bims-proteo Biomed News
on Proteostasis
Issue of 2026–02–22
sixty-four papers selected by
Eric Chevet, INSERM
  1. Beyond Vesicular Traffic: The ERES as the Gateway for Biosynthetic Secretion.
  2. Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.
  3. Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation.
  4. METTL18 Ensures Pancreatic Function by Maintaining Proper Translation and Proteostasis.
  5. Modulation of Ube2R1 activity by a nanobody that binds near its N-terminus.
  6. Proteasome activity maintains cell-type-specific gene expression.
  7. Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.
  8. De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.
  9. Composite SMG5-SMG6 PIN domain formation is essential for NMD.
  10. Bridged PROTAC, DNA-based PROTAC and hydrophobic tag technologies for targeted protein degradation.
  11. Degradation graphs reveal hidden proteolytic activity in peptidomes.
  12. Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life.
  13. PERK retains a predominantly monomeric state under ER stress conditions.
  14. SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling.
  15. Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs.
  16. High-throughput ligand diversification to discover chemical inducers of proximity.
  17. A Drosophila model for Dent's disease type 1 revealed impaired endoplasmic reticulum export of Cubilin as pathogenic mechanism.
  18. A regulatory circuit operated by KDELR1 and KDELR3 fine-tunes the composition of the early secretory pathway.
  19. Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
  20. The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
  21. Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
  22. Core principles of autophagy initiation mechanisms.
  23. The transcriptional repressor Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors.
  24. NanoTAC in targeted protein degradation: Intelligent delivery platforms and synergistic therapeutic paradigms.
  25. A Deep Learning Framework for Comprehensive Prediction of Human RNA G-Quadruplex-Binding Proteins.
  26. The integrated stress response promotes immune evasion through lipocalin 2.
  27. The microcephaly-associated protein YIPF5 differentially regulates ER export.
  28. Induced-proximity therapeutics for targeted protein and RNA degradation: An organic chemistry Perspective-A review.
  29. Insolubilome profiling defines molecular features that influence protein insolubility with aging.
  30. Structural insights into the Urm1-Uba4 pathway and its biological roles.
  31. Lysosome-targeting chimeras enable targeted protein degradation.
  32. Structure and mechanism of the HECT ligase HECTD3.
  33. Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.
  34. RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.
  35. PROTAC-Splitter: a machine learning framework for automated identification of PROTAC substructures.
  36. Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity.
  37. Endoplasmic Reticulum Stress-Induced Membrane Exposure of Calreticulin Serves as a Guide for Phagocytic Removal of Stressed-But-Viable Cytotrophoblasts.
  38. Ouabain Suppresses CD63 Loading into Extracellular Vesicles via Na+/K+-ATPase-Dependent Localization to Autophagosomes.
  39. The Crohn's disease-related RNF123 prevents NLRP3 inflammasome assembly by catalyzing unanchored K63-linked ubiquitination on NEK7.
  40. The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
  41. Lipidation as a post-translational code for protein liquid-liquid phase separation.
  42. PAN2 maintains mRNA poly(A) tail homeostasis and regulates translation during spermiogenesis in mice.
  43. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  44. Golgi Membrane-Associated Degradation (GOMED), a New Intracellular Proteolysis Mechanism.
  45. Antagonistic Ubiquitin Switching by USP7 and RNF40 Orchestrates KDM6A Homeostasis to License Coronavirus Susceptibility.
  46. Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response.
  47. Covalent capture and genetic code expansion enables chemoproteomic profiling and functional characterization of lysine acetoacetylation.
  48. FOSL2 drives acute myeloid leukemogenesis through suppression of ERAD-induced proteostatic collapse.
  49. Protocols for Monitoring Unconventional Protein Secretion Using Luminescence and Trapping Approaches.
  50. Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer.
  51. Single-cell and isoform-specific translational profiling of the mouse brain.
  52. Nanoscopic tau aggregates are not shared intermediates but disease-specific entities across tauopathies.
  53. A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
  54. DSN1 Promotes Colorectal Cancer Metastasis by Inhibiting FZR1-Mediated Ubiquitination of c-MYC.
  55. Unified modeling of 3D molecular generation via atomic interactions with PocketXMol.
  56. C-Terminal Fragment of Filamin C Containing Immunoglobulin-Like Domains 19-24 Selectively Interacts with the Small Heat Shock Protein HspB7.
  57. STING Innate Immunity Signalling from the Golgi.
  58. Investigating the Involvement of the Unfolded Protein Response in Bread Wheat Priming and Adaptation to Heat Stress.
  59. Nutrient Deprivation Promotes Bladder Cancer Metastasis through Beclin-1 Deacetylation-Mediated Autophagy Activation.
  60. Global mapping of circRNA-target RNA interactions reveal P-body-mediated translational repression.
  61. KDEL-mediated modulation of intracellular trafficking in cell-targeted protein drugs.
  62. ER-associated degradation pathway protein SEL1L plays an evolutionarily conserved role in platelet adhesion.
  63. Development of PROTACs Targeting the Moonlighting Enzyme Nicotinamide Phosphoribosyltransferase (NAMPT) for Breast Cancer Therapy.
  64. 16-h fasting optimizes cancer immunotherapy in mice and humans.
  1. Subcell Biochem. 2026 ;111 3-36
    Beyond Vesicular Traffic: The ERES as the Gateway for Biosynthetic Secretion.
    Meir Aridor.
      Biosynthetic secretion mobilizes about a third of the human proteome from the Endoplasmic Reticulum (ER) in route to cellular and extracellular destinations. Traffic from the ER to the Golgi Complex begins at distinct sites on the ER, the ER exit sites (ERES), which are functionally and physically connected with the Golgi. ERES are the first sorting sites in the secretory pathway. This chapter explores key molecular functionalities of the ERES.
    Keywords:  COPI; COPII; ERES; ERGIC; Golgi; TANGO1
    DOI:  https://doi.org/10.1007/978-3-032-16833-7_1
  2. J Clin Invest. 2026 Feb 19. pii: e196819. [Epub ahead of print]
    Neuronal SEL1L-HRD1 ER-associated degradation is essential for motor function and survival in mice.
    Mauricio Torres, You Lu, Brent Pederson, Hui Wang, Anna Gretzinger, Liangguang Lin, Jiwon Hwang, Xinxin Chen, Alan C Rupp, Abigail J Tomlinson, Andrew J Scott, Zhen Zhao, Daniel R Wahl, Martin Myers, Costas A Lyssiotis, Ling Qi.
      Hypomorphic variants in the SEL1L-HRD1 ER-associated degradation (ERAD) complex have been linked to severe neurological syndromes in children, including neurodevelopmental delay, intellectual disability, motor dysfunction, and early death. Despite this association, its physiological importance and underlying mechanisms in neurons remain poorly understood. Here, we show that neuronal SEL1L-HRD1 ERAD is essential for maintaining one-carbon metabolism, motor function, and overall viability. Neuron-specific deletion of Sel1L in mice (Sel1LSynCre) resulted in growth retardation, severe motor impairments, and early mortality by 9 weeks of age-mirroring core clinical features observed in affected patients-despite preserved neuronal numbers and only modest ER stress. Multi-omics analyses, including single-nucleus RNA sequencing and metabolomics, revealed significant dysregulation of one-carbon metabolism in ERAD-deficient brains. This included activation of the serine, folate, and methionine pathways, accompanied by elevated levels of S-adenosylmethionine and related metabolites, likely resulted from induction of the integrated stress response (ISR). Together, these findings uncover a previously unappreciated role for neuronal SEL1L-HRD1 ERAD in coordinating ER protein quality control with metabolic adaptation, providing new insight into the molecular basis of ERAD-related neurodevelopmental disease.
    Keywords:  Cell biology; Cell stress; Metabolomics; Mouse models; Neuroscience
    DOI:  https://doi.org/10.1172/JCI196819
  3. Biophys Chem. 2026 Feb 04. pii: S0301-4622(26)00023-2. [Epub ahead of print]332 107590
    Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation.
    Khaled M Jami, Katherine E Corbett, Daniel C Farb, Kayla M Osumi, Catelynn C Shafer, Sophie Criscione, Dylan T Murray.
      The loss of cellular proteostasis through aberrant stress granule formation is implicated in neurodegenerative diseases. Stress granules are formed by biomolecular condensation involving protein-protein and protein-RNA interactions. These assemblies are protective, but can rigidify, leading to amyloid-like fibril formation, a hallmark of the disease pathology. Key proteins dictating stress granule formation and disassembly, such as TDP43, contain low-complexity (LC) domains that drive fibril formation. HSPB8, a small heat shock protein, localizes to stress granules, has known aggregation delaying activity, and helps direct aggregated proteins to protein degradation pathways. It is not known how HSPB8 interacts with aggregation prone LC domains in stress granules. Here, we examine the interaction between isolated HSPB8 and the TDP43 LC using thioflavin T (ThT) and fluorescence polarization (FP) aggregation assays, fluorescence microscopy and photobleaching experiments, and crosslinking mass spectrometry (XL-MS). Our results indicate that HSPB8 delays TDP43 LC aggregation through domain-specific interactions with fibril nucleating species, without affecting fibril elongation rates. These findings provide mechanistic insight into how HSPB8 mediates LC domain aggregation and provides bases for investigating how the TDP43 LC subverts chaperone activity in neurodegenerative disease and comparing differing mechanisms between members of the HSPB protein family.
    Keywords:  ATP-independent chaperone; Biomolecular condensate; Liquid droplet; Protein aggregation; Protein fibril; RNA-binding protein; Small heat shock protein
    DOI:  https://doi.org/10.1016/j.bpc.2026.107590
  4. Mol Metab. 2026 Feb 17. pii: S2212-8778(26)00021-9. [Epub ahead of print] 102337
    METTL18 Ensures Pancreatic Function by Maintaining Proper Translation and Proteostasis.
    Tadahiro Shimazu, Megumi Gowa, Ayane Kataoka, Takehiro Suzuki, Kotaro Tomuro, Yuichi Shichino, Naoshi Dohmae, Shintaro Iwasaki, Yoichi Shinkai.
      Methyltransferases fine-tune various biomolecules by site-specific methylation. METTL18, an N3-position-specific histidine methyltransferase, modifies H245 of the ribosomal protein RPL3 (uL3), thereby regulating translation dynamics and proteostasis. However, the physiological role of this enzyme in vivo remains to be elucidated. Here, we show that METTL18 is essential for pancreatic function by regulating translation and suppressing protein aggregation. Mettl18 knockout (KO) mice exhibited partial preweaning lethality, and the surviving mice showed a marked reduction in N3-histidine methylation in the pancreas, diabetic phenotypes, and accumulation of pancreatitis-associated proteins. Ribosome profiling in a pancreatic acinar cell line revealed that loss of METTL18 caused global translational alterations, including accelerated elongation at proline codons. The improper ribosome traverse compromises protein folding, resulting in the aggregation of pancreatitis-associated proteins, including Reg1, and activation of the unfolded protein response. Our findings establish histidine methylation as a physiologically important post-translational modification and highlight METTL18 as a key regulator of pancreatic function through the maintenance of proteostasis.
    Keywords:  Glucose homeostasis; Histidine methylation; METTL18; Pancreatic function; RPL3/uL3; Ribosome function; Translation regulation
    DOI:  https://doi.org/10.1016/j.molmet.2026.102337
  5. Biochem J. 2026 Mar 04. 483(3): 345-363
    Modulation of Ube2R1 activity by a nanobody that binds near its N-terminus.
    Charlotte Wijne, Pavana Suresh, Richard Dela Rosa, Luc van Oss, Sabine Normann, William McKibben, Florian I Schmidt, Hidde Ploegh.
      Ube2R1 (Cdc34) is a K48-ubiquitin chain-specific ubiquitin-conjugating (E2) enzyme central to proteasomal degradation, yet the regulatory potential of its unique structural elements remains underexplored. Here, we report the isolation and biochemical characterization of a nanobody, VHH12R1, that binds selectively to the N-terminal extension of Ube2R1 with no detectable cross-reactivity to its paralog Ube2R2 or other E2s. Engagement of this N-terminal region by VHH12R1 transiently delays ubiquitin charging, promotes accumulation of stable mono-ubiquitin Ube2R1 conjugates, and markedly reduces self-directed polyubiquitination chain formation by Ube2R1 without impairing di-ubiquitin synthesis. Although Ube2R1 can catalyze ubiquitination of VHH12R1 in the absence of an E3 ligase, this modification occurs independently of stable nanobody binding and is not required for modulation of Ube2R1 activity. Together, these findings support a model in which VHH12R1 selectively restricts processive self-elongation by Ube2R1 through engagement of its N-terminal extension, without broadly inhibiting ubiquitin transfer reactions. Our results reveal an unappreciates regulatory role for the Ube2R1 N-terminus in controlling catalytic outcomes and highlight nanobody-based approaches as precise tools to dissect E2 enzyme function.
    Keywords:  Enzyme modulation; Nanobodies; Ube2R1; Ubiquitin-conjugating enzyme (E2); Ubiquitination
    DOI:  https://doi.org/10.1042/BCJ20250271
  6. Cell Rep. 2026 Feb 12. pii: S2211-1247(26)00051-3. [Epub ahead of print]45(2): 116973
    Proteasome activity maintains cell-type-specific gene expression.
    Xiuxiu Lu, Vasty Osei-Amponsa, Germán Michelis, Rithik E Castelino, Hitendra Negi, Sudipto Das, Jesse L Turner, Julianna C King, Daniel Martin, Yan Wang, Thorkell Andresson, Raj Chari, Achim Werner, Kylie J Walters.
      Regulated proteolysis in eukaryotes relies on the ubiquitin-proteasome system, which is critical to myriad cellular functions, including protein quality control, cell cycle regulation, and DNA repair. Here, we provide evidence that proteasome activity is also essential for maintaining cell identity. This finding was made by evaluating the impact of losing the ubiquitin-binding activity of proteasome substrate receptor hRpn10/PSMD4. The most dysregulated proteins in cells that express hRpn10 truncated before its ubiquitin interaction motifs (hRpn10VWA) are transcriptionally altered, with striking overrepresentation of proteins canonically restricted in expression to specific tissues. This dysregulation is partly driven by the accumulation of the proteasome substrate and deubiquitinase OTUD5, a known chromatin and transcriptional regulator. Our results thus identify proteasome-dependent mechanisms to safeguard cell-type-specific gene expression programs and expand proteasome biology to include governance of cell identity.
    Keywords:  CP: molecular biology; OTUD5; PSMD4; Rpn10; cell identity; gene expression; proteasome; protein degradation; tissue specificity; transcriptional regulation; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2026.116973
  7. Biochim Biophys Acta Mol Cell Res. 2026 Feb 17. pii: S0167-4889(26)00020-0. [Epub ahead of print] 120124
    Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines.
    Shannon McMahon, Dezerae Cox, Flora Cheng, Albert Lee, Justin J Yerbury, Heath Ecroyd.
      Maintaining proteome integrity is essential for cellular function and survival. Disruptions in proteostasis lead to the aggregation of proteins into inclusions, a process that underlies many neurodegenerative diseases. To quantitatively assess the proteostasis capacity of neuronal cells, we employed an aggregation-prone double mutant form of firefly luciferase (denoted FlucDM) as a reporter protein. We compared two commonly used neuronal cell lines, mouse neuroblastoma cells (Neuro-2a) and a motor neuron-like hybrid line (NSC-34), to evaluate their ability to prevent the aggregation of proteins into intracellular inclusions. We observed a significantly greater propensity of FlucDM to form inclusions in NSC-34 cells compared to Neuro-2a cells. This suggests a reduced capacity of NSC-34 cells for managing aggregation-prone proteins. Proteomic profiling of FlucDM inclusions purified from both cell types revealed cell-type-specific engagement of the proteostasis machinery with aggregation-prone proteins. Comparing the proteomic profiles of key arms of the proteostasis network between these two cell lines revealed that the endoplasmic reticulum (ER) unfolded protein response is differentially expressed. This study establishes a quantitative platform for assessing cellular proteostasis capacity and underscores the importance of cell-type context in proteome maintenance. These insights have implications for understanding the selective vulnerability of neurons in protein misfolding disorders.
    Keywords:  Aggregation index; Inclusions; Neurodegenerative disorders; Protein aggregation; Proteostasis capacity
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120124
  8. bioRxiv. 2026 Feb 12. pii: 2025.12.22.695711. [Epub ahead of print]
    De novo design of protein binders that target DELE1 to inhibit the mitochondrial stress response.
    Rui Yang, Kaiyuan Zheng, McGuire Metts, Yiluo Wang, Danyan Yin, Kevin P Li, Agnieszka A Prazmowska, David F Kashatus, Brian Kuhlman, Jie Yang.
      Mitochondrial stress activates the integrated stress response (ISR) through the mitochondrial protein DELE1, which relays stress signals to the cytosolic kinase HRI to induce ATF4. Dysregulation of DELE1-mediated signaling has been implicated in pathological conditions, yet molecular strategies to modulate DELE1 remain unavailable. Here, we report de novo designed proteins that bind DELE1, block its oligomerization, and inhibit DELE1-mediated ISR activation. Several designs form stable complexes with DELE1 and disrupt its oligomerization in vitro while preserving DELE1's ability to bind HRI. In cells, these designs suppress ATF4 induction during mitochondrial stress and impair the recovery of elongated mitochondrial morphology following transient insult. Crystal structure analysis, structural modeling, and targeted mutagenesis confirm that the designed proteins engage a critical interface required for DELE1 oligomerization. These findings establish DELE1 as a druggable target and demonstrate that de novo designed proteins offer precise tools to modulate this pathway, laying groundwork for therapeutic development.
    DOI:  https://doi.org/10.64898/2025.12.22.695711
  9. Nat Commun. 2026 Feb 19. pii: 1934. [Epub ahead of print]17(1):
    Composite SMG5-SMG6 PIN domain formation is essential for NMD.
    Katharina Kurscheidt, Sophie Theunissen, Natalia Pasquali, Kerstin Becker, Volker Boehm, Elena Conti, Niels H Gehring.
      Nonsense-mediated mRNA decay (NMD) relies on the coordinated assembly and action of multiple protein factors. Degradation of target mRNAs begins with endonucleolytic cleavage near premature stop codons, but the mechanisms of endonuclease activation and regulation remain unclear. Using structural predictions, biochemical in vitro assays, and cell-based NMD analysis, we show that SMG5 and SMG6 interact via their PIN domains to form a composite interface (cPIN) with full endonuclease activity. In vitro reconstituted SMG5-SMG6 cPIN heterodimers show high activity, as SMG5 completes the SMG6 active site and substrate binding site. Mutations in residues at their predicted interaction surfaces, RNA-binding sites, or active site attenuate or abolish cPIN activity in vitro and impair cellular NMD. Our findings demonstrate how paralogous PIN domains complement each other to assemble a highly active endonuclease in NMD, providing a structural and mechanistic explanation for efficient NMD substrate degradation.
    DOI:  https://doi.org/10.1038/s41467-026-69819-w
  10. Adv Drug Deliv Rev. 2026 Feb 16. pii: S0169-409X(26)00053-0. [Epub ahead of print]232 115819
    Bridged PROTAC, DNA-based PROTAC and hydrophobic tag technologies for targeted protein degradation.
    Pengcheng Gao, Yue Zhong, Kaixiu Luo, Jian Jin.
      Proteolysis targeting chimeras (PROTACs) represent an important breakthrough in therapeutic discovery by leveraging the ubiquitin-proteasome system (UPS) to induce targeted protein degradation (TPD). Unlike conventional small-molecule inhibitors, PROTACs catalytically degrade target proteins, thereby abolishing all functions of target proteins. Over the past decade, PROTAC technology has demonstrated broad therapeutic utilities across diverse disease-relevant proteins and many PROTACs have progressed into clinical development. However, classical PROTACs rely on the availability of small-molecule binders for both proteins-of-interest (POIs) and E3 ligases, thus limiting the degradable proteome. To overcome these limitations, innovative strategies such as bridged PROTACs, DNA-based PROTACs, and hydrophobic tag-based degraders (HyTs) have been developed. Bridged PROTACs take advantage of endogenous protein-protein interactions to target the "undruggable" POIs or underexplored E3 ligases. DNA-based PROTACs use DNA oligonucleotides linked to E3 ligase ligands to degrade undruggable transcription factors (specifically termed TF-PROTAC), which lack small-molecule binding pockets and ligands. HyTs utilize a hydrophobic tag to potentially induce POI misfolding and subsequent degradation. HyTs, which have lower molecular weight than typical PROTACs, can be orally bioavailable. Collectively, these technologies expand the targetable proteome and significantly advance the TPD field.
    Keywords:  Bridged PROTAC; DNA-based PROTAC; Hydrophobic tag; Targeted protein degradation
    DOI:  https://doi.org/10.1016/j.addr.2026.115819
  11. PLoS Comput Biol. 2026 Feb;22(2): e1013972
    Degradation graphs reveal hidden proteolytic activity in peptidomes.
    Erik Hartman, Johan Malmström, Jonas Wallin.
      Protein degradation is a regulated process that reshapes the proteome and generates bioactive peptides. Peptidomics and degradomics enables large-scale measurement of these peptides, yet most data analyses approaches treat peptides as isolated endpoints rather than intermediates produced by sequential cleavage. Here, we introduce degradation graphs, a probabilistic framework that represents proteolysis as a directed acyclic network of cleavage events with explicit absorption. From single-snapshot peptidomes, we infer graph weights by gradient descent or linear-flow optimization, quantify flows through branches and bottlenecks, and correct a core bias in conventional quantification. Across three biological datasets, failure to model downstream trimming leads to 3-4-fold underestimation of upstream proteolytic activity. Moreover, degradation graphs provide graph-structured features that enable machine learning models to capture protease-specific signatures from both graph topology and sequence context. Taken together, these findings establish explicit degradation modeling as a practical approach to mechanistic and interpretable peptidomics, bridging the fields of degradomics and peptidomics.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013972
  12. Cell. 2026 Feb 17. pii: S0092-8674(26)00055-3. [Epub ahead of print]
    Giant DNA viruses encode a hallmark translation initiation complex of eukaryotic life.
    J Maximilian Fels, Aidan B Hill, Richard Han, Jasmine M Garcia, Hugo Bisio, Chantal Abergel, Philip J Kranzusch, Amy S Y Lee.
      In contrast to living organisms, viruses were long thought to lack protein synthesis machinery and instead depend on host factors to translate viral transcripts. Here, we discover that giant DNA viruses encode a distinct and functional IF4F translation-initiation complex to drive protein synthesis, thereby blurring the line between cellular and acellular biology. During infection, eukaryotic IF4F on host ribosomes is replaced by an essential viral IF4F that regulates viral translation, virion formation, and replication plasticity during altered host states. Structural dissection of viral IF4F reveals that the mRNA cap-binding subunit mediates exclusive interactions with viral mRNAs, constituting a molecular switch from translating host to viral proteins. Thus, our study establishes that viruses express a eukaryotic translation-initiation complex for protein synthesis, illuminating a series of evolutionary innovations in a core process of life.
    Keywords:  5′ m7G RNA cap; eIF4F; giant DNA viruses; mimivirus; translation; translation-initiation factors
    DOI:  https://doi.org/10.1016/j.cell.2026.01.008
  13. J Mol Cell Cardiol. 2026 Feb 18. pii: S0022-2828(26)00021-0. [Epub ahead of print]
    PERK retains a predominantly monomeric state under ER stress conditions.
    Konstantina Georgoula, Luo Liu, Simone Jung, Iqra Sohail, Paolo Annibale, Gabriele G Schiattarella.
      The unfolded protein response (UPR) is a central adaptive mechanism that safeguards protein homeostasis in the endoplasmic reticulum (ER). In the heart, UPR signaling contributes to cellular remodeling and survival across a range of pathological contexts, including ischemia, pressure overload, and cardiometabolic stress. Among the three canonical UPR branches, the PKR-like ER kinase (PERK) pathway plays a critical role in modulating translational control and redox balance during stress adaptation. Despite its functional importance, the molecular dynamics of PERK activation and assembly remain incompletely understood. Here, we investigate the oligomerization behavior of PERK in living cells using advanced fluorescence microscopy. We identify a concentration-dependent mechanism of PERK self-association, as well as a distinct population of oligomeric PERK whose assembly state remains stable upon ER stress induction. These findings challenge the traditional view of stress-induced oligomerization as a prerequisite for PERK activation and suggest the existence of non-canonical modes of PERK assembly with potential regulatory significance.
    Keywords:  Cardiomyocytes; Molecular brightness; Oligomerization; PERK; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.02.005
  14. Aging Cell. 2026 Feb;25(2): e70384
    SIRT6 Regulates Protein Synthesis and Folding Through Nucleolar Remodeling.
    Daniel Stein, Christian Gallrein, Miguel Portillo, Shai Kaluski-Kopach, Alfredo Garcia-Venzor, Yuval Lachberg, Ekaterina Eremenko, Dmitrii Smirnov, Shiran Dror, Monica Einav, Ekaterina Khrameeva, Anat Ben-Zvi, Björn Schumacher, Debra Toiber.
      An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis, leading to cellular stress. However, the causal mechanisms driving this loss are unclear. We show that SIRT6 has a critical role in maintaining proteostasis. Mechanistically, SIRT6 negatively regulates global translation by controlling ribosomal genes, nucleolar function and TIP5 chromatin localization. SIRT6 deletion increases nucleolar size, rRNA production and protein translation. However, the expression of chaperones remains unchanged, failing to compensate for the excessive translation, leading to reduced folding capacity and production of aggregates. In vivo, we establish a C. elegans model (sir-2.4 KO) that shows reduced heat shock resistance and an accelerated age-dependent reduction in motility. Sir-2.4 depletion crossed with a neuron-specific polyQ strain led to premature motility loss and premature death. These results point to proteostasis-stress intolerance in the absence of SIRT6, that can be rescued by pharmacologically reducing protein translation rates. Our data suggest that SIRT6 deficiency results in proteostasis loss through nucleolar dysfunction. These results highlight that deficient proteostasis begins with chromatin dysregulation resulting in neurodegeneration.
    Keywords:  SIRT6; aging; neurodegeneration; nucleolar expansion; proteostasis
    DOI:  https://doi.org/10.1111/acel.70384
  15. Adv Sci (Weinh). 2026 Feb 17. e15740
    Decoding the Integrated Stress Response of Pancreatic Cancer: Identifying a Serine-dependent Tumor Subset Under Metabolic Relationships With CAFs.
    Sauyeun Shin, Mehdi Liauzun, Jacobo Solorzano, Morgane Le Bras, Christine Jean, Benjamin Fourneaux, Margaux Dore, Lea Fevrier, Ismahane Belhabib, Alexia Brunel, Cindy Neuzillet, Marion Larroque, Carine Joffre, Stephane Rocchi, Nicolas Fraunhoffer, Aurelie Perraud, Muriel Mathonnet, Vera Pancaldi, Laetitia Linares, Juan Iovanna, Nelson Dusetti, Ola Larsson, Remy Nicolle, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau.
      Pancreatic ductal adenocarcinoma (PDA) transcriptomic profiling has identified prognostic subtypes, yet patient-specific first-line therapies remain elusive. Here, we stratified PDA tumors by mRNA translation rates, a frequently dysregulated step in gene expression, using translatome profiling of 27 patient-derived xenografts (PDXs). Unsupervised analysis revealed a distinct tumor subset with low global protein synthesis but sustained translation of Integrated Stress Response (ISR) mRNAs, including ATF4. These ISR-activated cancer cells exhibited broad chemoresistance and apoptosis resistance, yet were auxotrophic for serine due to loss of PHGDH and CBS expression, impairing serine and cysteine biosynthesis. This vulnerability correlated with improved overall survival in patients with low expression of both enzymes. Notably, cancer-associated fibroblasts (CAFs) reprogrammed by ISR-activated cells, shifting from myCAF to iCAF phenotype with reduced collagen synthesis and glycine-to-serine conversion, produced serine and sustained tumor growth in amino acid-depleted environments. Our findings demonstrate the power of translatome profiling to reveal stable, drug-resistant PDA cell states and identify a targetable CAF-tumor metabolic symbiosis, opening new avenues for therapeutic intervention in this highly lethal malignancy.
    Keywords:  cancer‐associated fibroblast; integrated stress response; mRNA translation; pancreatic cancer; serine metabolism
    DOI:  https://doi.org/10.1002/advs.202515740
  16. Nat Chem Biol. 2026 Feb 16.
    High-throughput ligand diversification to discover chemical inducers of proximity.
    James B Shaum, Miquel Muñoz I Ordoño, Erica A Steen, Daniela V Wenge, Hakyung Cheong, Jordan Janowski, Moritz Hunkeler, Eric M Bilotta, Zoe J Rutter, Paige A Barta, Abby M Thornhill, Natalia Milosevich, Lauren M Hargis, Timothy R Bishop, Trever R Carter, Bryce da Camara, Matthias Hinterndorfer, Lucas Dada, Wen-Ji He, Fabian Offensperger, Hirotake Furihata, Sydney R Schweber, Charlie Hatton, Yanhe Wen, Benjamin F Cravatt, Keary M Engle, Katherine A Donovan, Bruno Melillo, Seiya Kitamura, Alessio Ciulli, Scott A Armstrong, Eric S Fischer, Georg E Winter, Michael A Erb.
      Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein-ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4CRBN complex through an extended interface of protein-protein contacts and only engages CRBN after pre-forming the ENL:dHTC1 complex. We also identified dHTC3, a molecular glue that selectively dimerizes BRD4 bromodomain 1 to SCFFBXO3, an E3 ligase not previously accessible for chemical rewiring. Altogether, this study introduces HTC as a facile tool to discover new CIPs and new effectors for proximity pharmacology.
    DOI:  https://doi.org/10.1038/s41589-025-02137-2
  17. Kidney Int. 2026 Feb 12. pii: S0085-2538(26)00087-6. [Epub ahead of print]
    A Drosophila model for Dent's disease type 1 revealed impaired endoplasmic reticulum export of Cubilin as pathogenic mechanism.
    Salómon Christer, Zvonimir Marelja, Indira Dibra, Hannah Hauschild, Marine Berquez, Hetvi Gandhi, Yung-Hsin Shih, Svenja Keller, Martin Helmstädter, Christoph Schell, Olivier Devuyst, Matias Simons.
       INTRODUCTION: Mutations in the CLCN5 gene encoding the chloride-hydrogen exchanger ClC-5 cause Dent's disease type 1, a genetic disorder of the endolysosomal pathway in the proximal tubules of the kidneys. A hallmark of this disease is the downregulation of the protein uptake receptor consisting of megalin, cubilin and amnionless, causing low-molecular-weight proteinuria. Why these receptors are downregulated is not fully understood.
    METHODS: To clarify this, we established an in vivo model for Dent's disease using Drosophila nephrocytes that share similarities with podocytes and proximal tubule cells. Dissected nephrocytes were subjected to immunostaining, uptake tracer studies and transmission electron microscopy. Additionally, histological analysis, immunostainings and Western blotting were performed on Clcn5Y/- mice.
    RESULTS: Upon depletion of ClC-c, the fly homologue of CLCN5, Cubilin was lost from the plasma membrane of nephrocytes, leading to a strong decrease in albumin uptake and ectopic slit diaphragms. Importantly, Cubilin exhibited a strong accumulation in the endoplasmic reticulum, while its binding partner Amnionless was overall reduced. This was accompanied by a fragmentation of the endoplasmic reticulum (ER) morphology and an increase in ER exit sites and associated Golgi stacks. Additionally, the actin and microtubular cytoskeleton as well as recycling endosomes showed a strong cortical accumulation, whereas cholesterol-enriched autophagic compartments emerged in the perinuclear area. Similar phenotypes were observed upon silencing of the C subunit of the vacuolar proton-ATPase suggesting they might depend on defects in acidification and glycosylation in the Golgi apparatus. Amnionless loss and ER retention of cubilin was confirmed in ClC-5 knockout mice, underscoring the relevance of this pathomechanism for Dent's disease.
    CONCLUSIONS: Our findings suggest that in addition to its endosomal role ClC-c/ClC-5 acts in the secretory pathway to promote surface trafficking of the Cubilin/Amnionless complex. This function may partly explain low-molecular-weight proteinuria in patients with Dent's disease.
    Keywords:  endocytosis; endoplasmic reticulum; proteinuria; proximal tubule
    DOI:  https://doi.org/10.1016/j.kint.2026.01.016
  18. Cell Mol Life Sci. 2026 Feb 18.
    A regulatory circuit operated by KDELR1 and KDELR3 fine-tunes the composition of the early secretory pathway.
    Federica Cecilia Palazzo, Marco Dalla Torre, Yuta Amagai, Xue Han, Tiziana Tempio, Caterina Valetti, Jose Garcia Manteiga, Masaki Matsumoto, Matthias Feige, Michele Sallese, Kenji Inaba, Roberto Sitia, Tiziana Anelli.
      KDEL receptors (KDELRs) prevent the secretion of soluble chaperones and enzymes meant to reside in the endoplasmic reticulum. While a single KDELR exists in yeast (ERD2), three variants are present in mammals, displaying high sequence similarity. All three can prevent the secretion of KDEL-bearing clients. However, their diverse tissue distribution and the high phylogenetic conservation of the differences suggest functional specialization. Accordingly, we show here that while KDELR2 plays a major role in client retrieval, KDELR1 and KDELR3 regulate the production of AGR2, a key assistant of mucin folding, in opposite ways. AGR2 transcripts increase dramatically upon silencing KDELR3 but decrease when KDELR1 is downregulated. Silencing ERp44, but no other ER residents, phenocopies KDELR3 knockdown, suggesting that AGR2 regulation depends on ERp44-KDELR3 interactions. Our findings identify a novel regulatory circuit, distinct from the unfolded protein response, that controls the molecular composition of the early secretory pathway based on specific interactions between KDELRs and ER residents.
    Keywords:  AGR2; Chaperones; ERp44; Endoplasmic reticulum; KDEL receptors; PDI; Protein trafficking; Secretion; Signalling
    DOI:  https://doi.org/10.1007/s00018-025-06049-1
  19. Nat Metab. 2026 Feb 20.
    Single-cell spatial proteomics maps human liver zonation patterns and their vulnerability to disruption in tissue architecture.
    Caroline A M Weiss, Lauryn A Brown, Lucas Miranda, Paolo Pellizzoni, Sophia Steigerwald, Kirsten Remmert, Jonathan M Hernandez, Karsten Borgwardt, David E Kleiner, Shani Ben-Moshe, Florian A Rosenberger, Natalie Porat-Shliom, Matthias Mann.
      Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here we show the application of single-cell Deep Visual Proteomics to perform spatially resolved proteome analysis of individual cells in native liver tissue. We built a robust framework comprising strategic cell selection and continuous protein gradient mapping, allowing the investigation of larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analysing hundreds of isolated hepatocytes from 18 individuals. Among the 2,500 proteins identified per cell, about half exhibited zonated expression patterns. Cross-species comparison with male mice revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of samples with disrupted liver architecture demonstrated widespread loss of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive and open-access resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.
    DOI:  https://doi.org/10.1038/s42255-026-01459-2
  20. J Biol Chem. 2026 Feb 16. pii: S0021-9258(26)00162-6. [Epub ahead of print] 111292
    The Hsp40 co-chaperone DNAJC7 regulates polyglutamine aggregation and exhibits context-dependent effects on polyglycine aggregation.
    Biswarathan Ramani, Kean Ehsani, Martin Kampmann.
      Protein-encoding nucleotide repeat expansion diseases, including polyglutamine (polyQ) and polyglycine (polyG) diseases, are characterized by the accumulation of aggregation-prone proteins. In the polyQ diseases, including Huntington's disease and several spinocerebellar ataxias, substantial prior evidence supports a pathogenic role for mutant polyQ-expanded protein misfolding and aggregation, with molecular chaperones showing promise in suppressing disease phenotypes in cellular and animal models. The goal of this study is to establish a scalable cell-based model to systematically evaluate genetic modifiers of protein aggregation in both polyQ and polyG diseases. We developed FRET-based reporter systems that model polyQ and polyG aggregation in human cells and used them to perform high-throughput CRISPR interference screens targeting all known molecular chaperones. In the polyQ model, the screen identified multiple Hsp70 chaperones and Hsp40 co-chaperones previously implicated in polyQ aggregation and additionally revealed the Hsp40 co-chaperone DNAJC7 as a potent and previously unrecognized suppressor of polyQ aggregation. In contrast, in a FRET-based polyG aggregation model of neuronal intranuclear inclusion disease, CRISPRi screening showed minimal overlap of chaperone modifiers of the polyQ screen. Direct knockdown of DNAJC7 also did not affect polyG aggregation, yet overexpressed DNAJC7 co-localized with both polyQ and polyG aggregates in cells and reduced their aggregation. In addition to establishing new inducible, scalable cellular models for polyQ and polyG aggregation, this work expands the role of DNAJC7 in regulating folding of disease-associated proteins.
    Keywords:  aggregation; chaperone; high-throughput screening; neurodegeneration; polyglutamine disease
    DOI:  https://doi.org/10.1016/j.jbc.2026.111292
  21. Adv Sci (Weinh). 2026 Feb 17. e19792
    Mitophagy and Ubiquitination Coordinate Context-Specific Mitochondrial Quality Control and EMT/MET Plasticity to Drive Cancer Cell Invasion.
    Bin-Hsu Mao, Bo-Kai Su, Ying-Jan Wang, Ting-Yuan Tu.
      Metastatic invasiveness emerges from coordinated intrinsic programs and microenvironmental cues that converge on mitochondrial quality control (MQC). Here, we use "context" to denote stage- and site-aware constellations of tumor-intrinsic states (e.g., mtROS tone, mtDNA integrity, epigenetic wiring, cellular stiffness, oncogenic mutations) and extrinsic landscapes (oxygen-nutrient availability, ECM mechanics, stromal/inflammatory signals). These axes jointly shape mitochondrial adaptation by tuning bioenergetics, redox balance, metabolic plasticity, fission-fusion dynamics, mechanosensitive hubs, and Ca2 + homeostasis. As pressures intensify, mitochondrial vulnerabilities-such as mtDNA compromise and mtUPR activation-signal the engagement of mitophagy to preserve organelle fitness under stress. Through these coupled changes in mitochondrial performance and stress responses, context governs EMT/MET plasticity and transitions across migratory, invasive, and proliferative states. Mechanistically, ubiquitin conjugation, via E3 ligases and deubiquitinases, serves as an integrating conduit that links mitochondrial remodeling and mitophagy to cytoskeletal reprogramming and invasive behavior. This ubiquitin-mitochondria interface therefore represents a coherent therapeutic entry point; translational strategies including PROTAC-enabled targeting and selective E3/DUB or mitophagy-pathway modulators may rebalance pathological ubiquitin signaling, restore mitochondrial homeostasis, and constrain tumor dissemination.
    Keywords:  EMT–MET plasticity; extracellular matrix mechanics; hypoxia and nutrient deprivation; mitochondrial ROS; mitochondrial dynamics; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1002/advs.202519792
  22. Nat Struct Mol Biol. 2026 Feb 20.
    Core principles of autophagy initiation mechanisms.
    Tetsuya Kotani, Hitoshi Nakatogawa.
      Autophagy is a conserved intracellular degradation system essential for maintaining cellular homeostasis and adapting to a variety of environmental or metabolic cues. Different types of autophagy are induced in response to various physiological signals through distinct mechanisms. In this Review, we highlight recent advances in understanding the molecular mechanisms that induce autophagic degradation of cytoplasmic material in bulk upon nutrient or energy deprivation, and those that trigger the selective autophagic removal of specific cellular components for their quality or quantity control. We discuss mechanistic principles shared across different types of autophagy, such as phase-separation-mediated assembly and activation of related factors, and the coordination between cargo recognition and membrane biogenesis, delineating how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.
    DOI:  https://doi.org/10.1038/s41594-026-01752-4
  23. Immunity. 2026 Feb 18. pii: S1074-7613(26)00035-X. [Epub ahead of print]
    The transcriptional repressor Fli1 inhibits proteostasis during nutrient stress to limit NK cell persistence in solid tumors.
    Jeong Hyun Ji, Wesley R Armstrong, Joey H Li, Areeba Lalani, Cassidy D Lee, Varchas Bharadwaj, Kenneth Ho, Jingtong Liang, Alexander Muir, Timothy E O'Sullivan.
      Tumor-infiltrating natural killer (NK) cells display reduced persistence and effector functions. Here, we examined the mechanisms underlying NK cell dysfunction in cancer. Gene expression analyses of matched tumor-infiltrating and tumor-adjacent human NK cells revealed that regulators of proteostasis were associated with worse survival outcomes. In mice, NK cells accumulated intracellular protein aggregates within 24 h of tumor infiltration. Nutrient stress in the tumor microenvironment (TME) triggered proteostasis imbalance in primary human NK cells, decreasing translation of cytokine receptors and inhibiting NK cell activation. SCENIC regulon and multiomic analyses identified FLI1 as a transcriptional repressor of the unfolded protein response (UPR) in NK cells. FLI1 induction following IL-15 signaling suppressed pro-survival UPR gene expression, limiting human NK cell proteostasis and intra-tumoral persistence. Fli1 deletion reduced protein aggregates and enhanced NK cell-mediated tumor control in vivo. Thus, the TME metabolome induces NK cell dysfunction through proteostasis imbalance, and FLI1 targeting may enhance NK cell anti-tumor function.
    Keywords:  Fli1; dysfunction; metabolism; natural killer cells; protein aggregate; proteostasis; solid tumors; tumor interstitial fluid; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.017
  24. Adv Drug Deliv Rev. 2026 Feb 17. pii: S0169-409X(26)00055-4. [Epub ahead of print] 115821
    NanoTAC in targeted protein degradation: Intelligent delivery platforms and synergistic therapeutic paradigms.
    Jieying Qian, Hongtao Duan, Qingqi Zheng, Yuzhao Yang, Xiaowan Huang, Bingyang Shi, Yunjiao Zhang.
      Targeted protein degradation (TPD) has reshaped therapeutic strategy by catalytically eliminating pathogenic proteins through engagement with endogenous proteolytic systems. In contrast to conventional inhibitors that transiently block enzymatic activity, TPD achieves durable target silencing by physically removing the protein entirely, thereby overcoming resistance mechanisms and extending therapeutic durability. This approach enables the pharmacological modulation of previously "undruggable" entities, such as transcription factors and scaffolding proteins, that lack canonical binding pockets. However, clinical translation of existing TPD platforms, including PROTACs and molecular glues, remains limited by poor bioavailability, off-target toxicity, and suboptimal tissue selectivity. Nanoparticle-assisted targeted protein degraders (NanoTACs) offer a compelling solution by coupling the catalytic efficiency of TPD with the spatial precision and tunability of nanotechnology. Through rational nanocarrier engineering, NanoTACs overcome key limitations of small-molecule degraders, including poor solubility, rapid systemic clearance, and inadequate targetability, while enabling direct and selective degradation of pathogenic proteins with minimal structural modification. This integration affords programmable control of biodistribution, cellular uptake, and release kinetics, as well as microenvironment-responsive degradation that is difficult to achieve with traditional modalities. Beyond functioning as delivery vehicles, NanoTACs actively recruit degradation machinery, modulate intracellular proteostasis, and permit synergistic co-delivery of therapeutic payloads. Emerging data demonstrate their capacity to degrade oncogenic drivers, suppress inflammatory signaling, and eliminate pathological protein aggregates across diverse disease models. This Review delineates the conceptual foundations, design principles, and translational prospects of NanoTACs, positioning them as a next-generation platform at the intersection of nanomedicine, chemical biology, and precision oncology.
    Keywords:  Disease therapy; Drug delivery; NanoTAC; Targeted protein degradation (TPD)
    DOI:  https://doi.org/10.1016/j.addr.2026.115821
  25. Bioinformatics. 2026 Feb 19. pii: btag088. [Epub ahead of print]
    A Deep Learning Framework for Comprehensive Prediction of Human RNA G-Quadruplex-Binding Proteins.
    Serena Rosignoli, Sophie Taraglio, Francesco Di Luzio, Elisa Lustrino, Dario Marzella, Arne Elofsson, Massimo Panella, Alessandro Paiardini.
       MOTIVATION: G-quadruplex-binding proteins (G4BPs) play key roles in RNA metabolism and stress response, yet their identification remains experimentally challenging. Here, we present a deep learning framework for the prediction of RNA G4BPs (RG4BPs), integrating diverse encoding strategies and neural architectures. Our best-performing model, which includes ESM-2 protein language model embeddings and consists of an LSTM architecture, achieved 86% accuracy in distinguishing RG4BPs from non-binders proteins. The application of this model to the human proteome uncovered 2,160 high-confidence RG4BP candidates, many of which display intrinsically disordered regions (IDRs) and enrichment in stress granule organelles. These findings reveal a potential link between G-quadruplex recognition and cellular stress responses. To enable easy and broad access to the framework, we developed G4REP, a web server for RG4BP prediction and analysis. Overall, an effective approach to explore the RG4BPs landscape and uncover novel players in RNA regulation is provided.
    AVAILABILITY: Source code for the G4REP Model training and evaluation is available at: https://github.com/G4REP/G4REPmodel and at https://doi.org/10.5281/zenodo.17963046 G4REP Server is hosted at: https://schubert.bio.uniroma1.it/g4/.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btag088
  26. Nature. 2026 Feb 18.
    The integrated stress response promotes immune evasion through lipocalin 2.
    Jozef P Bossowski, Ray Pillai, John Kilian, Angela Wong Lau, Mari Nakamura, Ali Rashidfarrokhi, Yuan Hao, Ruxuan Li, Katherine Wu, Takamitsu Hattori, Eliezra Glasser, Akiko Koide, Lidong Wang, Andre L Moreira, Cristina Hajdu, Sahith Rajalingam, Sarah E LeBoeuf, Hortense Le, Seungeun Lee, Jin Woo Oh, Cheolyong Joe, Hyemin Kim, Chan-Young Ock, Se-Hoon Lee, Hao Wang, Angana A H Patel, Volkan I Sayin, Aristotelis Tsirigos, Kwok-Kin Wong, Sergei B Koralov, Mario Pende, Francisco J Sánchez-Rivera, Diane M Simeone, Ioannis K Zervantonakis, Shohei Koide, Thales Papagiannakopoulos.
      Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.
    DOI:  https://doi.org/10.1038/s41586-026-10143-0
  27. iScience. 2026 Feb 20. 29(2): 114791
    The microcephaly-associated protein YIPF5 differentially regulates ER export.
    Francesca Bruno, Mihaela Anitei, Domenico Di Fraia, William Durso, Therese Dau, Emilio Cirri, Mara Sannai, Christina Valkova, Julija Maldutyte, Elizabeth A Miller, Ignacio Rubio, Vera Garloff, Noortje Kersten, Ginny G Farias, Alessandro Ori, Iván Mestres, Federico Calegari, Christoph Kaether.
      YIPF5 is an ER-membrane protein implicated in ER-Golgi transport. Mutations in YIPF5 cause MEDS2 (microcephaly, epilepsy, and neonatal diabetes syndrome), a fatal disorder manifesting in early childhood. We demonstrate that YIPF5 is involved in ER export of a subset of proteins, including cargoes of the ER export receptor SURF4, with which it directly interacts. YIPF5 knockout cells display altered cell surface and secretome profiles, with reduced neuronal adhesion molecules and increased secretion of ER chaperones affecting migration. YIPF5 depletion enhances cell migration in a wound-healing assay and alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from ER exit sites. Kinetic analysis suggests that YIPF5 negatively regulates SURF4-mediated ER export. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology. Our findings suggest that YIPF5 and SURF4 coordinate ER export of key proteins and disruption may underlie cortical development defects leading to microcephaly.
    Keywords:  Cell biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.114791
  28. Curr Res Struct Biol. 2026 Jun;11 100181
    Induced-proximity therapeutics for targeted protein and RNA degradation: An organic chemistry Perspective-A review.
    Mohammad Rizehbandi, Ehsan Dadfar, Mahyar Rezaei Nami, Mahdi Rezaei Nami, Mehran Rezaei Nami.
      Induced-proximity therapeutics have emerged as a transformative paradigm in chemical biology and drug discovery, enabling selective control of cellular processes beyond conventional inhibitors. Between 2020 and 2025, major progress has been achieved across five modalities: proteolysis-targeting chimeras (PROTACs), molecular glues, lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs) and related tethering strategies, and ribonuclease-targeting chimeras (RIBOTACs). Each exploits endogenous degradation or regulatory pathways using chemically engineered bifunctional or monofunctional small molecules, thereby expanding the druggable proteome and transcriptome. This review provides a comparative analysis of their underlying organic chemistry, design principles, and mechanistic diversity. We highlight structure activity relationships, linker optimization, and chemical motifs that govern induced proximity and degradation efficiency. Advances in ligand discovery, modular synthetic methodologies, and strategies to improve pharmacokinetics and tissue selectivity are emphasized. Schematic diagrams illustrate key mechanistic steps, offering a visual framework for comparing similarities and differences across approaches. While prior reviews have focused on mechanistic and pharmacological aspects, our perspective emphasizes synthetic strategies, linker chemistry, SAR studies, and ligand optimization principles that underpin each degrader class. We examine how advances in synthetic design, modular assembly, and chemical reprogramming of ligases or receptors have broadened therapeutic potential. By critically assessing strengths, limitations, and chemical challenges across modalities, we propose a unifying organic chemistry perspective that distinguishes induced-proximity strategies from conventional small-molecule inhibition and outlines future opportunities in degrader design.
    Keywords:  Linker chemistry; Molecular glues; PROTACs; RiboTACs; Structure–activity relationships (SAR); Targeted protein degradation
    DOI:  https://doi.org/10.1016/j.crstbi.2026.100181
  29. Dev Cell. 2026 Feb 19. pii: S1534-5807(26)00038-9. [Epub ahead of print]
    Insolubilome profiling defines molecular features that influence protein insolubility with aging.
    Anna Stephan, Flavia A Graca, Vishwajeeth R Pagala, Liam C Hunt, Chia-Lung Chuang, John Grime, Daniel Alford, Xusheng Wang, Anthony A High, Junmin Peng, Fabio Demontis.
      Solubility regulates protein function, but how it is governed by aging remains elusive. Here, we utilized mass spectrometry to define the relative composition of the soluble and insoluble tissue/organ fractions during mouse aging. In the young, there is a wide (∼100-1,000×) range of insoluble/soluble protein ratios that differ tissue-specifically. With aging, some proteins become relatively more insoluble, while others are conversely regulated or unaffected. Age-related insoluble/soluble changes are not merely dictated by histological similarity, diverge in related tissues with distinct degeneration propensities, and correlate tissue-specifically with structural features. Proteins that become age-insoluble in multiple organs include aggregation-prone circulating factors and ectopically expressed proteins. For instance, although primarily expressed by the epidermis, hornerin insolubility increases with aging in skeletal muscle, and experimental hornerin upregulation causes muscle weakness. Thus, age-insoluble proteins are useful biomarkers but can also contribute to age-related functional decline, highlighting a multifaceted remodeling of the insolubilome with aging.
    Keywords:  aging; ectopic proteins; insolubilome; inter-organ signaling; protein solubility; proteostasis
    DOI:  https://doi.org/10.1016/j.devcel.2026.01.015
  30. Essays Biochem. 2025 Dec 22. pii: EBC20253041. [Epub ahead of print]69(4):
    Structural insights into the Urm1-Uba4 pathway and its biological roles.
    Dominika Kwasna, Keerthiraju E Ravichandran, Anna Biela, Sebastian Glatt.
      Ubiquitin-related modifier 1 (Urm1) is a unique and evolutionarily conserved member of the ubiquitin-like protein (UBL) family that represents a molecular link between ancestral sulfur carrier proteins (SCPs) and canonical eukaryotic UBLs. Urm1 is required for the thiolation of tRNAs and a non-canonical post-translational modification, called 'urmylation'. Activation of Urm1 by its E1-like enzyme, ubiquitin-like protein activator 4 (Uba4), involves the sequential adenylation, thioesterification, and thiocarboxylation of Urm1's C-terminus. Thereby, Urm1 can provide sulfur for the tRNA modification reaction or catalyze its conjugation to target proteins through a mechanism that is independent of E2-conjugating enzymes and E3 ligases. Recent structural studies have resolved several key intermediates of the fungal Uba4-Urm1 system, shedding light onto its two distinct subdomains and their dynamical interplay. Notably, Urm1 also interacts with several additional up- or downstream partners of the two pathways. Foremost, urmylation couples an UBL-conjugation reaction with the persulfidation of a cysteine residue in the target proteins. This protective oxidative post-translational modification underscores Urm1's central role in redox regulation and cellular stress responses. Here, we aim to summarize the most recent mechanistic insights and structural advances in the eukaryotic Urm1-Uba4 pathway.
    Keywords:  TRNA; Urm1; persulfidation; thiolation; ubiquitin signaling; ubiquitins
    DOI:  https://doi.org/10.1042/EBC20253041
  31. Cell Chem Biol. 2026 Feb 18. pii: S2451-9456(26)00028-0. [Epub ahead of print]
    Lysosome-targeting chimeras enable targeted protein degradation.
    Bozhao Li, Yanyan Li, Jian Zhang, Siren Badama, Xian Zhao, Liping Wang, Tian Zhang, Xueting Wang, Xiaoqing Yi, Guo-Bin Ding, Xudong Wang, Guangjun Nie.
      Targeted protein degradation (TPD) has emerged as a powerful therapeutic paradigm by enabling the selective elimination of disease-associated proteins beyond the reach of conventional inhibition strategies. Among TPD approaches, lysosome-targeting chimeras (LYTACs) uniquely enable the degradation of extracellular and membrane-associated proteins through receptor-mediated endocytosis and lysosomal delivery. This Review provides a mechanistic and conceptual overview of LYTAC technology, emphasizing molecular classification based on ligand architecture, lysosome-targeting receptor engagement, and endocytic trafficking pathways. We discuss how receptors such as the cation-independent mannose-6-phosphate receptor and asialoglycoprotein receptor dictate internalization efficiency and degradation outcomes, and highlight key biochemical and cellular determinants governing target recognition, intracellular routing, and lysosomal processing. Finally, we examine major translational challenges, including tissue selectivity, pharmacokinetics, immunogenicity, and manufacturing constraints, and outline emerging design strategies such as ligand and linker engineering, modular scaffold optimization, and synthetic receptor recruitment that may enable next-generation LYTAC therapeutics with improved precision and clinical potential.
    Keywords:  LYTACs; extracellular protein degradation; lysosome-targeting chimeras; receptor-mediated endocytosis; targeted protein degradation
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.008
  32. Nat Commun. 2026 Feb 14.
    Structure and mechanism of the HECT ligase HECTD3.
    Jessica Huber, Diego Esposito, Sarah Maslen, Dominic O Chambers, J Mark Skehel, Katrin Rittinger.
      HECT E3 ligases regulate many cellular processes, yet how they recognise their substrates and synthesise specific types of poly-ubiquitin chains is still incompletely understood. HECTD3, a member of the "other HECT" family, is implicated in the regulation of inflammation, apoptosis, and infection and highly expressed in several cancers. These functions are largely attributed to its ligase activity and modification of diverse substrates with different types of ubiquitin chains. We present a detailed analysis of the ligase activity of HECTD3, including its ubiquitin linkage preferences, oligomeric state and substrate ubiquitination. Using cryo-EM, we provide the full-length structures of HECTD3 in both apo and ubiquitin-loaded forms, revealing key insights into its domain organisation, including discovery of a distinct fold of the N-terminal region, and mechanistic features. Some of these are shared with other HECT ligases, while others are unique to HECTD3 and contribute to differences in its catalytic mechanisms and functional diversity.
    DOI:  https://doi.org/10.1038/s41467-026-69520-y
  33. Geroscience. 2026 Feb 17.
    Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.
    Irini Topalidou, Nicolas Lehrbach.
      The proteasome is essential for cellular protein homeostasis through selective destruction of damaged and misfolded proteins. Failure of proteasome-dependent turnover accompanied by accumulation and aggregation of aberrant proteins is a hallmark of aging and late-onset neurodegenerative diseases. SKN-1A/Nrf1, a member of the NFE2L/Nrf family of transcription factors, is a master regulator of proteasome biogenesis. Through transcriptional control of proteasome subunit gene expression, SKN-1A/Nrf1 controls homoeostatic and stress-responsive upregulation of proteasome levels in adaptation to proteasome dysfunction or protein misfolding. SKN-1A/Nrf1 acts in concert with another Nrf family transcription factor, SKN-1C/Nrf2, to regulate many aspects of physiology including stress responses, redox balance, immunity, and metabolism. Here, we demonstrate that a small deletion in the promoter of the pbs-5 gene, which encodes an essential proteasome subunit, uncouples its expression from transcriptional regulation by SKN-1A/Nrf1. This disruption leads to compensatory SKN-1A/Nrf1-dependent upregulation of other proteasome subunit genes, resulting in a homeostatic imbalance in proteasomal gene expression. This pbs-5 regulatory mutation phenocopies some, but not all, aspects of SKN-1A/Nrf1 inactivation, providing evidence that coordinated regulation of proteasomal subunit gene expression underlies a subset of SKN-1A/Nrf1's physiological roles. In comparing the effects of the pbs-5 promoter deletion with isoform-specific inactivation of SKN-1A or SKN-1C, we show that the pbs-5 promoter mutation completely abrogates multiple lifespan extension paradigms. These results reveal that coordinated homeostatic regulation of proteasome subunit gene expression is critical for longevity and healthy aging.
    Keywords:  NFE2L1; Nrf1; PSMB5; Proteasome; Proteostasis; SKN-1A
    DOI:  https://doi.org/10.1007/s11357-026-02146-6
  34. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2532234123
    RNA-binding activity of PHGDH drives amyloid-beta production in a human brain organoid model of sporadic Alzheimer's disease.
    Junchen Chen, Ming Xu, Yuan Liu, Fatemeh Hadi, Shuanghong Xue, Shu Chien, Sheng Zhong.
      Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-β (Aβ), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives Aβ production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of EIF2AK1 mRNA, enabling the physical interaction between PHGDH and the EIF2AK1 protein. By facilitating the recruitment of EIF2AK1 to its substrate EIF2α, this complex drives EIF2α phosphorylation, thereby selectively promoting the translation of BACE1, the rate-limiting enzyme for Aβ generation. We demonstrate that PHGDH overexpression elevates BACE1 protein and intracellular Aβ in neurons and astrocytes across mouse models and human brain organoids, independent of its canonical enzymatic or transcriptional roles. Mechanistically, this process requires a specific RNA-binding surface within PHGDH and the EIF2AK1 3'UTR. These findings define a PHGDH-EIF2AK1-EIF2α-BACE1 axis as a key driver of the earliest amyloid pathology in sAD.
    Keywords:  Alzheimer’s disease; PHGDH; RNA binding; amyloid-β; brain organoids
    DOI:  https://doi.org/10.1073/pnas.2532234123
  35. J Cheminform. 2026 Feb 20. pii: 30. [Epub ahead of print]18(1):
    PROTAC-Splitter: a machine learning framework for automated identification of PROTAC substructures.
    Stefano Ribes, Ranxuan Zhang, Télio Cropsal, Anders Källberg, Christian Tyrchan, Eva Nittinger, Rocío Mercado.
      Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules composed of an E3 ligase ligand, a linker, and a warhead targeting a protein of interest. Despite their modular structure, accurately identifying and annotating these components in PROTACs is challenging and typically relies on manual curation and predefined substructure matching. To address this, we developed PROTAC-Splitter, a machine learning framework designed for automated annotation of PROTAC substructures. To address data scarcity, we generated and openly released a synthetic dataset containing approximately 1.3 million PROTAC structures with annotated ligand splits. Leveraging this dataset, we developed two complementary approaches for PROTAC substructure annotation: a Transformer-based sequence-to-sequence model and a graph-based XGBoost model. We evaluated both approaches on held-out public data and structurally novel PROTACs from AstraZeneca's proprietary collection. The Transformer-based model achieved high exact-match accuracy (86%) on public data but dropped significantly (18%) on structurally novel internal PROTACs due to occasional hallucinations. In contrast, the XGBoost model can ensure chemical validity and perfect reassembly accuracy on both sets, with lower exact-match accuracy on open-data (42.2%) but comparable performance on the internal set (23%). To improve reliability, we implemented a wrapper function for the Transformer (Transformer- Δ ), which corrects partial prediction errors, raising reassembly accuracy to 96% on public and 70% on internal datasets. Combining the strengths of both models, we propose a hybrid approach that reliably annotates PROTACs across diverse chemical spaces. PROTAC-Splitter provides a robust, scalable tool to facilitate automated PROTAC analysis and is available open-source at https://github.com/ribesstefano/PROTAC-Splitter.
    Keywords:  Cheminformatics; Drug discovery; Machine learning; PROTAC; Targeted protein degradation
    DOI:  https://doi.org/10.1186/s13321-025-01135-9
  36. J Neurosci. 2026 Feb 18. pii: e1727252026. [Epub ahead of print]
    Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity.
    Christian B Lessard, Diego Rubio Rubio, Samantha Tolton, Marangelie Criado-Marrero, Sakthivel Ravi, Tristyn N Garza, John Koren, Jennifer Philips, Pritha Bagchi, Karen McFarland, Deepak Chhangani, Todd Golde, Benoit I Giasson, Jada Lewis, Paramita Chakrabarty, Matthew J LaVoie, David Borchelt, Nicholas T Seyfried, Stefan Prokop, Diego E Rincon-Limas, Jose F Abisambra.
      The unfolded protein response (UPR) sensor PERK exists in haplotypes A and B. PERK-B confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tauopathy remain unknown. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. Puromycin-based proteomics highlighted a subset of mRNA translation events was permissible under the PERK-B, but not the PERK-A, dependent UPR. One of the targets that escaped PERK-B suppression was the transcription factor DLX1, which is genetically linked to PSP risk. We found that DLX1 solubility shifted to a detergent-insoluble fraction in human brain tissue from male and female PSP donors. Furthermore, silencing the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.Significance Statement Progressive supranuclear palsy (PSP) is a devastating neurodegenerative tauopathy with no effective treatments. This study identifies how a genetic risk factor for PSP, the PERK-B haplotype, contributes to disease pathogenesis. Using novel cellular and animal models, we demonstrate that PERK-B selectively promotes translation of DLX1, a transcription factor genetically linked to PSP. Importantly, DLX1 accumulates in a detergent insoluble fraction in human PSP brains, and reducing DLX1 mitigates tau-induced toxicity in vivo. These findings reveal a previously unknown PERK-B/DLX1 pathway that drives tauopathy. By elucidating this mechanism, our work opens new avenues for therapeutic intervention in PSP and related tauopathies. More broadly, this research highlights the importance of haplotype-specific effects and selective translational regulation in neurodegenerative disease, with implications for personalized medicine approaches.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1727-25.2026
  37. J Obstet Gynaecol Res. 2026 Feb;52(2): e70209
    Endoplasmic Reticulum Stress-Induced Membrane Exposure of Calreticulin Serves as a Guide for Phagocytic Removal of Stressed-But-Viable Cytotrophoblasts.
    Midori Ikezaki, Kaho Nishioka, Kazuchika Nishitsuji, Megumi Fujino, Noa Mori, Kenji Uchimura, Kazuhiko Ino, Naoyuki Iwahashi, Yoshito Ihara.
       AIM: Calreticulin (CRT), a protein in the endoplasmic reticulum (ER), plays critical roles in protein quality control and homeostasis of cytosolic and ER calcium levels. We previously reported that ER stress, a risk factor for poor placentation and preeclampsia, induced extracellular release of CRT in a cytotrophoblast (CTB) BeWo cell model; extracellular CRT impaired CTB syncytialization. Several stresses, including ER stress, reportedly exposed CRT on membranes, but the roles of membrane-exposed CRT in CTBs have remained unclear.
    METHODS: We investigated whether ER stress-induced membrane exposure of CRT in CTBs and whether membrane-exposed CRT acted as a guide for phagocytic removal of stressed CTBs.
    RESULTS: Immunohistochemical analysis of preeclamptic placentas demonstrated increased expression of immunoglobulin heavy chain-binding protein, which indicated enhanced ER stress in preeclamptic placentas. The ER stress inducers thapsigargin and tunicamycin-induced membrane exposure of CRT in BeWo cells and primary human CTBs. Phorbol ester-differentiated THP-1 cells phagocytosed ER-stressed and CRT-exposing CTBs, which were blocked by an anti-CRT antibody.
    CONCLUSIONS: Our results thus propose a pathway for removal of damaged CTBs and thus for maintaining pregnancy. Because ER stress is a risk factor for poor placentation, investigation of physiological and pathological roles of CRT exposure-mediated phagocytic removal deserves future study.
    Keywords:  Calreticulin; endoplasmic reticulum stress; trophoblast
    DOI:  https://doi.org/10.1111/jog.70209
  38. Biol Pharm Bull. 2026 ;49(2): 291-300
    Ouabain Suppresses CD63 Loading into Extracellular Vesicles via Na+/K+-ATPase-Dependent Localization to Autophagosomes.
    Haruki Adachi, Takeshi Yoshida, Reina E Itoh, Chitose Oneyama.
      Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transferring lipids, proteins, and nucleic acids. However, the mechanisms determining selective cargo loading into EVs remain poorly understood. Here, we identify the cardiac glycoside ouabain as a selective inhibitor of CD63 loading into EVs. Using a luciferase-based high-throughput assay with CD9- and CD63-tagged reporter cells, ouabain was found to specifically suppress CD63 loading into EVs without affecting CD9 loading into EVs. Ouabain, Na+/K+-ATPase inhibitor, did not suppress EV secretion but markedly decreased CD63 incorporation. Other cardiac glycoside with strong Na+/K+-ATPase inhibitory activity, such as bufalin, exhibited similar effects, whereas weak inhibitors did not. Ouabain induced the internalization of Na+/K+-ATPase (ATP1A1) with CD63, resulting in the disappearance of CD63 from the plasma membrane. Furthermore, ouabain activated autophagy and promoted the colocalization of CD63 with autophagosomes, thereby selectively inhibiting the loading of CD63 into EVs. These effects required both Na+/K+-ATPase-dependent endocytosis and autophagy, as rapamycin-induced autophagy alone did not remove surface CD63. Our findings reveal a previously unrecognized mechanism in which cardiac glycoside regulates EV cargo composition by coupling Na+/K+-ATPase-mediated endocytosis with autophagy. Given that endogenous and therapeutic cardiac glycosides are implicated in cardiovascular and cancer biology, this mechanism may broadly influence EV-mediated intercellular communication and represent a potential target for modulating EV functions.
    Keywords:  CD63; Na+/K+-ATPase; autophagy; cardiac glycoside; extracellular vesicle
    DOI:  https://doi.org/10.1248/bpb.b25-00715
  39. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2518759123
    The Crohn's disease-related RNF123 prevents NLRP3 inflammasome assembly by catalyzing unanchored K63-linked ubiquitination on NEK7.
    Feng Liu, Wanxin Zhuang, Yuan Yang, Wenting Zhao, Siyuan Li, Ziyue Zhang, Yifan Liu, Bingyu Liu, Xiaopeng Qi, Wei Zhao, Lintai Da, Chengjiang Gao.
      The NLRP3 inflammasome is crucial for host defense against pathogen invasion and is implicated in various inflammatory disorders. The pathogenic association and the involved mechanism between the NLRP3 inflammasome and inflammatory diseases have garnered significant attention. Here, we demonstrate that Crohn's disease-associated SNP RNF123-R854H aggravates colitis in vivo through the NLRP3-dependent pathway. Deficiency of RNF123 also aggravates dextran sodium sulfate-induced colitis, LPS (lipopolysaccharide)-induced endotoxemia, and Alum-induced peritonitis and enhances host defense against bacterial infection via the NLRP3-dependent pathway in vivo and promotes the NLRP3 inflammasome activation in cells. We establish RNF123 as a regulator for the NLRP3 inflammasome, highlighting its implication in the NLRP3 inflammasome-driven inflammatory diseases. Mechanistically, RNF123 catalyzes unanchored K63-linked ubiquitination of NEK7, thereby preventing NEK7-mediated dissociation of the inactive cage-like NLRP3 aggregates and the subsequent NLRP3 inflammasome assembly. Additionally, we prove that K63-linked polyubiquitin chains can be specifically captured by NEK7 in vitro and inhibit the NEK7-licensed NLRP3 inflammasome assembly. We propose that NEK7-captured unanchored K63-polyubiquitin chains serve as a key determinant for the NLRP3 inflammasome activation, acting as a molecular brake to limit the excessive NLRP3 inflammasome activation and preserve immune homeostasis. Our work yields mechanistic insights into the NLRP3 inflammasome regulation and its pathogenic link to inflammatory disease.
    Keywords:  NEK7; NLRP3; RNF123; inflammatory disease; unanchored K63-linked polyubiquitin chains
    DOI:  https://doi.org/10.1073/pnas.2518759123
  40. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2532796123
    The ISR downstream effector ATF4 promotes mGluR-dependent long-term depression and associated behavior.
    Niaz Mahmood, Cong Loc Dang, Pei You Wu, Ziying Huang, Jung-Hyun Choi, Konstantina Psycharis, Reuben Portugese, Arkady Khoutorsky, Mauro Costa-Mattioli, R Anne McKinney, Nahum Sonenberg.
      The integrated stress response (ISR) plays a crucial role in cognition via bidirectional modulation of the two major forms of synaptic plasticity, long-term potentiation, and long-term depression (LTD). Specifically, inhibition of the ISR blocks metabotropic glutamate receptor-dependent LTD (mGluR-LTD), whereas its activation facilitates this form of synaptic depression. However, the contribution of activating transcription factor 4 (ATF4), the best studied downstream effector of the ISR, to mGluR-LTD remains unknown. Here, we show that pharmacological activation of group I mGluRs in mouse hippocampal slices increases ATF4 protein levels without altering its transcription and concurrently downregulates the expression of oxidative phosphorylation (OXPHOS) proteins. Selective deletion of ATF4 in excitatory neurons impairs mGluR-LTD and prevents the downregulation of OXPHOS proteins. Notably, administration of a small molecule inhibitor of OXPHOS rescues the impaired mGluR-LTD in ATF4-depleted hippocampal slices, indicating that ATF4 regulates this type of synaptic plasticity by modulating mitochondrial function. Moreover, ATF4 deletion in excitatory neurons disrupts object-place learning, an mGluR-LTD-dependent behavior paradigm. Together, these findings reveal a role of ATF4 as a key mediator of protein synthesis-regulated synaptic depression and related behaviors.
    Keywords:  integrated stress response; mGluR-LTD; synaptic plasticity
    DOI:  https://doi.org/10.1073/pnas.2532796123
  41. J Lipid Res. 2026 Feb 13. pii: S0022-2275(26)00027-1. [Epub ahead of print] 101001
    Lipidation as a post-translational code for protein liquid-liquid phase separation.
    Soodabeh Abbasi Sani, Agnieszka Chytła, Martin Sztacho.
      Liquid-liquid phase separation has emerged as a central organizing mechanism that drives the formation of biomolecular condensates and enables cells to spatially and temporally coordinate metabolism, signaling, and gene expression. While the influence of post-translational modifications such as phosphorylation and ubiquitination on condensate behavior is well established, the contribution of lipidation, the covalent attachment of lipid moieties to proteins, to these processes has received far less attention. Lipidation dictates protein hydrophobicity, membrane affinity, and subcellular distribution, yet how these parameters influence LLPS and thereby modulate condensate dynamics remains unclear. We propose that lipidation operates as a molecular code that integrates membrane association with phase separation, thereby tuning the assembly, composition, and thus functional output of condensates. Extending this concept beyond classical membrane systems, we further suggest that nuclear phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) may act as an unconventional lipid modifier that structures membrane-less nuclear compartments through a process termed PIPoylation. Drawing on recent findings, we outline how canonical covalent lipidations, including palmitoylation, myristoylation, prenylation, and phospholipidation, govern membrane nanodomain organization, autophagy, and nuclear condensate architecture. We discuss how covalent lipidation influences condensate wetting, membrane curvature, and lipid-protein demixing, and how PI(4,5)P2 metabolism links chromatin remodeling with transcriptional control via LLPS. Together, these mechanisms underscore lipidation as a crucial regulator of condensate-membrane communication across cellular compartments.
    Keywords:  biomolecular condensates; cell signaling; lipid rafts; membrane organization; phosphoinositides; phospholipids; post-translational modifications; transcription
    DOI:  https://doi.org/10.1016/j.jlr.2026.101001
  42. Nat Commun. 2026 Feb 19.
    PAN2 maintains mRNA poly(A) tail homeostasis and regulates translation during spermiogenesis in mice.
    Xuan Wu, Yu-Ke Wu, Meng-Yan Jia, Zhuoyue Niu, Jingwen Liu, Wen-Jing Wang, Zhi-Yan Jiang, Falong Lu, Lu Chen, Liling Liu, Heng-Yu Fan.
      The elongation and shortening of poly(A) tails are the most common types of post-transcriptional mRNA regulation in eukaryotic cells. PAN2-PAN3 and CCR4-NOT complexes are the main cytoplasmic enzymes that trim the poly(A) tails of mRNAs. However, the in vivo function of PAN2-PAN3 in mammals remains unclear. Here, we found that the germline-specific deletion of Pan2 causes male infertility due to a step-8/9 spermatogenic arrest, while meiotic prophase proceeds normally. Using PAIso-seq2 and mass spectrometry analyses, we define stage-specific remodeling of poly(A) tails that is disrupted in Pan2-null round spermatids (RS). Ribo-lite reveals a global reduction in translation efficiency in Pan2-deficient RS, correlating with proteomic changes and impairing pathways for spermatid differentiation. Endogenous IP-MS identifies PAN2 association with PABPC1 and initiation factors (EIF4E, EIF4A1, EIF5A), whose protein levels decline upon Pan2 loss, indicating compromised stability of key translational machinery. Together, these findings highlight the important physiological functions of PAN2 in spermiogenesis and expand our understanding of the post-transcriptional regulation of mRNAs in specific physiological processes.
    DOI:  https://doi.org/10.1038/s41467-026-69639-y
  43. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  44. Subcell Biochem. 2026 ;111 331-350
    Golgi Membrane-Associated Degradation (GOMED), a New Intracellular Proteolysis Mechanism.
    Shigeomi Shimizu, Shinya Honda, Satoru Torii, Satoko Arakawa, Masatsune Tsujioka, Hirofumi Yamaguchi, Hajime Tajima Sakurai.
      The Golgi apparatus is a crucial organelle that is involved in various cellular processes, including cellular secretion, and is primarily responsible for the modification, sorting, and transport of proteins and lipids. However, recently, we discovered a novel Golgi function, namely, Golgi membrane-associated degradation (GOMED). GOMED is a cellular function in which the trans-Golgi membrane undergoes deformation and becomes spherical, breaking down proteins and lipids that have been internalized. This process is conserved from yeast to mammalian cells. GOMED primarily plays a role in the quality control of hormones, cytokines, and cell membrane receptors that pass through the Golgi apparatus, and is crucial for maintaining the normal function of pancreatic β cell, neurons, and intestinal epithelial cells. Therefore, abnormalities in GOMED can lead to neurodegenerative diseases and inflammatory bowel diseases.
    Keywords:  Autophagy; GOMED; Golgi apparatus; ULK1; Wipi3
    DOI:  https://doi.org/10.1007/978-3-032-16833-7_14
  45. Adv Sci (Weinh). 2026 Feb 15. e18058
    Antagonistic Ubiquitin Switching by USP7 and RNF40 Orchestrates KDM6A Homeostasis to License Coronavirus Susceptibility.
    Meng-Zhuo Huang, Zhong-Yuan Yang, Shi Wang, Yan Ge, Lan Lin, Mia Madel Alfajaro, Renata B Filler, Wan-Yao Song, Ming-Zhu Kong, Jin Wei.
      Lysine demethylase 6A (KDM6A) is a critical epigenetic regulator implicated in development, cancer, and viral infection. Although KDM6A enhances coronavirus entry by modulating viral receptor expression, the mechanisms governing its protein stability remain unknown. Here, we show that ubiquitin-specific protease 7 (USP7) promotes diverse coronavirus infection, including SARS-CoV, SARS-CoV-2, MERS-CoV, and MHV, and represents a broad-spectrum anti-coronavirus target. Genetic and pharmacological inhibition of USP7 attenuates the expression of coronavirus receptors ACE2, DPP4, and Ceacam1, thereby impeding viral entry. Mechanistically, USP7 deubiquitinates KDM6A by removing K48-linked polyubiquitin chains to prevent its proteasomal degradation. Conversely, the E3 ubiquitin ligase RNF40 catalyzes K6- and K11-linked ubiquitination of KDM6A, which serves as a signal for recognition by TAX1BP1 for autophagic degradation, to restrict diverse coronavirus infection. Pharmacological inhibition of USP7 with FT671 and XL177A reduces KDM6A stability and viral receptor expression, and confers resistance to MERS-CoV, SARS-CoV, and all major SARS-CoV-2 variants of concern, including those resistant to remdesivir in primary human airway and intestinal epithelial cells. In mice, FT671 treatment was well tolerated, reduced Ceacam1 expression, and protected against MHV-A59 infection. Collectively, our findings unveil an antagonistic ubiquitin-mediated regulatory circuit that controls KDM6A stability, viral receptor levels, and coronavirus infection.
    Keywords:  Autophagy; Coronavirus; KDM6A homeostasis; Ubiquitination; Viral receptor
    DOI:  https://doi.org/10.1002/advs.202518058
  46. ACS Med Chem Lett. 2026 Feb 12. 17(2): 495-502
    Discovery of Isohexide Bisglycolamides as Inhibitors of the Integrated Stress Response.
    Vincent J Colandrea, Amruta Joshi-Pangu, Robert T Nolte, Randy K Bledsoe, Paris Ward, Jack Glancy, Matthew D Kowalski, Chelsea A Huff, Sapna Desai, Rakesh Nagilla, Nicholas J Laping, Jeffrey M Axten, Karen A Evans.
      ISRIB reactivates protein synthesis for cells under stress through the stabilization of eukaryotic initiation factor 2 beta (eIF2B). We discovered that diaminoisohexides, derived from isomannide and isosorbide serve as a bioisostere for the diamino cyclohexane core in ISRIB. These scaffolds conferred improved solubility but also showed activity for the human ether-a-go-go-related gene (hERG). Herein we describe our efforts to mitigate hERG activity while maintaining target potency. The first high resolution (2.25Å) X-ray cocrystal structure of the eIF2B (α,β,δ)2 complex with compound 7a is reported, which can inform subsequent SAR.
    Keywords:  ISRIB; eIF2B; hERG; integrated stress response; isomannide; isosorbide
    DOI:  https://doi.org/10.1021/acsmedchemlett.5c00698
  47. Sci Adv. 2026 Feb 20. 12(8): eaeb5106
    Covalent capture and genetic code expansion enables chemoproteomic profiling and functional characterization of lysine acetoacetylation.
    Xiaohan Song, Yuhan Lu, Xinlong Guo, Yanan Zheng, He Huang.
      Lysine acetoacetylation (Kacac) driven by metabolite acetoacetic acid represents a molecular mechanism by which ketone bodies regulate cellular functions beyond energy provision. However, comprehensive characterization of Kacac has been hindered by technical limitations in detection and functional validation. Here, we report an integrated platform for systematic Kacac investigation. Exploiting the unique reactive ketone carbonyl moiety, we developed Aca-Bio, a hydroxylamine-based probe enabling specific enrichment of Kacac peptides through ketone-targeted covalent labeling and pH-controlled reversible enrichment. Application to mouse liver identified 260 Kacac sites across 125 proteins, revealing notable enrichment in metabolic pathways. Concurrently, we established a genetic code expansion system enabling site-specific Kacac incorporation. Using this approach, we demonstrated that K310acac in HMGCS2 substantially attenuates catalytic activity through impaired substrate binding. This dual-platform approach establishes a comprehensive framework for global profiling and site-specific functional characterization of Kacac, thereby facilitating systematic exploration of its physiological roles and pathological implications.
    DOI:  https://doi.org/10.1126/sciadv.aeb5106
  48. Biochem Biophys Res Commun. 2026 Feb 18. pii: S0006-291X(26)00257-3. [Epub ahead of print]809 153493
    FOSL2 drives acute myeloid leukemogenesis through suppression of ERAD-induced proteostatic collapse.
    Wangshi Li, Meiling Sun, Binyu Yao, Xinyu Li, Ting Qiu, Xingzhi Lv, Yue Wu, Xingxing Du, Fukai Liu, Ruolin Xiu, Yanhong Zhao, Shengjin Fan, Keyang Luo, Huitao Fan.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by poor clinical outcomes and high relapse rates, driven largely by intrinsic or acquired chemoresistance. Despite advances, the standard "7 + 3″ chemotherapy backbone offers limited long-term survival, underscoring the urgent need for novel molecular targets to overcome therapeutic bottlenecks. While the AP-1 transcription factor FOSL2 is implicated in solid tumors, its role in AML remains unexplored. Here, we identify and validate FOSL2 as a critical oncogenic driver in AML. Comprehensive bioinformatic analysis across multiple independent patient cohorts reveals that its aberrant overexpression is a key feature and robust biomarker, correlating significantly with adverse clinical outcomes. Functional studies using shRNA-mediated silencing demonstrated that FOSL2 is indispensable for leukemic cell survival and proliferation. Its genetic depletion profoundly abrogated clonogenic potential, induced G0/G1 cell-cycle arrest and apoptosis, and promoted myeloid differentiation in vitro. In a xenograft mouse model, FOSL2 knockdown markedly suppressed leukemic tumor burden and significantly extended overall survival. Mechanistically, transcriptomic profiling revealed that FOSL2 depletion upregulates the E3 ubiquitin ligase HRD1 suggesting that FOSL2 depletion may hyperactivate the endoplasmic reticulum-associated degradation (ERAD) pathway. This uncontrolled ERAD activity dismantles cellular proteostasis, culminating in heightened ER stress and significant DNA damage, as evidenced by comet assays. Consequently, this FOSL2-deficient state profoundly sensitizes AML cells to conventional chemotherapies, including doxorubicin and cytarabine, as well as ER stress-inducing agents. Collectively, these findings establish that FOSL2 orchestrates a key proteostatic vulnerability. Targeting the FOSL2-ERAD axis represents a compelling therapeutic strategy to dismantle chemoresistance and improve patient outcomes in AML.
    Keywords:  Acute myeloid leukemia; DNA damage; ERAD; FOSL2; HRD1
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153493
  49. Curr Protoc. 2026 Feb;6(2): e70326
    Protocols for Monitoring Unconventional Protein Secretion Using Luminescence and Trapping Approaches.
    Eloïse Néel, Morgane Denus, William Fargues, Charline Gal, Camille Enjolras, Ana Boulanger, Marie-Laure Parmentier, Julien Villeneuve.
      Unconventional protein secretion (UcPS) enables the export of cytosolic proteins through pathways that bypass the canonical endoplasmic reticulum-Golgi secretory route. Although increasingly recognized as essential for intercellular communication, stress responses, and tissue homeostasis, UcPS remains difficult to quantify due to low secretion efficiency, high intracellular background, and the challenge of distinguishing active secretion from passive leakage. Recent methodological advances, including NanoLuc split luciferase-based reporters and the Retention Using Selective Hooks (RUSH) system for synchronized protein transport, have improved sensitivity and temporal control of trafficking. Here, we present complementary protocols integrating these tools to provide a highly sensitive, quantitative workflow centered on a split NanoLuc (HiBiT/LgBiT) complementation assay for monitoring UcPS in mammalian cells. The Basic Protocol describes a robust luminescence-based secretion assay, while the Support Protocols detail the generation of stable HiBiT reporter cell lines, approaches for probing UcPS mechanisms using siRNA-mediated gene knockdown and pharmacological perturbation, and the incorporation of the RUSH system to synchronize cargo release and identify potential trafficking intermediates. Together, these protocols provide a sensitive, scalable, high-throughput toolkit that enables analysis of UcPS mechanisms across diverse cargo proteins, cell types, and perturbations. This methodological framework allows for rigorous dissection of UcPS pathways in both physiological and disease-relevant contexts. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Split luciferase complementation assay for quantifying UcPS in mammalian cells Support Protocol 1: Generation of stable cell lines expressing HiBiT-tagged cargo proteins for the split luciferase assay Support Protocol 2: siRNA-mediated knockdown to assess the role of candidate genes in UcPS Support Protocol 3: Pharmacological perturbation of UcPS Support Protocol 4: Integration of the RUSH system to synchronize UcPS.
    Keywords:  RUSH; Retention Using Selective Hooks; intracellular compartments; protein trafficking; secretory pathways; split luciferase; unconventional protein secretion
    DOI:  https://doi.org/10.1002/cpz1.70326
  50. Sci Adv. 2026 Feb 20. 12(8): eadz3026
    Structures of the 26S proteasome in complex with the Hsp70 co-chaperone Bag1 reveal a mechanism for direct substrate transfer.
    Moisés Maestro-López, Tat Cheung Cheng, Jimena Muntaner, Margarita Menéndez, Melissa Alonso, Andreas Schweitzer, Masato Ishizaka, Robert J Tomko, Jorge Cuéllar, José María Valpuesta, Eri Sakata.
      Coupling between the chaperone and degradation systems, particularly under stress, is essential for eliminating unfolded proteins. The co-chaperone Bag1 links Hsp70 to the 26S proteasome, recruiting Hsp70-bound clients for proteasomal degradation. Here, we present cryo-electron microscopy structures of the Bag1-bound 26S proteasome, revealing unprecedented conformational rearrangements within the 19S regulatory particle. Bag1 binding to the Rpn1 induces a marked reconfiguration of AAA+ adenosine triphosphatase (ATPase) ring, disrupting its canonical spiral staircase and remodeling the central channel architecture. This reconfiguration generates a large cavity above the substrate entry gate of the 20S core particle. The conserved pore-2 loops of ATPases Rpt2 and Rpt5 play critical roles in opening of the 20S gate, enabling substrate entry into proteolytic chamber independently of ubiquitination. These findings suggest a previously unknown mechanism of the proteasomal degradation, by which remodeling the central cavity and 20S gate in the presence of Bag1, possibly bypassing the need for ubiquitination.
    DOI:  https://doi.org/10.1126/sciadv.adz3026
  51. Nature. 2026 Feb 18.
    Single-cell and isoform-specific translational profiling of the mouse brain.
    Samantha L Sison, Federico Zampa, Eric R Kofman, Su Yeun Choi, Pratibha Jagannatha, Grady G Nguyen, Jack T Naritomi, Asa Shin, Akanksha Khorgade, Wenhao Jin, Chun-Yuan Chen, David M Sievert, Sourish Mukhopadhyay, Orel Mizrahi, Steven M Blue, Ryan J Marina, Dong Yang, Cailynn C Wang, Zhengyuan Pang, Kristopher W Brannan, Li Ye, Aziz M Al'Khafaji, Gene W Yeo, Giordano Lippi.
      The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation1-11. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders12-17. However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain18. We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.
    DOI:  https://doi.org/10.1038/s41586-026-10118-1
  52. Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00012-4. [Epub ahead of print]45(2): 116934
    Nanoscopic tau aggregates are not shared intermediates but disease-specific entities across tauopathies.
    Dorothea Böken, Melissa Huang, Yunzhao Wu, Emre Fertan, Matthew W Cotton, Georg Meisl, Jeff Y L Lam, Shaan Baig, James B Rowe, Colin Smith, Annelies Quaegebeur, Dezerae Cox, William A McEwan, David Klenerman.
      Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterize these small tau aggregates from postmortem brain of individuals with Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Pick's disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine 356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets.
    Keywords:  Alzheimer’s disease; CBD; CP: Neuroscience; PSP; Pick’s disease; Simoa; single molecule; super-resolution microscopy; tau; tau aggregates; tauopathies
    DOI:  https://doi.org/10.1016/j.celrep.2026.116934
  53. Cell. 2026 Feb 19. pii: S0092-8674(26)00056-5. [Epub ahead of print]
    A GPX1-OSBPL8 axis mediates noncanonical in vivo ferroptosis and cancer growth suppression.
    Zhangchuan Xia, Xin Yang, Sviatlana N Samovich, Yulia Y Tyurina, Vladimir A Tyurin, Ning Kon, Jiankang Zhang, Xuejun Jiang, Brent R Stockwell, Jian Jin, Hülya Bayir, Valerian E Kagan, Wei Gu.
      Ferroptosis is a tumor-suppressive mechanism with therapeutic potential. While canonical ferroptosis is usually triggered by inducers, such as erastin and RSL-3, or by glutathione peroxidase (GPX)4 loss, how ferroptosis occurs naturally in vivo without these triggers has been unclear. Building on evidence that p53 can mediate ferroptosis as a natural tumor-suppressive pathway, we describe a noncanonical, in vivo ferroptosis driven by reactive oxygen species (ROS)-induced phosphatidic acid (PA) peroxidation that proceeds without inducers. We identify GPX1 as a key regulator of this ROS-induced ferroptosis by modulating PA peroxidation. GPX1's effects depend on OSBPL8, an endoplasmic reticulum (ER)-membrane-associated oxysterol-binding protein. ROS-driven lipid peroxidation accumulates at the ER before plasma membrane rupture and cell death; GPX1 is recruited to the ER via OSBPL8 and directly reduces oxidized PA. OSBPL8 and GPX1 are overexpressed in cancers; knockdown of either promotes ROS-induced ferroptosis and suppresses tumor growth. Our data link the GPX1-OSBPL8 axis to in vivo ferroptosis and tumor suppression.
    Keywords:  GPX1; GPX4; OSBPL8; ROS; cancer; ferroptosis; lipid peroxidation; p53; phosphatidic acid; phosphatidylethanolamine; tumor suppression
    DOI:  https://doi.org/10.1016/j.cell.2026.01.009
  54. Exp Cell Res. 2026 Feb 17. pii: S0014-4827(26)00061-3. [Epub ahead of print] 114944
    DSN1 Promotes Colorectal Cancer Metastasis by Inhibiting FZR1-Mediated Ubiquitination of c-MYC.
    Chenkai Zhang, Ziming Yuan, Hanqing Hu, Chunlin Wang, Jiaqi Wang, Jun Xiang, Nana Zhang, Wenyang Li, Songtao Yu, Danil Galiullin, Ibatullin Artur, Hao Zhang, Guiyu Wang.
      Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the need to clarify its molecular drivers. Here, we identify DSN1 as a key promoter of CRC invasion and metastasis. Analysis of clinical samples and public datasets revealed that DSN1 is significantly upregulated in CRC tissues and associated with poor overall survival. Functional assays demonstrated that DSN1 knockdown markedly suppressed CRC cell migration and invasion in vitro and reduced metastases in vivo. Mechanistically, DSN1 knockdown accelerated c-MYC protein degradation without affecting its mRNA levels. Cycloheximide chase and proteasome inhibition assays confirmed that DSN1 stabilizes c-MYC by preventing its ubiquitin-proteasome-mediated degradation. We further identified FZR1 as a c-MYC targeting E3 ligase and showed that DSN1 competes with c-MYC for FZR1 binding, thereby attenuating c-MYC ubiquitination. Rescue experiments confirmed that c-MYC overexpression reversed the anti-metastatic effects of DSN1 silencing. Collectively, our findings uncover a DSN1-FZR1-c-MYC regulatory axis that sustains c-MYC stability and drives CRC progression, highlighting DSN1 as a potential therapeutic target.
    Keywords:  Cell Biology; Metastasis; Signal pathway; c-MYC; ubiquitination
    DOI:  https://doi.org/10.1016/j.yexcr.2026.114944
  55. Cell. 2026 Feb 18. pii: S0092-8674(26)00050-4. [Epub ahead of print]
    Unified modeling of 3D molecular generation via atomic interactions with PocketXMol.
    Xingang Peng, Ruihan Guo, Fenglin Guo, Ziyi Wang, Jiayu Sun, Jiaqi Guan, Yinjun Jia, Yan Xu, Yanwen Huang, Muhan Zhang, Jian Peng, Xinquan Wang, Chuanhui Han, Zihua Wang, Jianzhu Ma.
      We present PocketXMol, an atom-level model that unifies generative tasks related to protein pocket interactions. Using atomic prompts as task specifications, PocketXMol supports various molecular tasks, including structure prediction and de novo design of small molecules and peptides, without task-specific fine-tuning. PocketXMol achieved strong performance on 11 of 13 computational benchmarks and remained competitive on the remaining two, outperforming 55 baseline models. We applied PocketXMol to design caspase-9-inhibiting small molecules, achieving efficacy comparable with commercial pan-caspase inhibitors. We also adopted PocketXMol to generate PD-L1-binding peptides, resulting in a success rate that largely exceeds library screening. Three representative peptides underwent further experiments, which validated their cellular specificity and confirmed their potential for molecular probing and therapeutics. PocketXMol provides a general platform for AI-aided drug discovery and enables a wide range of future applications.
    Keywords:  atom-level interaction; drug design; foundation model; generative model; molecular docking; molecular interaction; molecular structure prediction; peptide design; protein pocket; unified AI model
    DOI:  https://doi.org/10.1016/j.cell.2026.01.003
  56. Biochemistry (Mosc). 2026 Jan;91(1): 188-198
    C-Terminal Fragment of Filamin C Containing Immunoglobulin-Like Domains 19-24 Selectively Interacts with the Small Heat Shock Protein HspB7.
    Maria A Zamotina, Lidia K Muranova, Pyotr A Tyurin-Kuzmin, Nikolai N Sluchanko, Nikolai B Gusev.
      Filamin C is an adapter protein involved in the regulation of cytoskeleton; it interacts with more than 90 protein partners, including small heat shock proteins (sHsps). However, the details of filamin C interaction with sHsps remain poorly characterized. Here, we used immunochemistry methods, size-exclusion chromatography, native gel electrophoresis, and chemical crosslinking to investigate the interactions of a long C-terminal fragment of filamin C containing immunoglobulin (Ig)-like domains 19-24 (FLNC19-24) with sHsps. Out of five analyzed sHsps (HspB1, phosphorylation-mimicking 3D mutant of HspB1, HspB5, HspB6, HspB7, and HspB8), only HspB7 formed complexes with FLNC19-24. Taking into account that HspB7 interacted with the isolated Ig-like domain 24 and filamin fragments containing Ig-like domains 22-24 and 19-24, we concluded that HspB7 is a bona fide partner of filamin C. Selective binding of the α-crystallin domain of HspB7 with the Ig-like domain 24 induced dissociation of filamin dimers, which might promote filamin C translocation in the cell and facilitate the repairs of damaged contractile apparatus.
    Keywords:  filamin C; immunoglobulin-like domains; small heat shock proteins
    DOI:  https://doi.org/10.1134/S0006297925603624
  57. Subcell Biochem. 2026 ;111 317-329
    STING Innate Immunity Signalling from the Golgi.
    Tomohiko Taguchi.
      The cGAS-STING pathway has recently emerged as a critical driver of inflammation in a variety of settings, such as double-stranded DNA (dsDNA) virus infection, cellular stress, and tissue damage. The pathway senses microbial and host-derived dsDNA in the cytosol, and triggers the production of the type I interferons through the activation of TBK1 (kinase) and IRF3 (transcription factor). The detailed mechanistic understanding of the pathway has enabled the development of pharmacological agents for the treatment of chronic inflammation and cancer. STING is a transmembrane protein that localizes at the endoplasmic reticulum (ER). Once bound to cGAMP, a second messenger that is generated by dsDNA-bound cGAS, STING translocates from the ER to the Golgi. STING then activates TBK1 and IRF3 at the trans-Golgi network (TGN). Dysregulated Golgi-to-ER traffic underlies the pathogenesis of COPA syndrome, a monogenic autoinflammatory disease caused by missense mutations of coatomer protein complex subunit α (COP-α). In this chapter, I focus on emerging issues regarding the regulation of STING activation by membrane traffic between the ER and the Golgi, and also on the molecular mechanism underlying the specific activation of TBK1/IRF3 at the TGN.
    Keywords:  Cholesterol; IRF3; Innate immune signalling; Protein palmitoylation; STING; TBK1; The trans-Golgi network
    DOI:  https://doi.org/10.1007/978-3-032-16833-7_13
  58. Physiol Plant. 2026 Jan-Feb;178(1):178(1): e70806
    Investigating the Involvement of the Unfolded Protein Response in Bread Wheat Priming and Adaptation to Heat Stress.
    Maxime Dupont, Céline Dupuits, Said Mouzeyar, Jacques Le Gouis, Jane Roche.
      The temperature increase caused by climate change induces the accumulation of misfolded proteins in the endoplasmic reticulum. To restore protein homeostasis, plants activate the Unfolded Protein Response (UPR). In this study, the involvement of UPR in improving severe heat stress tolerance through molecular priming was explored in Triticum aestivum. The UPR activation and turn-off dynamics were determined. Moreover, the importance of the TaIRE1/TabZIP60 induction branch in the response to ER stress was assessed using TaIRE1 knockout mutants. The results indicate that plants primed with dithiothreitol exhibit a faster and higher TabZIP60 splicing response to temperature stress than unprimed plants. This suggests that UPR induction by TaIRE1/TabZIP60 is a finely regulated adaptive mechanism that alleviates the ER stress caused by heat increase. Moreover, UPR was defined as a molecular primer insofar as it participates in enhancing the stress response. Furthermore, the development and photosynthetic capacity of TaIRE1 mutants were negatively affected, resulting in increased cellular damage in response to ER stress. The TaIRE1/TabZIP60 induction branch, crucial for ER stress recovery, does not appear to be fully compensated by TabZIP28. This study provides new insights into the role of the UPR in response to abiotic stresses and proposes potential strategies to improve wheat heat tolerance.
    Keywords:   Triticum aestivum ; IRE1 knockout; molecular priming; unfolded protein response
    DOI:  https://doi.org/10.1111/ppl.70806
  59. Cancer Lett. 2026 Feb 16. pii: S0304-3835(26)00100-X. [Epub ahead of print] 218337
    Nutrient Deprivation Promotes Bladder Cancer Metastasis through Beclin-1 Deacetylation-Mediated Autophagy Activation.
    Yan Sun, Hang Tong, Guozhi Zhao, Linfeng Wu, Xiaoyu Zhang, Tinghao Li, Junlong Zhu, Kunyao Zhu, Hubin Yin, Xinyuan Li, Weiyang He.
      Deprivation of nutrients in the tumor microenvironment drives malignant progression, yet the molecular mechanisms linking metabolic stress to metastasis in bladder cancer remain incompletely understood. Here, we report that nutrient-deprivation stress promotes metastasis by orchestrating a post-translational modification cascade centered on Beclin-1. Clinical analysis revealed that acetylation of Beclin-1 at lysine residues K430 and K437 was significantly reduced in muscle-invasive bladder cancer (MIBC) compared with non-muscle-invasive bladder cancer (NMIBC), a molecular signature inversely correlated with elevated phospho-eIF2α, a marker of cellular starvation. Mechanistically, nutrient deprivation dynamically regulates the expression of the deacetylase SIRT1 and acetyltransferase p300, shifting the balance toward Beclin-1 deacetylation. This deacetylation event serves a dual function: it enhances Beclin-1 protein stability by shielding it from TRIM21-mediated K48-linked ubiquitination and proteasomal degradation, and it promotes autophagosome formation by strengthening its interaction with pro-autophagic partners VPS34, ATG14, and UVRAG while weakening its binding to the inhibitor Rubicon. Consequently, this leads to sustained autophagy activation and epithelial-mesenchymal transition. Genetic and pharmacological interventions further confirmed the central role of this axis, demonstrating that SIRT1 activation by resveratrol promoted metastasis, whereas p300 activation by CTB suppressed it. Crucially, these effects were abrogated in cells expressing acetylation-mimetic Beclin-1 mutants, suggesting a direct causal link. Our study unveils the SIRT1/p300-Beclin-1-TRIM21 axis as a key nutrient-sensing pathway that promotes bladder cancer metastasis through crosstalk between acetylation and ubiquitination. These findings identify new therapeutic vulnerabilities in advanced bladder cancer.
    Keywords:  Bladder cancer; acetylation; autophagy; nutrient deprivation; ubiquitination
    DOI:  https://doi.org/10.1016/j.canlet.2026.218337
  60. Mol Cell. 2026 Feb 16. pii: S1097-2765(26)00038-9. [Epub ahead of print]
    Global mapping of circRNA-target RNA interactions reveal P-body-mediated translational repression.
    Peng Li, Hongmei Zhang, Zhaokui Cai, Yuyang Zhang, Ruiyun Yang, Rong Ye, Jingxin Li, Hailian Zhao, Bowen Liu, Zhen Yuan, Xuekun Li, Xi Wang, Ping Zhu, Yuanchao Xue.
      Circular RNAs (circRNAs) are primarily produced through pre-mRNA back-splicing, yet their target repertoire and functional mechanisms remain elusive. Here, we present circTargetMap, a computational framework for globally mapping circRNA targets using RNA-RNA interactomes obtained via RNA in situ conformation sequencing (RIC-seq) in the hippocampus and ten human cell lines. This approach identified 117,163 high-confidence circRNA-target RNA interactions, with 83% of target mRNAs bound by multiple circRNAs. Functionally, CDR1as and circRMST repress target mRNA translation by sequestering them into processing bodies (P-bodies)-membraneless granules-through sequence-specific base-pairing, probably independent of AGO2, DICER, and microRNA (miRNAs). To directly capture granule-associated interactions, we developed the granule RIC-seq (GRIC-seq) method, revealing the broad role of circRNA-target RNA interactions in translational repression. Moreover, pathogenic variants are significantly enriched around circRNA-target RNA interaction sites, suggesting potential roles in disease. Our study provides valuable resources for circRNA functional exploration and a framework for investigating RNA-RNA interactions within membraneless organelles.
    Keywords:  P-bodies; RIC-seq; RNA-RNA interactions; RNA-binding protein; circular RNA; granule RIC-seq; translational repression
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.018
  61. Eur J Pharm Biopharm. 2026 Feb 12. pii: S0939-6411(26)00041-X. [Epub ahead of print] 115020
    KDEL-mediated modulation of intracellular trafficking in cell-targeted protein drugs.
    Eric Voltà-Durán, Lorena Alba-Castellon, Lourdes A Arena, Julieta M Sánchez, Isolda Casanova, Ramón Mangues, Antonio Villaverde, Esther Vázquez, Ugutz Unzueta.
      The biological activity of therapeutic proteins, upon intracellular delivery, is dramatically minimized by lysosomal proteolytic digestion. This is a limitation when developing cell-targeted pharmaceuticals that penetrate target cells via receptor recognition and endosomal engulfment. Since proteins benefit from functional and conformational versatility, editable by genetic engineering, endosomolytic protein domains are often fused to the functional polypeptide to promote their cytosolic delivery, aiming at minimizing proteolysis in mature lysosomes. This straightforward strategy has, however, rendered irregular results, linked to the fusogenic nature of most of the tested domains. Alternatively, proteolysis of protein drugs might be controlled by bypassing the lysosomal route, forcing an unconventional traffic of the uptaken protein material to be secreted from the endoplasmic reticulum (ER). This possibility, used in nature by several plant and microbial proteins, has been evaluated here by functionalizing a protein-only antitumoral drug, based on a cell-targeted diphtheria toxin, with a C-terminal KDEL motif. Thus, if KDEL were able to reprogram the intracellular trafficking, KDEL-tagged cell delivered proteins would be expected to avoid the lysosomal degradation, resulting in enhanced stability and activity. The obtained results validate this hypothesis and point out KDEL as a promising functional agent in cell-targeted protein drugs.
    Keywords:  Protein drugs; Protein engineering; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.ejpb.2026.115020
  62. J Clin Invest. 2026 Feb 16. pii: e191433. [Epub ahead of print]136(4):
    ER-associated degradation pathway protein SEL1L plays an evolutionarily conserved role in platelet adhesion.
    Anna R Dahlgren, Francesca Careddu, Jeffrey W Norris, Christian A Di Buduo, Livia Stanger, Reheman Adili, Erin M Kropp, Qing Li, Michael Holinstat, Ida Biunno, Alessandra Balduini, Fern Tablin, Jordan A Shavit, Carrie J Finno.
      SEL1L is a well-known protein in the ER-associated degradation (ERAD) pathway. While it is known to be expressed in platelets, SEL1L has never been shown to play an active role. Here, we present evidence that SEL1L regulates platelet function. We first identified SEL1L through the study of Atypical Equine Thrombasthenia (AET), an autosomal recessive platelet disorder found in thoroughbred horses. A missense variant in SEL1L (c.1810A>G p.Ile604Val) was found in AET-affected horses, which we show is associated with decreased protein expression. SEL1L is intracellular in equine platelets and localizes to the surface upon activation with thrombin. Platelets from homozygous horses exhibited substantially decreased spreading on immobilized collagen. Human megakaryocytes were found to have 2 SEL1L protein isoforms that increase in expression during megakaryopoiesis, although only 1 isoform was delivered to mature platelets. Studies using inducible mouse and constitutive zebrafish KOs demonstrated that SEL1L is necessary for efficient platelet or thrombocyte (fish equivalent) adhesion to sites of endothelial injury. These data reveal a previously undescribed and conserved role for the ERAD pathway in the etiology of AET and platelet function, and GWAS data suggest that it may play a role in human platelet disorders as well.
    Keywords:  Coagulation; Genetic diseases; Genetics; Hematology; Platelets; Vascular biology
    DOI:  https://doi.org/10.1172/JCI191433
  63. J Med Chem. 2026 Feb 19.
    Development of PROTACs Targeting the Moonlighting Enzyme Nicotinamide Phosphoribosyltransferase (NAMPT) for Breast Cancer Therapy.
    Ubaldina Galli, Marianna Moro, Federica Carolina Balestrero, Giorgia Colombo, Marco Koten, Benedetta Roncaglio, Armando A Genazzani, Silvio Aprile, Alberto Massarotti, Giuseppe Orsomando, Tracey Pirali, Ambra A Grolla.
      PROTACs (proteolysis-targeting chimeras) enable selective protein degradation through the ubiquitin-proteasome system and offer opportunities to target moonlighting proteins with nonenzymatic functions. We report the design, synthesis, and biological evaluation of NAMPT-directed PROTACs derived from our previously described inhibitor MV78 (7). A modular click chemistry strategy facilitated rapid assembly of a focused library by varying linker architectures and E3 ligase recruiters, with emphasis on the impact of a triazole unit. Structure-activity relationship studies revealed that eliminating the triazole from the linker and introducing an (S)-methyl group on the VHL ligand markedly enhanced degradation. The optimized degrader, U42, exhibited low nanomolar antiproliferative activity, robust intracellular and extracellular NAMPT degradation, excellent metabolic stability, favorable pharmacokinetics, and sustained efficacy in mammosphere models, three-dimensional breast cancer cultures not previously explored with NAMPT degraders. These findings highlight U42 as a lead compound and provide strong rationale for advancing NAMPT-directed PROTACs as a therapeutic strategy in breast cancer.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c01827
  64. Cell Metab. 2026 Feb 19. pii: S1550-4131(26)00014-8. [Epub ahead of print]
    16-h fasting optimizes cancer immunotherapy in mice and humans.
    Sheng Chen, Tianyi Hu, Kaixiang Zhu, Yue Liu, Yidong Yang, Xiangyuan Li, Jinjie He, Wenyu Cui, Zhexu Chi, Weiwei Yu, Duojiao Chen, Zhen Wang, Jian Zhang, Ruya Sun, Dehang Yang, Siqi Dai, Qianzhou Yu, Quanquan Wang, Qian Xiao, Junbin Qian, Kefeng Ding, Di Wang.
      Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8+ T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8+ clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.
    Keywords:  diet intervention; immune checkpoint therapy; immunometabolism; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.015
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