protein interactions mediated by molecular glue mechanisms. We believe the expanded ligand diversity discovered in this study may pave the way for tuning the selectivity and efficacy of interactions involving GID4 and its neosubstrates.
    Keywords:  GID/CTLH E3 ligase; GID4; ligand; targeted protein degradation
    DOI:  https://doi.org/10.1002/cmdc.202500849
  17. Cell Death Differ. 2026 Apr 01.
    STING is the scaffold protein for stress granule pre-condensation at the ER.
    Eunchong Eom, Jihyun Kim, Jaehoon Kim, Suk-Jo Kang.
      Stress granules (SGs) are dynamic, membraneless ribonucleoprotein condensates that assemble in response to cellular stress and coordinate diverse cellular stress responses and diseases. Although SG have been reported to associate with the endoplasmic reticulum (ER), how ER-localized stress granule assembly is organized and regulated remains unclear. STING (stimulator of interferon genes) is a central innate immune adaptor that has recently been implicated in diverse non-canonical cellular functions, yet its potential link to SG regulation has not been established. Independent of its canonical functions in innate immune signaling, we identified a novel role of STING as a regulator of SG formation. We found that prior to stress stimulation, STING interacts with key SG core components G3BP1 and UBAP2L via its C-terminal domain (CTD) at the ER, forming a pre-condensation complex that facilitates SG maturation in response to stress. Loss of STING reduces SG formation and increases stress-induced cell death, whereas ER-anchored STING CTD is sufficient to reverse them. Mechanistically, STING enhances basal interactions between G3BP1 and UBAP2L, lowering the threshold for SG maturation upon stress. In addition, STING promotes the pathologic effects of TDP-43 mutations associated with amyotrophic lateral sclerosis. Our findings implicate STING as an ER-resident regulator of SG dynamics that contributes to neurodegenerative pathology, highlighting it as a potential therapeutic target in diseases associated with aberrant SG assembly.
    DOI:  https://doi.org/10.1038/s41418-026-01734-5
  18. bioRxiv. 2026 Mar 26. pii: 2026.03.25.713363. [Epub ahead of print]
    A Deep-Learning Atlas of XPO1-Mediated Nuclear Export at Proteome Scale.
    Sajina Dhungel, Sihara de Zoysa, DeAnna Burns, Linden McGregor, R P Rajesh, Ridila Alam, Diya Arain, Vivaan Bhaskar, Jayden Jeong, Aarush Kikani, Eashan Kolli, Zain Mardini, Aanya Parasramka, Eden Potterton, Saachi Thomas, Chintan K Kikani.
      Exportin 1 (XPO1/CRM1) is the principal nuclear export receptor for cargos bearing hydrophobic nuclear export sequences (NESs). Dysregulation of XPO1-dependent export is implicated in cancer, neurodegeneration, and other diseases, yet a comprehensive view of XPO1 function remains limited by the poor reliability of sequence-based NES prediction. Existing predictors are largely derived from a small set of XPO1-cargo structures and are therefore biased toward canonical docking geometries, limiting their ability to detect NESs that engage XPO1 through noncanonical pocket-occupancy patterns. We hypothesized that deep learning-based structural modeling could overcome this limitation by directly sampling binding geometries. Using AlphaFold 3, we modeled full-length cargo-XPO1-RanGTP complexes for more than 4,000 human proteins and identified over 3,000 previously uncharacterized, high-confidence NESs. Integration of AlphaFold predictions with unsupervised structural geometry analysis and experimental validation identified both canonical NESs and noncanonical sequence patterns exhibiting atypical anchor-residue usage, expanding the structural language of XPO1-recognized NESs. Groove-resolved contact maps further revealed helix rotation within the export groove as a regulatory feature that can rewire pocket usage without altering the core NES sequence, enabling PTM- and cofactor-sensitive tuning of export strength. This exportome atlas resolves many previously ambiguous or unidentified NESs in disease-associated proteins and across major cellular systems, including centrosome organization, mRNA processing, ubiquitin signaling, kinase networks, ribosome quality control, and macroautophagy. We further identified recurrent NES-NLS tandem motifs encoded in primary sequence, suggesting coordinated regulation of nucleocytoplasmic transport. Together, our deep learning-based exportome atlas, integrated with NLS maps and accessible through a web-searchable resource, defines an expanded and regulatable code of nuclear transport at proteome scale and offers a framework for dissecting nuclear trafficking and its dysregulation in human disease.
    DOI:  https://doi.org/10.64898/2026.03.25.713363
  19. Annu Rev Biochem. 2026 Mar 30.
    Membrane Protein Insertion in Mammalian Cells.
    Alina Guna, Vy N Nguyen, Taylor A Stevens, Rebecca M Voorhees.
      Integral membrane proteins play critical roles in mammalian cells, ranging from mediating cell-cell interactions to regulating apoptosis. These increasingly diverse functions necessitated the evolution of membrane proteins with more complex biophysical properties and architectures. In turn, specialized complexes called insertases have coevolved to integrate these proteins into the appropriate lipid bilayer. Notably, key sites of membrane protein biogenesis such as the endoplasmic reticulum and the outer and inner membranes of the mitochondria rely on distinct sets of insertases that work in concert, each specializing in membrane protein segments with particular features or properties. Here, we describe recent discoveries that shed light both on the molecular mechanisms of these insertases and on the many distinct pathways required for the insertion and folding of the mammalian membrane proteome.
    DOI:  https://doi.org/10.1146/annurev-biochem-080125-020218
  20. FEBS Open Bio. 2026 Mar 30.
    Intercompartmental communication in senescence.
    Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng, Myriam Gorospe.
      Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.
    Keywords:  Golgi; SASP; endoplasmic reticulum; interorganellar communication; organelles; senescence
    DOI:  https://doi.org/10.1002/2211-5463.70236
  21. PLoS Biol. 2026 Apr 02. 24(4): e3003747
    Specificity and recognition of the ADP-ribosyl-ubiquitin modification in the DNA damage response.
    Chatrin Chatrin, Kang Zhu, Michael D R Simmons, Lucy Maginn, Kira Schützenhofer, Yang Lu, Nina Đuki, Sven Wijngaarden, Max S Kloet, Katarzyna Wiktoria Kliza, Gerbrand J van der Heden van Noort, Dmitri V Filippov, Dragana Ahel, Rebecca Smith, Ivan Ahel.
      ADP-ribosylation (ADPr) is a post-translational modification that has regulatory roles in multiple cellular pathways including the DNA damage response and in innate immunity. Recently, it has been uncovered that ADP-ribose can be further modified by a family of ubiquitin E3 ligases, the DELTEXES, which catalyze ubiquitin transfer directly onto ADP-ribose, creating a hybrid ADPr-Ub modification which can be recognized by proteins with dedicated ADPr-Ub binding domains. With this hybrid modification recently been identified in cellular systems, we use a series of in vitro and cellular assays in human cells to investigate the amino acid preference for ADPr-Ub production as well as conditions required for reversal of the modification. We show that ADPr on both serine and glutamate-linked peptides can be ubiquitinated by the RING-DTC domains of DTX2 and DTX3L in vitro and that this can be recognized by RNF114, RNF138 and RNF166 for ubiquitin chain elongation. Finally, we demonstrate that DTX2 rather than DTX3L plays a role in ADPr-Ub production at sites of DNA damage to promote the recruitment of RNF114, RNF138, and RNF166 in an HPF1-independent manner.
    DOI:  https://doi.org/10.1371/journal.pbio.3003747
  22. J Extracell Vesicles. 2026 Apr;15(4): e70268
    Extracellular Vesicle-Mediated Nucleolin Transfer in Glioblastoma: A Targetable Axis Driving Blood-Tumour Barrier Formation.
    Hongzhen Chen, Junyi Zhao, Fang Qiu, Zhuqian Wang, Jie Li, Lingqiang Zhang, Aiping Lu, Chao Liang.
      Glioblastoma (GBM) remains a significant therapeutic challenge. While GBM-derived extracellular vesicles (EVs) are known to remodel the normal blood-brain barrier (BBB) into a blood-tumour barrier (BTB), the underlying mechanism is largely not understood. Here, we reveal that nucleolin (NCL) is transferred via GBM-derived EVs to the surface of brain endothelial cells, where it promotes BTB formation. Furthermore, the NCL-specific aptamer AS1411 exploits this pathway, crossing the BTB through receptor-mediated transcytosis and selectively entering GBM cells in an NCL-dependent manner. Proteolysis-targeting chimeras (PROTACs), heterobifunctional molecules that recruit E3 ligases to degrade target proteins, show therapeutic potential but are hindered by inefficient brain penetration in GBM. Capitalizing on the BTB-penetrating capability of AS1411 and our prior finding that AS1411 can intracellularly recruit the E3 ligase MDM2 via employing NCL as a molecular bridge, we engineered AS1411-based PROTACs against VEGFR2 and EGFR. These PROTACs induced NCL- and MDM2-dependent ubiquitination and degradation of VEGFR2 or EGFR in GBM cells, demonstrating potent anti-tumour activity. Collectively, our findings identify EV-transferred NCL as a key mediator of BTB formation and a functional transcytosis receptor for AS1411, providing a promising strategy for developing BTB-permeable, targeted therapy for GBM.
    Keywords:  AS1411; PROTACs; blood‐tumour barrier; glioblastoma; nucleolin
    DOI:  https://doi.org/10.1002/jev2.70268
  23. Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2534936123
    Structures of folding intermediates on BAM show diverse substrates fold by a conserved mechanism.
    Benjamin D Thomson, Melissa D Marquez, Shaun Rawson, Thiago M A Dos Santos, Stephen C Harrison, Daniel Kahne.
      The outer membranes of mitochondria, chloroplasts, and Gram-negative bacteria contain β-barrel membrane proteins that are assembled by conserved multisubunit machines. In bacteria, the β-barrel assembly machine (BAM) folds over a hundred compositionally different substrates into barrels that vary greatly in size. Some larger barrels require globular proteins to plug the barrel lumen. How a single machine can assemble such different barrels is unknown. Here we report three structures representing progressively folded stages of a 16-stranded barrel engaged with BAM, as well as the structure of a late-stage folding intermediate of a 26-stranded substrate folding around its soluble lipoprotein plug on BAM. We find that BAM catalyzes folding of these substrates by a uniform mechanism in which BAM undergoes major distortions to accommodate the nascent barrel.
    Keywords:  beta-barrel assembly machine; cryo-electron microscopy; folding intermediates; protein folding
    DOI:  https://doi.org/10.1073/pnas.2534936123
  24. Cell Chem Biol. 2026 Apr 02. pii: S2451-9456(26)00077-2. [Epub ahead of print]
    A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway.
    Bide Tong, Yulei Wang, Junyu Wei, Zixuan Ou, Huaizhen Liang, Jie Lei, Dingchao Zhu, Hanpeng Xu, Lei Tan, Zhiwei Liao, Cao Yang.
      Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication. However, the mechanisms governing their degradation remain poorly understood. In this study, we demonstrated that EVs are predominantly degraded via the lysosomal pathway. Mechanistically, MAP1LC3B recognizes SNX18 on the surface of endosome-escaped EVs to facilitate their sorting into the autolysosomal pathway for degradation. Leveraging this mechanism, we optimized the lysosomal sorting efficiency of EVs by surface display of LIR motifs and constructed an EV-based targeted protein degradation nanoplatform. The EV-based nanoplatform is highly modular and can be combined with monoclonal antibodies in a plug-and-play manner. It demonstrated remarkable efficiency and selectivity in degrading EGFR, PD-L1, and VEGF. Moreover, the nanoplatform demonstrated multi-targeting capability by simultaneously degrading EGFR and VEGF. Our findings uncover a previously unrecognized mechanism of EVs degradation and provide a novel strategy to harness the EVs degradation machinery as a nature-inspired nanoplatform for the degradation of multiple targeted proteins.
    Keywords:  autophagy; extracellular vesicles; lysosome; nanopartcles; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.007
  25. Cell Chem Biol. 2026 Apr 01. pii: S2451-9456(26)00100-5. [Epub ahead of print]
    Assessing the suitability of deubiquitylases as substrates for targeted protein degradation.
    Joel Tong, J Monty Watkins, James M Burke, Thomas Kodadek.
      The development of selective inhibitors of deubiquitylase enzymes (DUBs) is difficult due to a high level of homology in the active sites of the ≈100 such enzymes in the human proteome. A potential way to achieve this in a more facile manner would be to develop proteolysis-targeting chimera (PROTAC) or molecular glues that engage the target DUB in a less conserved region outside of the catalytic domain. However, this raises the concern that auto-deubiquitylation would make DUBs poor substrates for this modality. Here, we describe a chemical genetics system to evaluate this issue. We find that some DUBs are readily degradable via the Ubiquitin-proteasome pathway, and some are not. Of the latter category, some resist turnover through auto-deubiquitylation, and some are simply poor proteasome substrates.
    Keywords:  PROTAC; degradation; deubiquitylase; targeted protein
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.009
  26. bioRxiv. 2026 Mar 23. pii: 2026.03.21.713401. [Epub ahead of print]
    RNase L Regulates Antiviral Responsiveness through Cleavage of XBP1 mRNA.
    Yoshika Takenaka, Yasutoshi Akiyama, Tsubasa Inaba, Daiki Shinozuka, Katsuki Aoyama, Ransu Ogasawara, Nana Kunii, Takaaki Abe, Eiji Morita, Yoshihisa Tomioka, Pavel Ivanov.
      During viral infection, viral replication perturbs endoplasmic reticulum (ER) homeostasis and triggers the unfolded protein response (UPR). XBP1s, a transcription factor generated by one branch of the UPR, is known to potentiate both innate and adaptive immunity, but its role in antiviral responses remains incompletely understood beyond its ability to augment type I interferon (IFN) mRNA induction. Here, we show that XBP1s positively regulates the RIG-I-like receptors (RLRs), ribonuclease L (RNase L), and protein kinase R (PKR) pathways, indicating that it enhances all three major antiviral response pathways. We further show that RNase L activation rapidly decreases XBP1 mRNA levels in an RNase activity-dependent manner, leading to a prompt reduction in XBP1s expression. Consistent with this, RNase L deletion significantly increased both thapsigargin-mediated XBP1s induction and XBP1s expression following Japan encephalitis virus infection. Poly(I:C)-induced IFNB mRNA expression was significantly enhanced in RNase L-knockout cells. This enhancement was completely abolished by RNase L reconstitution. XBP1 knockdown also significantly attenuated IFNB mRNA expression in RNase L-knockout cells. These findings suggest a negative-feedback loop in which RNase L suppresses XBP1s, thereby fine-tuning antiviral responsiveness during viral infection.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.03.21.713401
  27. Aging Cell. 2026 Apr;25(4): e70452
    Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
    Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.
      Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.
    Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine
    DOI:  https://doi.org/10.1111/acel.70452
  28. Redox Biol. 2026 Feb 28. pii: S2213-2317(26)00100-X. [Epub ahead of print]92 104102
    SMURF2 attenuates NRF2-driven tumor progression by acting as a nuclear brake on NRF2 during cellular stress.
    Wanting Xu, Lei Dong, Jiaqian Li, Shuai Fan, Yadong Wang, Qin Xia.
      Constitutive activation of the transcription factor NRF2 confers therapeutic resistance in glioblastoma (GBM), however, this hyperactivation frequently persists despite the presence of intact KEAP1, suggesting the existence of KEAP1-independent regulatory mechanisms. Here, we identify the E3 ubiquitin ligase SMURF2 as a key nuclear regulator that restricts NRF2 activity and attenuates tumor progression. We demonstrate that SMURF2 overexpression suppresses the NRF2-mediated adaptive response to oxidative and proteotoxic stress, thereby reducing protein aggregation and promoting apoptosis. Mechanistically, cellular stress triggers the nuclear translocation of SMURF2, where it interacts with and degrades nuclear NRF2 via K48-linked polyubiquitination, independently of the canonical KEAP1 pathway. Consequently, a mutation in the nuclear localization sequence (NLS) of SMURF2 prevents its nuclear localization and fails to degrade NRF2. Additionally, the expression of an ubiquitination-resistant NRF2 mutant (K555R) prevents NRF2 degradation and abolishes stress-induced apoptosis. Clinically, high SMURF2 expression correlates with improved survival in patients with GBM exhibiting constitutive NRF2 activation. These findings uncover a novel axis of NRF2 regulation and highlight SMURF2 as a potential therapeutic target for NRF2-driven malignancies.
    Keywords:  Glioblastoma; NRF2; Nucleus ubiquitination; Protein aggregates; SMURF2; UPS
    DOI:  https://doi.org/10.1016/j.redox.2026.104102
  29. bioRxiv. 2026 Mar 26. pii: 2026.03.23.713741. [Epub ahead of print]
    Pan-cancer proteogenomic interrogation of the Ubiquitin Proteasome System.
    Tania J Gonzalez Robles, Paul Sastourne-Haletou, Maha Khan, Marisa Triola, Yuki Kito, Aron Bartha, Hua Zhou, Sharon Kaisari, David Fenyo, Gergely Rona, Yadira Soto-Feliciano, Benjamin Neel, Kelly Ruggles, Michele Pagano.
      Components of the Ubiquitin Proteasome System (UPS) are attractive candidates for targeted protein degradation therapies owing to their key roles in maintaining protein homeostasis in healthy and malignant cells. How cancer driver mutations rewire UPS components to support tumor growth and survival remains incompletely understood. By mapping tissue- and cancer-specific expression of UPS components across more than 20 tissues and 10 tumor types using harmonized multiomic datasets, we present an integrated pan-cancer proteogenomic analysis focused on E3 ubiquitin ligases. These analyses uncovered (1) mutation-associated UPS protein level changes; (2) clinically actionable E3s based on recurrent alterations, tissue-enriched expression, and prognostic value; and (3) E3 regulatory networks based on co-expression, co-dependency, and protein-protein interactions. We also introduce UbiDash, an interactive platform for exploring UPS alterations across cancers. This study identifies clinically relevant E3s and mutation-defined proteostatic dependencies and provides resource for mechanistic insight and therapeutic prioritization of UPS components in cancer.
    DOI:  https://doi.org/10.64898/2026.03.23.713741
  30. Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]
    Unexpected role of the integrated stress response in cancer immune evasion.
    Lucia Borriello, Lorenzo Galluzzi.
      Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.
    Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
  31. J Biochem. 2026 Apr 01. pii: mvag026. [Epub ahead of print]
    Regulatory dynamics of monosomes and polysomes in cellular adaptation.
    Hirotatsu Imai, Akio Yamashita.
      Cytosolic 80S ribosomes have long been considered a uniform translation apparatus, with the only distinction being that they exist as either monosomes or polysomes. However, emerging evidence has revealed that monosomes and polysomes exhibit distinct translational profiles, contributing to selective protein synthesis and localized messenger RNA (mRNA) translation in specific subcellular compartments in mammals. When mammalian cells encounter environmental or metabolic stress, global gene expression is dynamically reprogrammed, accompanied by a marked shift in the monosome-to-polysome ratio, suggesting context-dependent roles for monosome- and polysome-mediated mRNA translation in cellular adaptation. In parallel, accumulating evidence indicates that distinct types of eukaryotic non-translating monosomes are formed under various biological conditions. Moreover, monosomes participate in the first round of mRNA translation on newly synthesized mRNAs, a process coupled with several early events such as nonsense-mediated mRNA decay and messenger ribonucleoprotein (mRNP) remodeling. In this review, we summarize current advances in understanding the roles of monosomes as crucial regulatory layers that shape the proteome across diverse physiological conditions in mammals.
    Keywords:  mRNA translation; monosome; polysome; ribosome
    DOI:  https://doi.org/10.1093/jb/mvag026
  32. Neurochem Int. 2026 Mar 31. pii: S0197-0186(26)00044-6. [Epub ahead of print] 106153
    Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion.
    Masaru Fujiwara, Ryohei Sakai, Masayuki Takahashi, Gen Matsumoto, Tadafumi Hashimoto, Tomohiro Kabuta.
      Mutations in components of the endosomal sorting complex required for transport (ESCRT)-III, such as CHMP2B and VPS4A/B, are known to cause neurological disorders, including frontotemporal lobar degeneration (FTLD) and developmental encephalopathies. Although ESCRT complexes are required for macroautophagy and for certain forms of microautophagy, the effects of ESCRT-III dysfunction on intracellular protein degradation remain unclear. In this study, we investigated how ESCRT-III dysfunction affects intracellular protein clearance using multiple genetic manipulations, including a dominant-negative form of VPS4 and an FTLD-associated CHMP2B mutant. We found that despite marked suppression of macroautophagic flux, inhibition of ESCRT-III promoted protein clearance in multiple cell types, including Neuro2a cells. Such clearance was also observed in ATG13- or ATG5-knockout cells, confirming that this process occurs independently of macroautophagy. Imaging revealed increased punctate accumulation of substrate proteins in lysosomes, suggesting the activation of a microautophagy-like pathway independent of ESCRT-III. In addition, ESCRT-III inhibition enhances extracellular vesicle-independent protein secretion. Cell-to-cell transmission of aggregated tau, assessed using conditioned medium, was also promoted by ESCRT-III inhibition. These findings suggested that ESCRT-III dysfunction, while impairing canonical autophagy, paradoxically activates alternative degradation and secretion pathways that may contribute to the pathogenesis of neurological disorders.
    Keywords:  ESCRT; autophagy; lysosome; microautophagy; neurodegenerative disorder
    DOI:  https://doi.org/10.1016/j.neuint.2026.106153
  33. Cell Death Differ. 2026 Apr 02.
    PINK1 and STUB1 pathway orchestrates peroxisomal selective autophagy by PEX13 depletion.
    Doo Sin Jo, Na Yeon Park, Ae-Kyeong Kim, Sunhoe Bang, Yong Hwan Kim, Ji-Eun Bae, Kyunghee Noh, Jeong-Hoon Kim, Min Jae Lee, Seong-Kyu Choe, Peter K Kim, Jongkyeong Chung, Kyu-Sun Lee, Dong-Hyung Cho.
      Peroxisomes are dynamic organelles essential for lipid metabolism, oxidative balance, and cellular stress responses. Their dysfunction contributes to various diseases, including metabolic and neurodegenerative disorders. Selective autophagy, or pexophagy, preserves peroxisomal quality by removing damaged or excess peroxisomes. Here, we propose a novel ATM-PINK1-STUB1-ABCD3-SQSTM1 signaling cascade that orchestrates pexophagy in response to peroxisomal impairment. Through siRNA screening, we find that PINK1 is a key regulator of pexophagy induced by PEX13 depletion. PINK1 phosphorylates STUB1, enhancing its E3 ligase activity to ubiquitinate ABCD3, which in turn recruits SQSTM1 for peroxisomal degradation. We further identify that ATM activates PINK1 under peroxisomal stress, linking cellular stress signaling to organelle quality control. These findings provide new insights into the molecular mechanisms underlying peroxisome turnover and may have implications for therapeutic strategies targeting diseases related to peroxisomal dysfunction.
    DOI:  https://doi.org/10.1038/s41418-026-01726-5
  34. Nat Commun. 2026 Mar 31. pii: 2699. [Epub ahead of print]17(1):
    A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.
    Farzaneh S Mirfakhar, Jacob A Marsh, Chihiro Sato, Kylie J Schache, Miguel A Minaya, Roland E Dolle, Stephen C Pak, Gary A Silverman, David H Perlmutter, Shannon L Macauley, Celeste M Karch.
      Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.
    DOI:  https://doi.org/10.1038/s41467-026-70473-5
  35. bioRxiv. 2026 Mar 28. pii: 2026.03.27.711928. [Epub ahead of print]
    ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
    Amber Crabtree, Mohd Mabood Khan, Estevao Scudese, Calixto Pablo Hernandez Perez, Prasanna Venkhatesh, Andrea G Marshall, Benjamin Rodriguez, Edgar Garza Lopez, Okwute M Ochayi, Estélio Henrique Martin Dantas, Pamela Martin, Matheus Baffi, Fabiana Scartoni, Margaret Mungai, Kit Neikirk, Jennifer Streeter, Renata Oliveira Pereira, Dao Fu Dai, Han Le, Harrison Mobley, Jeremiah Afolabi, Bret C Mobley, Celestine N Wanjalla, Duane Hall, Julia Berry, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Prasanna Katti, Chantell Evans, Andre Kinder, Joyonna Gamble George, Melanie McReynolds, Annet Kirabo, Sepiso Kenias Masenga, Antentor Hinton.
      Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations remain incompletely understood. The aim of this study was to investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aging muscle using complementary human population and mouse model approaches. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including decreased volume, surface area, and branching index, as well as a shift toward smaller, more fragmented, and spherical mitochondria. These structural changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.
    DOI:  https://doi.org/10.64898/2026.03.27.711928
  36. Nat Commun. 2026 Mar 31. pii: 3116. [Epub ahead of print]17(1):
    The ribosome-associated N-terminal acetyltransferase B coordinates global proteostasis and autophagy in plants by creating Ac/N-degrons.
    Xiaodi Gong, Marlena Pożoga, Jean-Baptiste Boyer, Yuxing Xue, Thierry Meinnel, Tanja Bange, Carmela Giglione, Rüdiger Hell, Markus Wirtz.
      The N-terminal acetyltransferase B (NatB) acetylates ~20% of the eukaryotic proteome. However, the role of NatB-mediated N-terminal acetylation (NTA) for the regulation of the proteome fate remains unclear in eukaryotes. In this study, we demonstrate that CRISPR-Cas9-mediated deletion of NatB activity in plants results in significantly lowered global protein turnover due to decreased ubiquitin-proteasome system (UPS) activity and protein translation. Quantitative proteomics uncovers that NatB substrates are significantly enriched in the fraction of stabilized proteins in natb mutants. We provide direct evidence that the absent NTA of KIN11, a subunit of the autophagy-controlling energy sensor SnRK1, protects it from UPS-mediated destruction. The resulting accumulation of KIN11 is responsible for the increased resistance of natb mutants to energy limitation induced by prolonged darkness. Our findings establish NatB as a central regulator of UPS-autophagy interplay and highlight its role in maintaining proteome stability and enabling dynamic stress responses in plants.
    DOI:  https://doi.org/10.1038/s41467-026-71208-2
  37. FEBS Open Bio. 2026 Mar 30.
    Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.
    Sandesh Neupane, Lea Nikolić, Lorenzo Maraio, Thomas Goiran, Nathan Karpilovsky, Stefano Sellitto, Vangelis Bouris, Jiang-An Yin, Ronald Melki, Edward A Fon, Adriano Aguzzi, Elena De Cecco.
      In Parkinson's disease and other synucleinopathies, αSynuclein (αSyn) misfolds and forms Ser129-phosphorylated aggregates (pSyn129) with the factors controlling this process largely unknown. Here, we used arrayed CRISPR-mediated gene activation and ablation to discover new pSyn129 modulators. Using quadruple-guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondria, trafficking, and motility functions in HEK293 cells. After exposure of cells to αSyn fibrils, pSyn129 signals were recorded by high-throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn129 was increased by activating the mitochondrial protein OXR1, which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn129 was reduced by ablation of the endoplasmic reticulum (ER)-associated protein EMC4, which enhanced ER-driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn129 across diverse αSyn polymorphs. These findings were confirmed in human iPSC-derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in αSyn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.
    Keywords:  CRISPR screening; autophagy‐lysosomal pathway; mitochondrial dysfunction; neurodegeneration; synucleinopathies; αSynuclein aggregation
    DOI:  https://doi.org/10.1002/2211-5463.70233
  38. J Affect Disord. 2026 Mar 31. pii: S0165-0327(26)00571-9. [Epub ahead of print] 121720
    Transcriptomic reprogramming of the medial amygdala in chronic stress: Implications of ER proteostasis and neuropeptide signaling for anxiety-like behaviors.
    Shengru Hu, Zixu Zhang, Hao Li, Yihan Tian, Wei Xie, Mingdao Mu.
      Chronic stress is a pivotal risk factor for the etiology of anxiety disorders. However, the molecular maladaptations within the medial amygdala (MeA) remain insufficiently characterized. Here, we investigated the MeA transcriptomic landscape to elucidate mechanisms underlying stress-induced anxiety and identify potential therapeutic targets. We established a mouse model using a 10-day chronic restraint stress paradigm, which resulted in robust anxiety-like phenotypes validated by multiple behavioral tests. RNA sequencing identified 193 differentially expressed genes. Bioinformatic analyses revealed a dominant upregulation of endoplasmic reticulum (ER) protein processing and chaperone-mediated refolding. This indicates a coordinated transcriptional upregulation of endoplasmic reticulum proteostasis components, consistent with an adaptive response to proteotoxic stress. Beyond proteostasis, the MeA transcriptome exhibited significant transcriptional reprogramming in neuroactive ligand-receptor interactions, synaptic organization, and lipid metabolism. Network analysis further pinpointed two functional modules: a highly connected ER chaperone hub centered on Hspa5 (BiP) and a neuropeptide signaling cluster involving Nms, Kng2, Agt, and Pmch. Importantly, site-specific pharmacological inhibition of Hspa5 within the MeA successfully attenuated CRS-induced anxiety-like behaviors. Collectively, these findings demonstrate that chronic stress orchestrates extensive transcriptomic reprogramming in the MeA characterized by the recruitment of proteostasis mechanisms and neuropeptide reorganization. Our study highlights Hspa5-mediated regulation as a promising mechanistic target with functional/causal evidence for the treatment of anxiety disorders.
    Keywords:  Anxiety disorders; Chronic stress; Endoplasmic reticulum; Hspa5; Medial amygdala; RNA sequencing
    DOI:  https://doi.org/10.1016/j.jad.2026.121720
  39. bioRxiv. 2026 Mar 23. pii: 2026.03.19.712761. [Epub ahead of print]
    Loss of Lamp2a-dependent chaperone-mediated autophagy drives dry AMD-like retinal pathology in mice and is rescued by BK channel activation.
    Hilal Ahmad Mir, Gaddam Mahesh, Arunan Palanimuthu, Christopher L Cioffi, Konstantin Petrukhin.
      Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in elderly individuals for which no effective treatments are currently available. The photoreceptor loss in dry AMD is secondary to the demise of the retinal pigment epithelium (RPE) cells. The accumulation of extracellular deposits, known as drusen, resulting in part from deficient lysosomal and autophagosomal degradation, is a key feature of dry AMD pathogenesis. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that maintains proteostasis by targeting specific cytosolic proteins for lysosomal translocation and degradation. LAMP2A (lysosome-associated membrane protein 2A) functions as the key lysosomal receptor required for CMA. Using Lamp2a knockout mouse, we show that selective CMA dysfunction recapitulates AMD-like pathologies, including sub-RPE lipid and protein deposits, RPE atrophy, Bruch's membrane thickening, and impaired autophagic activity. Furthermore, we identify large-conductance Ca²⁺-activated K⁺ (BK) channels as a therapeutic target for restoring autophagic activity. Mechanistically, pharmacological activation of BK channels with the small-molecule agonist GLA-1-1 enhances macroautophagy and stimulates autophagic flux by promoting autophagosome-lysosome fusion. Importantly, oral administration of GLA-1-1 in markedly attenuates structural, functional, and molecular retinal abnormalities in Lamp2a -deficient mice, suggesting that pharmacological activation of macroautophagy through facilitating autophagosome-lysosome fusion can partially compensate for CMA deficiency. Together, these findings demonstrate that pharmacological activation of macroautophagy can ameliorate the retinal phenotype resulting from CMA dysfunction and support BK channel activation by GLA-1-1 as a promising therapeutic strategy for dry AMD.
    DOI:  https://doi.org/10.64898/2026.03.19.712761
  40. Sci Adv. 2026 Apr 03. 12(14): eaea4125
    Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation.
    Eulalia Belloc, Vittorio Calderone, Salvador Naranjo-Suarez, Lidia Mateo, Judit Martin, Florencia Malizia, Annarita Sibilio, Veronica Chanes, Marta Ramirez-Pedraza, M Eugenia Delgado, Uta Drebber, Karl-Peter Rheinwalt, Sabine Klein, Maximilian Joseph Brol, Robert Schierwagen, Jonel Trebicka, Patrick Aloy, Mercedes Fernandez, Raul Mendez.
      Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.
    DOI:  https://doi.org/10.1126/sciadv.aea4125
  41. Annu Rev Biochem. 2026 Apr 03.
    Proteostasis Deregulation by Metabolism Drives the Hallmarks of Cancer.
    Ashok R Venkitaraman.
      Cancer cells acquire hallmark behaviors through adaptations that extend beyond genetic and epigenetic changes. Proteostasis-the biochemical network governing protein synthesis, folding, trafficking, and degradation-is a fundamental, yet underappreciated, mediator of these adaptations that merits consideration as a hallmark-enabling mechanism. Metabolic alterations impose proteotoxic stress, globally rewire protein homeostasis, and selectively modulate key oncogenic and tumor suppressive proteins. A unifying framework is proposed wherein metabolic deregulation of proteostasis operates throughout carcinogenesis: early, by enhancing accumulation of premalignant clones bearing cancer-driving somatic mutations in response to environmental and systemic metabolic stress, and later, by buffering proteotoxic stress to sustain malignant growth in hostile tissue environments. This perspective connects cancer risk with genetic background, diet, microbiome-derived metabolites, and metabolic disease, introduces metabolic bypass of tumor suppression as an alternative to classical genetic models, and highlights the metabolism-proteostasis interface as a promising target for cancer prevention and therapy.
    DOI:  https://doi.org/10.1146/annurev-biochem-051424-052148
  42. Chimia (Aarau). 2026 Mar 25. 80(3): 150-156
    Recent Advances in Small-Molecule Modulators Targeting IRE1α.
    Yang Liu, Peng Wu.
      IRE1α is an important ER stress sensor located on the ER membrane with dual kinase and ribonuclease activity. It plays a crucial role in restoring ER proteostasis and is associated with various human diseases. Targeting IRE1α has become a promising therapeutic approach. Many IRE1α modulators have been identified in recent years, and some of these have demonstrated excellent pre-clinical efficacy. The modulation of IRE1α RNase activity by small molecules can be achieved through two main mechanisms: directly binding to the RNase domain to block RNA splicing, or allosteric modulation of its activity through binding to the kinase domain. Apart from monovalent inhibitors and activators, proteolysis targeting chimeras have been reported to degrade IRE1α and block its downstream signalling by recruiting the E3 ligase-ubiquitin system. In this review we summarize the recent advances of targeting IRE1α with small molecules, including inhibitors, activators, and bifunctional molecules, providing an insight into future development of chemical modalities targeting IRE1α.
    Keywords:  Allosteric inhibitors; PROTAC; RNA splicing; Ribonuclease and IRE1α; Small-molecule modulators
    DOI:  https://doi.org/10.2533/chimia.2026.150
  43. Cell Chem Biol. 2026 Mar 30. pii: S2451-9456(26)00073-5. [Epub ahead of print]
    ER-localized ceramide accumulation contributes to replicative senescence.
    Shweta Chitkara, Mengru Li, Natasha Gozali, Andrey Kuzmin, Artem Pliss, Paras Prasad, Yasemin Sancak, G Ekin Atilla-Gokcumen.
      Ceramides regulate diverse cellular processes through compartment-specific accumulation. While mitochondrial ceramide accumulation promotes apoptosis, its regulation and function during senescence remain incompletely understood. Here, we integrate lipidomics, transcriptomics, Raman spectroscopy, and biochemical characterizations to define sphingolipid remodeling in replicative senescence. Senescent cells exhibit elevated ceramide levels and depletion of very-long-chain sphingomyelins, despite unaltered sphingomyelin synthase 1 expression, implicating impaired ceramide-sphingomyelin turnover. Pharmacological inhibition of ceramide transfer protein (CERT), the ER-to-Golgi ceramide transporter, phenocopies sphingolipid remodeling and enhances senescence, suggesting disrupted ceramide trafficking as a driver of senescence. Raman spectroscopy suggests ceramide accumulation localized to the ER. In parallel, analysis of ER-enriched fractions confirms increased ceramide levels in ER fractions of senescent cells. Mechanistically, ceramide accumulation at the ER can contribute to ER stress. These findings identify altered ceramide trafficking as a contributor to ER stress and highlight ER-localized ceramide as a critical component of senescence-associated sphingolipid remodeling.
    Keywords:  ER stress; Raman BCA; ceramide; lipidomics; organelle enrichment; senescence; transcriptomics
    DOI:  https://doi.org/10.1016/j.chembiol.2026.03.003
  44. Nat Commun. 2026 Mar 28.
    Expanding the targeted protein degradation approach with small molecule chimeras directed to the 26S proteasome.
    Mireia Casasampere, Hector Carneros, Tania Roda, Alice Zuin, Núria Gallisà-Suñé, Alba González-Artero, Bernat Coll-Martínez, José Luis Abad, Abdulateef Alqahtani, Josefina Casas, Patricia Fernández-Nogueira, Antonio Delgado, Jordi Bujons, Gemma Fabriàs, Bernat Crosas.
      Classical proteolysis targeting chimeras (Protacs) bind specific targets and E3 ubiquitin-ligases, promoting ubiquitination and degradation of targets by the proteasome. Multiple chimeras that degrade proteins relevant in several diseases have been developed, and the number is quickly increasing, indicating their therapeutic projection. Given the specificities of proteolytic pathways and limitations in E3-based Protacs, alternative strategies in targeted protein degradation are pursued. Herein, using two targets relevant in oncology as models (IMPDH2 and CERT1), we provide proof of concept for 26S-oriented compounds based on small-molecule ligands of USP14, a 26S-associated deubiquitinase involved in substrate processing and allosteric regulation of 26S activity. Our findings will expand the potential of targeted protein degradation.
    DOI:  https://doi.org/10.1038/s41467-026-71132-5
  45. Nat Commun. 2026 Apr 01.
    TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.
    Yan Xiong, Jaiprakash Sharma, Meggie N Young, Wen Xiong, Ali Jazayeri, Karl F Poncha, Ma Xenia G Ilagan, Qing Wang, Bei Gao, Hui Zheng, Nicolas L Young, Marco Sardiello.
      Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues (423SPFPSLS429), generating a phosphodegron recognized by the E3 ligase β-TrCP2, which in turn targets TFEB for proteasomal degradation via ubiquitination of adjacent lysine residues (K430 and K431). Mutation of either the phosphosites or the ubiquitination sites stabilizes TFEB without impairing its ability to translocate to the nucleus, activate target gene expression, or promote tau clearance in a cell model of tauopathy. These findings establish IKK-β-TrCP2 as a core regulatory axis controlling TFEB protein turnover and levels and reveal a mechanistically distinct layer of TFEB regulation that may be leveraged to enhance lysosomal function in disease contexts.
    DOI:  https://doi.org/10.1038/s41467-026-71001-1
  46. NAR Genom Bioinform. 2026 Jun;8(2): lqag033
    G/C-ending and synonymous codon bias define functional translational programs that shape human tissue and cancer proteomes.
    Sherif Rashad, Kuniyasu Niizuma.
      Codon usage bias is a fundamental feature of the genetic code, yet its impact on messenger RNA translation is incompletely defined. Here, we integrate comparative genomics, human tissue proteomes, large cancer cell line, and patient cancer datasets to reveal a conserved codon-bias axis. Across mammals, we show that GC-biased gene conversion drives human-specific GC3 (third codon nucleotide bias score) drifts, yet the functional dichotomy is maintained: A/T-ending codons associate with proliferation and RNA processing, while G/C-ending (Third nucleotide Guanine or Cytosine) codons associate with differentiation and neuronal functions. At the isoacceptors level, synonymous codons segregate into distinct functional categories. To mechanistically connect codon usage to cancer, we introduce the ANN- and m7G-indices, capturing codons decoded by transfer RNA (tRNA) modifications t6A and m7G. Both indices negatively correlate with GC3 and enrich for pro-oncogenic proliferative pathways. Human tissue proteomes reveal strong codon bias discordance between RNA and protein levels, with nervous system tissues enriched for G/C-ending codons while proliferative organs are A/T-biased. Analysis of 2600 cancer cell lines and 21 cancer types revealed heterogeneous codon preferences in cancer cell lines but a global A/T-ending shift in human cancer-upregulated proteins. These findings establish synonymous codon divergence and tRNA modification indices as key determinants of translational reprogramming in health and cancer.
    DOI:  https://doi.org/10.1093/nargab/lqag033
  47. Mol Cell. 2026 Apr 01. pii: S1097-2765(26)00164-4. [Epub ahead of print]
    2'-O-Methylation maintains ribosome structural and translation integrity.
    Yu Zhao, Jay Rai, Lauren N Cohen, Yuerong Shu, Chong Xu, Hemant Goswami, Xin Chen, Hong Jin, Virginie Marchand, Yuri Motorin, Homa Ghalei, Hong Li.
      In eukaryotic ribosomes, ∼2% of RNA nucleotides undergo 2'-O-methylation, a conserved cellular mechanism thought to be critical for maintaining and regulating translation. Here, we use ribosome profiling, translation assays, proteomics, and high-resolution structural analyses to show that loss of native 2'-O-methylation in yeast ribosomes disproportionally affects the translation of ribosomal protein transcripts, driven by changes in codon usage and recognition of structured RNA. Translation reprogramming by the hypomethylated ribosomes is supported by reduced thermostability and high-resolution evidence of altered ribosomal structures and conformations. Consistent with the roles of the affected proteins in sustaining cellular fitness, hypomethylated ribosomes under stress exhibit a selective loss of downregulated proteins and misassembly associated with methylation loss. Our data provide structural and mechanistic insights into how 2'-O-methylation supports ribosome integrity and mediates cellular stress responses.
    Keywords:  IRES translation; RNA 2′-O-methylation; Ribo-seq; box C/D snoRNPs; fibrillarin; ribosome stability; translation; translation fidelity
    DOI:  https://doi.org/10.1016/j.molcel.2026.03.008
  48. J Med Chem. 2026 Apr 03.
    New PROTAC Designs for Targeted Protein Degradation in 2021-2025: Novel E3 Ligases and Pre-PROTACs.
    Wei Peng, Xiaoyan Pan, Shiqun Wang, Guang Huang, Yufeng Qian.
      Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative paradigm in pharmaceutical research. Despite significant progress in PROTACs, they are overwhelmingly dominated by the recruitment of a very restricted subset of canonical E3 ligases (e.g., CRBN and VHL), which hinders their potential therapeutic applications. As a result, recent developments have led to the emergence of PROTACs that utilize nonclassical E3 ligases. Another challenge is systemic toxicity caused by degradation on-target degradation in nonintended tissues, prompting the development of pre-PROTACs to achieve conditional and spatiotemporal modulation of target protein levels. Herein, we provide a comprehensive summary and discussion of recent advancements in PROTACs based on "novel" E3 ligases, as well as PROTAC prodrugs activated by external stimuli and the tumor microenvironment, highlighting prospects for the design of effective and selective PROTACs.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c03330
  49. Plant J. 2026 Apr;126(1): e70846
    Ubiquitin ligases in plant immunity: structural mechanisms and signaling.
    Natalie Hamada, Katherine A Hand, Nitzan Shabek.
      The ubiquitin system plays a central role in regulating plant growth, development, and immune responses. Within this system, E3 ubiquitin ligases act as key specificity factors that direct the modification and degradation of immune receptors, transcription factors, kinases, and hormone regulators. Recent advances reveal how diverse E3 ligase families, including Cullin-RING ligases (CRLs), RING-type, U-box, and RBR-type ligases, modulate both pattern-triggered and effector-triggered immunity. This review integrates new mechanistic and structural insights that clarify how E3s recognize substrates, assemble with E2 enzymes, and interface with pathogen effectors. Together, these studies uncover conserved catalytic principles and indicate pathogen-driven diversification of ubiquitin signaling. Emerging themes include feedback regulation, E3-E3 antagonism, and crosstalk with hormone pathways that balance defense and growth. Collectively, these findings redefine the ubiquitin-proteasome system as a dynamic regulatory network integrating perception, signaling, and proteostasis during plant immunity, offering new conceptual and practical avenues for enhancing disease resistance.
    Keywords:  Cullin–RING ligases (CRLs); E3 ubiquitin ligases; RING‐type ligases; U‐box ligases; effector‐triggered immunity (ETI); pattern‐triggered immunity (PTI); plant immunity; proteostasis; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1111/tpj.70846
  50. bioRxiv. 2026 Mar 24. pii: 2026.03.21.713407. [Epub ahead of print]
    A Novel Eukaryotic Ribosome Factor Enables Translation Restart Following Cellular Dormancy.
    Maciej Gluc, Higor Rosa, Maria Bozko, Lesley A Turner, Cassidy R Prince, Yelena Peskova, Heather A Feaga, Kathleen L Gould, Simone Mattei, Ahmad Jomaa.
      Dormancy is a survival strategy employed by all domains of life to withstand prolonged nutrient deprivation and environmental stress that is marked by a global shutdown of protein synthesis. However, the molecular mechanisms driving ribosome inactivation and reactivation during and after dormancy in eukaryotes remain poorly understood. Here, we identify SNOR, a novel SBDS-like ribosome-associated factor in Schizosaccharomyces pombe, that is upregulated and associates with ribosomes during induced dormancy triggered by glucose depletion. SNOR contributes to protein synthesis repression by binding the ribosome to probe the peptidyl transferase center (PTC), block tRNA-binding sites, and cap the polypeptide exit tunnel (PET). Importantly, we show that SNOR is essential for the restart of protein synthesis upon glucose reintroduction and exit from dormancy. SNOR is evolutionarily conserved and specifically upregulated in response to glucose stress in fungi. These findings reveal a previously unrecognized ribosome-associated factor that links glucose stress and cellular dormancy to surveillance of protein synthesis and highlight the power of in situ structural biology to uncover stress-responsive regulators of translation.
    DOI:  https://doi.org/10.64898/2026.03.21.713407
  51. Leukemia. 2026 Mar 30.
    BCR::ABL1 tyrosine kinase inhibitors induce ribosome collisions to activate ZAK-dependent ribotoxic stress and apoptosis in chronic myeloid leukemia.
    Jumin Park, Soo-Hyun Kim, Jongmin Park, Heeju Park, Hongtae Kim, Dong-Wook Kim, Chunghun Lim.
      Ribosome collisions act as molecular sensors of cellular stress, yet their role in disease physiology remains unclear. Here, we demonstrate that inhibition of the oncogenic kinase BCR::ABL1 in chronic myeloid leukemia (CML) cells induces ribosome collisions and activates the ribotoxic stress response (RSR). Clinical analyses revealed that CML progression from the chronic phase to the aggressive blast phase correlated with elevated expression of the RSR-initiating kinase ZAK. Although ZAK sustained CML cell proliferation by promoting AKT activity, loss of ZAK function paradoxically reduced the cytotoxic effects of BCR::ABL1 inhibitors. Mechanistically, BCR::ABL1 inhibition promoted phosphorylation of eukaryotic translation elongation factor 2 (EEF2) via the mTOR-EEF2K pathway, slowed translation elongation, and generated nuclease-resistant collided ribosomes that triggered ZAK-dependent p38 activation and apoptosis. Furthermore, pharmacological modulation of translation flux fine-tuned the efficacy of BCR::ABL1 inhibitors, including in primary patient cells. These findings define a ribosome-based stress pathway crucial for CML apoptosis and highlight ZAK-dependent RSR as a therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41375-026-02916-3
  52. Nature. 2026 Apr 01.
    AhR inhibition promotes axon regeneration via a stress-growth switch.
    Dalia Halawani, Yiqun Wang, Jiaxi Li, Daniel Halperin, Haofei Ni, Molly Estill, Aarthi Ramakrishnan, Li Shen, Arthur Sefiani, Cédric G Geoffroy, Roland H Friedel, Hongyan Zou.
      Axon regeneration is limited in the mammalian central nervous system1. Neurons must balance stress responses with regenerative demands after axonal injury2, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM (bHLH-PAS) transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models. Mechanistic studies reveal that axotomy-induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs. Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis and metabolic signalling to control the balance between stress adaptation and axonal repair.
    DOI:  https://doi.org/10.1038/s41586-026-10295-z
  53. Nucleic Acids Res. 2026 Mar 19. pii: gkag264. [Epub ahead of print]54(6):
    Exploration of the proxiOME of large subunit ribosomal proteins reveals Acl1 and Bcl1 as cooperating dedicated chaperones of Rpl1.
    Sébastien Favre, Benjamin Pillet, Fabiana Burchert, Devanarayanan Siva Sankar, Alfonso Méndez-Godoy, Stephan Kiontke, Jörn Dengjel, Gert Bange, Dieter Kressler.
      In eukaryotes, most newly synthesized ribosomal proteins (r-proteins) need to rapidly and safely get into the nucleus to reach their assembly site on pre-ribosomal particles. However, only for few r-proteins tailored support mechanisms involving so-called dedicated chaperones (DCs) could so far be revealed. Here, with the primary aim of identifying novel DCs, we performed TurboID-based proximity labelling with all 46 large subunit r-proteins of Saccharomyces cerevisiae, which unveiled the fungi-specific Acl1 and the conserved Bcl1 as candidate DCs of Rpl1. We show that the functionally cooperating Acl1 and Bcl1 both directly interact with Rpl1, form a trimeric Acl1-Rpl1-Bcl1 complex, and enable the nuclear import of Rpl1. Moreover, our crystal structure of the minimal Acl1-Rpl1 complex reveals how Acl1's ankyrin repeat domain shields a positively charged ribosomal RNA-binding surface of Rpl1. Our proximity labelling approach also permitted to establish novel interactions between four r-proteins and distinct importins and to illuminate r-protein neighbourhoods on successive pre-60S particles. Additionally, reciprocal proximity labelling with the known DCs indicates that almost all appear to be transiently associated with pre-ribosomal particles. Our study provides for the first time comprehensive insight into the physical proximities of large subunit r-proteins along their entire life cycle.
    DOI:  https://doi.org/10.1093/nar/gkag264
  54. Adv Exp Med Biol. 2026 ;1491 249-272
    Cytosolic Peptide: N-Glycanase (NGLY1)-from Basic Biology to Genetic Disorder, NGLY1 Deficiency.
    Haruhiko Fujihira, Tadashi Suzuki.
      The cytosolic peptide:N-glycanase (PNGase, NGLY1 in mammals) is an enzyme that removes N-glycans from misfolded glycoproteins. NGLY1 contributes to cytosolic glycan degradation (non-lysosomal glycan degradation) and is one of the quality control systems for newly synthesized proteins, i.e., ER-associated degradation (ERAD). NGLY1 is also responsible for the activation of a transcription factor, NFE2L1, which participates in several stress responses, including regulation of proteasome subunit expression and oxidative stress. In 2012, NGLY1 deficiency, a human genetic disorder caused by the biallelic mutations in the NGLY1 gene, was discovered. Since then, research on the physiological functions of NGLY1 and the pathogenic mechanism of NGLY1 deficiency has expanded rapidly. Here, we will briefly overview the early history of NGLY1 research and then introduce its versatile functions. We will also provide mechanistic insights into the pathogenesis of NGLY1 deficiency based on studies using model animals, such as worms, flies, and rodents.
    Keywords:   Genetic disorder; Model animal/cell analyses; NGLY1
    DOI:  https://doi.org/10.1007/978-3-032-04153-1_16
  55. Sci Immunol. 2026 Apr 03. 11(118): eaeb6484
    Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF.
    Biao Ma, Wenxin Lyu, John Rizk, Xiaoyue Han, Majken Kjær, Vinnycius Pereira Almeida, Malin Jessen, Max Benjamin Sauerland, Carol Sze Ki Leung, Benoit J Van den Eynde, Xin Lu, Mads Gyrd-Hansen.
      Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5' untranslated region of TNFRSF1A and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including TLR4, IFNAR1, and IFNGR2, is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb6484
  56. Cell Death Dis. 2026 Mar 28.
    Deltex E3 ubiquitin ligase 2 potentiates STING-mediated type I interferon response by K63-linked ubiquitination.
    Zhuang Liu, Runze Li, Caihong Fan, Yuheng Liu, Jia Liu, Mingchen Yin, Ni Shang, Xudong Wang, Zhi Qi, Yanna Shen, Chang Liu.
      Stimulator of interferon genes (STING) signaling, as a pivotal DNA-sensing mechanism, orchestrates antiviral and antitumor immunity through the induction of type I interferon response. Precise modulation of STING signaling is critical for maintaining immune homeostasis, yet its regulatory landscape has not been fully elucidated. Here, we identify the Deltex E3 ubiquitin ligase 2 (DTX2) as a positive regulator of STING-type I interferon response. Loss of Dtx2 in mouse macrophages and embryonic fibroblasts (MEFs) markedly impairs the type I interferon production upon double-stranded DNA (dsDNA) or cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) stimulation. Correspondingly, Dtx2-/- mice exhibit more susceptibility to DNA viral infection compared to its counterparts. Mechanistically, DTX2 interacts with STING to promote K63-linked ubiquitination at residue K236 and K370, which facilitates the translocation of STING from the endoplasmic reticulum (ER) to the Golgi apparatus and activates downstream signaling cascades. Furthermore, we demonstrate that DTX2 potentiates STING-mediated type I interferon response in multiple tumor cell lines, and enhances anti-tumor immunity in murine head and neck cancer models. Collectively, our work uncovers DTX2 as a previously unrecognized regulator of STING, revealing a ubiquitin-dependent mechanism for fine-tuning innate immune response with implications for combating infections and cancer.
    DOI:  https://doi.org/10.1038/s41419-026-08659-4
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