bims-proteo Biomed News
on Proteostasis
Issue of 2026–09–13
forty-four papers selected by
Eric Chevet, INSERM
  1. ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans.
  2. Proteostasis in the regulation of pancreatic islet cell plasticity.
  3. Protein Age Bias in Target Degradation by PROTACs.
  4. eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.
  5. The RNA helicase domain of NAT10 promotes the biogenesis of hypomodified ribosomes to enhance cancer cell proliferation.
  6. Investigating Translocation Mechanisms of TDP-43 Into the Endoplasmic Reticulum Using Budding Yeast Models.
  7. Molecular Glue Degraders in Early Development for Cancer Therapy.
  8. Beyond the ER: UFMylation and Mitochondrial Ribosome Quality Control.
  9. A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.
  10. Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.
  11. Long-range mRNA folding shapes expression and sequence of bacterial genes.
  12. SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages.
  13. PARP16 is a Druggable Regulator of Ribosome MARylation and Protein Homeostasis in Ovarian Cancer Cells.
  14. Ribosome stalling position, spacing, and A-site occupancy impact translation and cotranslational mRNA decay in plants.
  15. InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity.
  16. Spatiotemporal control of Atg9 vesicle fusion in autophagosome formation.
  17. Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.
  18. Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.
  19. The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.
  20. Protocol for fluorescence-activated mitochondria sorting in endoplasmic reticulum-mitochondria contact reporter cells.
  21. Biomolecular Condensates Dictate the Folding Landscape of Protein Alpha-Helices.
  22. Click-Activated Supramolecular Targeting Chimeras for Spatiotemporally Resolved Protein Degradation In Vivo.
  23. Backbone and side chain 1H, 13C and 15N chemical shift assignment of the cargo-recognition domain MOTH of human TANGO1.
  24. Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.
  25. Proximity-guided graph learning reveals tumour-associated proximity antigens.
  26. Kinetic Frustration of Collagen Folding Drives Condensate-Mediated Fibrous Assembly.
  27. Nucleolar dynamics are determined by the ordered assembly of the ribosome.
  28. Covalent warheads as a versatile platform for molecular glue development.
  29. p97-mediated proteostasis is a checkpoint for late-stage thymocyte positive selection.
  30. Metabolic regulation of calcium homeostasis via SERCA succination.
  31. The 4EHP/GIGYF2 translation repressor complex is co-opted by the vaccinia virus K3L protein as a potential mechanism of immunoevasion.
  32. The alarmone pGpp inhibits translation through GTP depletion.
  33. Phosphorylation-dependent interaction between VAP proteins and INF2 influences ER morphology.
  34. Directed evolution of Lantern enables rapid RNA and protein proximity labeling.
  35. ESMDynamic: Fast and accurate prediction of protein dynamic contact maps from single sequences.
  36. The E3 ubiquitin ligase WWP2 regulates the stability and tumor suppressive properties of the chromatin remodeler ARID1B.
  37. Artificial intelligence-enabled induced-proximity drug discovery: Designing productive molecular associations.
  38. AI-assisted design and virtual profiling of targeted degraders for pancreatic cancer therapy via PROTAC technology.
  39. A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.
  40. Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.
  41. Macrophages transfer functional proteins to their surface during live-cell uptake.
  42. Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
  43. Recent advances of dual PROTACs for potential therapeutic applications.
  44. Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.
  1. PLoS Genet. 2026 Sep;22(9): e1012301
    ER-to-Golgi transport machinery promotes the excessive cargo-triggered unfolded protein response in C. elegans.
    Liying Guan, Tong Zhang, Zhigao Zhan, Yingchun Wang, Xun Huang, Mei Ding.
      Disruption of endoplasmic reticulum (ER) homeostasis activates the unfolded protein response (UPR) to restore proteostasis. Although defects in the secretory machinery can induce ER stress, whether specific trafficking components actively couple cargo handling to UPR signaling remains unclear. Here, using Caenorhabditis elegans genetics, imaging, and biochemical assays, we show that neuronal overexpression of the gap junction protein UNC-9 cell-autonomously activates the IRE-1-XBP-1 branch of the ER UPR. Loss of the early secretory pathway proteins ERGI-2 or ERGI-3 suppresses this response and disrupts UNC-9 localization, revealing functions for these proteins that extend beyond cargo trafficking. ERGI-2 and ERGI-3 interact with both UNC-9 and the ER chaperone HSP-4/BiP, suggesting that they couple the handling of excessive UNC-9 to UPR activation. This requirement is cargo-selective: ERGI-2 and ERGI-3 are dispensable for UPR activation induced by overexpression of another innexin, UNC-7, or unrelated proteins. Moreover, activation of the IRE-1-XBP-1 pathway reduces abnormal UNC-9 accumulation in ergi-2 and ergi-3 mutants. Together, our findings identify ER-to-Golgi trafficking proteins as cargo-selective regulators that link secretory-pathway demand to adaptive UPR.
    DOI:  https://doi.org/10.1371/journal.pgen.1012301
  2. J Diabetes Investig. 2026 Sep 11.
    Proteostasis in the regulation of pancreatic islet cell plasticity.
    Jun Shirakawa.
      Pancreatic islet cells continuously synthesize and secrete large quantities of peptide hormones, making them uniquely dependent on robust proteostasis networks to maintain cellular function. Traditionally, the unfolded protein response (UPR) is considered a stress-responsive pathway that protects cells from endoplasmic reticulum (ER) dysfunction or triggers apoptosis when ER stress is excessive. Here, we propose that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long-term homeostasis, extending beyond its conventional role in the response to cellular damage. In pancreatic β cells, glucose signaling suppresses the expression of the proapoptotic factor CHOP through both IRS2-dependent and IRS2-independent pathways, indicating that metabolic signaling directly remodels the ER stress response. In contrast, the CHOP-GADD34-eIF2α dephosphorylation axis constitutes a negative feedback mechanism that fine-tunes translational recovery and determines the balance between adaptation and cell death. Moreover, 4E-BP1-mediated inhibition of mRNA translation and modulation of mTOR signaling alleviate proteotoxic stress and promote β-cell survival under conditions of increased secretory demand. In addition to translational control, IGF2 receptor-mediated signaling has recently been implicated in the regulation of autophagy, further linking lysosomal quality control to β-cell proteostasis. Importantly, proteostasis also affects α-cell biology, where UPR signaling regulates glucagon secretion and contributes to α-to-β cell transdifferentiation, highlighting a previously unrecognized role of ER homeostasis in endocrine cell identity. Finally, recent findings indicate that progressive impairment of proteostasis is a hallmark of islet aging, integrating defects in protein folding, translation, autophagy, and stress adaptation into the pathogenesis of diabetes.
    Keywords:  ER stress; alpha cell; beta cell; islet cell; proteostasis
    DOI:  https://doi.org/10.1111/jdi.70438
  3. ACS Chem Biol. 2026 Sep 08.
    Protein Age Bias in Target Degradation by PROTACs.
    Bingbing X Li, Xiangshu Xiao.
      Targeted protein degradation (TPD) by PROteolysis TArgeting Chimeras (PROTACs) has emerged as a powerful chemical biology and therapeutic modality, yet many degraders exhibit incomplete target clearance and characteristic rebound kinetics despite continuous exposure. The mechanistic basis for this behavior remains poorly understood. Here, we uncover protein age as a previously unrecognized determinant of PROTAC efficacy. Using CG-SLENP, a chemical genetics strategy that selectively labels newly synthesized and pre-existing proteins within the same living cell, we directly resolve PROTAC-induced degradation of distinct intracellular protein populations. Applying this approach to the bromodomain protein BRD4, we show that two mechanistically and structurally distinct PROTACs, dBET6 and MZ-1, preferentially degrade pre-existing BRD4, while newly synthesized BRD4 is degraded substantially more slowly and incompletely. This age-dependent degradation bias is observed in live-cell imaging, across compound concentrations and time scales, and for both reporter and endogenous BRD4. BRD9-targeting PROTAC VZ185 exhibited similar degradation preference. These findings reveal that PROTAC-mediated degradation is governed not only by target engagement and ternary complex formation but also by the dynamic balance between protein synthesis and degradation. By identifying temporal proteostasis as a critical parameter in TPD, this work provides a mechanistic framework for incomplete degradation and rebound kinetics and therefore establishes protein maturation state as an important consideration for degrader design and evaluation.
    DOI:  https://doi.org/10.1021/acschembio.6c00591
  4. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2533876123
    eIF5A and polyamines restrict mRNA levels in response to ribosome stalls.
    Chloe M Wohlenberg, Parissa C Monem, Natalia Barbosa, Judith Frydman, Joshua A Arribere.
      Obstacles to translation elongation stall ribosomes and allow deleterious proteins to accumulate, which threatens cellular health. Cells recognize and clear stalled ribosomes via several interrelated pathways, although the mechanisms by which cells distinguish stalled from normally elongating ribosomes and mount an appropriate response are incompletely understood. While recent work highlights how ribosome collisions help cells to recognize stalled ribosomes, how other factors contribute to detection remains unclear. Here, we report a requirement for the translational factor eIF5A in the mRNA decay response to ribosomal stalling, i.e., No-Go mRNA Decay (NGD). We identified the Caenorhabditis elegans polyamine transporter, catp-6, via a forward genetic screen as a factor required for NGD. During our mechanistic dissection of the catp-6 phenotype, we uncovered a role for cellular polyamines and the translation elongation factor eIF5A in NGD, and we show this requirement is conserved from C. elegans to Saccharomyces cerevisiae. Our analyses support the idea that cells use eIF5A to identify ribosomal stalls and execute NGD and uncover a molecular function for a core protein synthesis factor in limiting expression from stall-inducing mRNAs. Our work offers insight into how cells identify and remove problematic mRNAs from the translational pool. Our work also raises the possibility that dysregulated mRNA decay is an unrecognized pathophysiology associated with polyaminopathies and eIF5A disorders, of relevance to varied neurodegenerative and aging phenotypes and efforts to pharmacologically inhibit eIF5A.
    Keywords:  NGD; PARK9; eIF5A; polyamine; ribosome
    DOI:  https://doi.org/10.1073/pnas.2533876123
  5. Nat Commun. 2026 Aug 08. pii: 9529. [Epub ahead of print]17(1):
    The RNA helicase domain of NAT10 promotes the biogenesis of hypomodified ribosomes to enhance cancer cell proliferation.
    Mahmood H Dalhat, Sharath Narayan, Maria Eleftheriou, James Russell, James Heslop, Hannah Serio, Khulood A Alzahrani, Adam Suh, Ajay Edakkara, Sweta Raikundalia, Lea Landmann, Ryan Asby, Evangelia Stamou, Judith López, Yogeshkumar Malam, Demetrios Aspris, Emmely A Patrasso, Stephanie Mou, George Giotopoulos, Walid T Khaled, Brian J P Huntly, Fotios Sampaziotis, Konstantinos Tzelepis, Daniel Arango.
      N-acetyltransferase 10 (NAT10) is a multifunctional enzyme that harbors RNA acetyltransferase and RNA helicase domains and has emerged as a therapeutic vulnerability in solid and hematological malignancies. By coupling Proteolysis Targeting Chimera-mediated degradation of NAT10 with a deep mutational scanning assay, followed by validations in biochemical assays, human cell lines, and female mouse xenografts, we find that the RNA helicase domain of NAT10 enhances cancer cell proliferation and tumor growth. This proliferative function of NAT10 is independent of RNA acetylation but requires its RNA-binding activity. The RNA helicase domain of NAT10 is required for 18S rRNA binding, promoting biogenesis of the 40S ribosomal subunit, while simultaneously interfering with the deposition of the conserved 18S rRNA modification m¹acp³Ψ. Loss of m¹acp³Ψ in 18S rRNA enhances cancer cell proliferation, revealing that NAT10 promotes the biogenesis of hypomodified ribosomes to facilitate tumor growth. These findings uncover a mechanism by which NAT10 promotes cancer cell proliferation and establish its RNA helicase domain as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-76383-w
  6. Traffic. 2026 Sep;27(3): e70054
    Investigating Translocation Mechanisms of TDP-43 Into the Endoplasmic Reticulum Using Budding Yeast Models.
    Miku Saito, Hana Tsuzuki, Akira Hosomi.
      Signal peptides direct secretory and membrane proteins to the endoplasmic reticulum (ER), but proteins lacking classical signal peptides can occasionally engage the ER translocation machinery. TDP-43 is a nuclear RNA-binding protein implicated in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 pathology has been linked to extracellular TDP-43 species, association with the ER luminal oxidoreductase PDI, and ER stress-related phenotypes, yet whether TDP-43 fragments can directly access the ER lumen remains unclear. Here, we used budding yeast to examine signal peptide-independent ER entry of TDP-43. C-terminal fragments of TDP-43 acquired N-glycans in ste24Δ cells, whereas full-length TDP-43 showed little detectable ER entry. Endo H digestion confirmed N-glycosylation of the fragments, and a protease protection assay supported ER luminal localization of TDP-43(Δ2-89). ER entry was reduced by sec61-41 and sec66Δ, indicating engagement of a Sec61/Sec66-dependent translocation pathway. Deletion analyses identified opposing sequence elements: residues 320-343 facilitated ER entry, whereas an N-terminal region upstream of the nuclear localization signal suppressed it. TDP-43(Δ2-89) also accessed the secretory pathway, and selected disease-associated variants caused Ire1-dependent growth vulnerability without increasing detectable ER translocation. These findings reveal a Ste24-suppressed route for noncanonical ER entry of TDP-43 fragments.
    Keywords:  Ste24; TDP‐43; endoplasmic reticulum; signal peptide; translocon; yeast
    DOI:  https://doi.org/10.1111/tra.70054
  7. Med Res Rev. 2026 Sep 07.
    Molecular Glue Degraders in Early Development for Cancer Therapy.
    E Sila Ozdemir, Hyunbum Jang, Ozlem Keskin, Attila Gursoy, Ruth Nussinov.
      Molecular glue degraders are an emerging class of small molecule allosteric modulators that induce or stabilize protein-protein interactions, enabling targeted degradation of previously intractable proteins. By redirecting E3 ligases to recognize neosubstrates, proteins that are not typically recognized by a specific E3 ubiquitin ligase, they expand the scope of drug discovery beyond traditional paradigms. We review mechanistic principles underlying molecular glue activity, including cooperativity, weak affinity interactions, structural degrons, and higher-order complex formation. We discuss discovery strategies, from serendipitous identification to emerging rational and chemoproteomic approaches, and key E3 ligase systems with relevance to oncology. We highlight clinical and preclinical applications, alongside challenges such as resistance mechanisms, context-dependent activity, and limitations in predicting neosubstrates. Molecular glues are transitioning from serendipitous discoveries to a mechanism-driven therapeutic platform. Progress depends on integrating structural biology, proteomics, and computational modeling to enable rational design and improve predictability. Expanding the repertoire of E3 ligases and understanding context-specific degradation will be critical to fully realize their potential in oncology and beyond.
    Keywords:  E3 ubiquitin ligases; allostery; cancer therapy; molecular glue degraders; targeted protein degradation
    DOI:  https://doi.org/10.1002/med.70104
  8. Circ Res. 2026 Sep 11. 139(7): e329481
    Beyond the ER: UFMylation and Mitochondrial Ribosome Quality Control.
    Shelly Marinberg, Izhak Kehat.
      
    Keywords:  Editorials; hypertrophy; mitochondria; protein modification, translational; proteostasis; ribosomes
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.329481
  9. Genes Dev. 2026 Sep 10.
    A HUWE1 regulatory helix gates ASCL1 degradation through its C-terminal phospho-degron in small cell lung cancer.
    Keita Masuzawa, Kevin D Dong, Calvin XiaoYang Hu, Ting Peng, Yoochan Myung, Shilpa Singh, Xinyue Li, Tianchu Wang, Cyrus Jin, Joao A Paulo, Ka Yang, Ernst W Schmid, Matthew A Booker, Yixiang Li, Deli Hong, Suzan Lazo, Michael Y Tolstorukov, John G Doench, Leslie Duplaquet, Katherine A Donovan, Sumaiya Iqbal, Eric S Fischer, Brian B Liau, Steven P Gygi, Matthew G Oser.
      Lineage-defining transcription factors are key oncogenic drivers but remain difficult to target pharmacologically due to the absence of ligandable pockets. The molecular rules governing substrate recognition by large HECT ubiquitin ligases also remain incompletely understood, limiting efforts to exploit these enzymes for targeted protein degradation. Here we combine genome-wide CRISPR knockout screening with base editor tiling screens at amino acid resolution, both coupled to an endogenous knock-in reporter of the SCLC lineage oncogenic transcription factor ASCL1, to systematically interrogate the mechanisms governing its degradation. These complementary screens unbiasedly identify the HECT ubiquitin ligase HUWE1 as the dominant regulator of ASCL1 stability in small cell lung cancer (SCLC) and resolve a conserved C-terminal phospho-degron centered on Ser207 and terminal Trp/Phe residues that are required for HUWE1 docking and ubiquitin-mediated degradation. Unexpectedly, base editor screening further uncovers a previously unrecognized regulatory module within HUWE1: a short negatively charged helix that functions as an autoinhibitory gate controlling access of phospho-degron substrates to HUWE1. Charge-flipping mutations within this regulatory helix relieve autoinhibition and accelerate degradation of multiple HUWE1 phospho-degron substrates, including ASCL1 and the canonical HUWE1 substrate DDIT4. Stabilization of ASCL1 through degron disruption paradoxically impairs SCLC proliferation, revealing that dynamic proteasome-coupled turnover is required for transcription factor function. Together, these findings reveal molecular rules governing HUWE1 phospho-degron recognition and identify a regulatory gate controlling substrate engagement. They also illustrate a generalizable strategy for resolving degradation mechanisms of undruggable transcription factors in their endogenous cellular context.
    Keywords:  ASCL1; HUWE1; base editor screens; protein degradation; small cell lung cancer
    DOI:  https://doi.org/10.1101/gad.353898.126
  10. Cell Rep. 2026 Sep 09. pii: S2211-1247(26)01072-7. [Epub ahead of print]45(9): 117994
    Mitochondrial Fis1 tunes Rab7A activity via TBC1D15 modulating STING degradation.
    Eunice Dominguez-Martin, Linlin Lei, Jennifer D Petersen, Peng-Peng Zhu, Katherine R Tucker, Richard J Youle.
      The mechanisms governing the final trafficking steps of the cyclic dinucleotide innate immune receptor stimulator of interferon genes (STING) are not fully understood. Here, we identify the mitochondrial protein Fis1 as a regulator of STING endolysosomal degradation. The absence of Fis1 in HeLa cells stabilizes STING, boosting downstream signaling without affecting its initial endoplasmic reticulum (ER)-to-Golgi traffic. Instead, Fis1 loss impairs STING delivery to endolysosomes. Fis1 recruits the Rab7A-GAP TBC1D15 to mitochondria and upon STING activation, TBC1D15 localization shifts to the Golgi. In the absence of Fis1, the interaction between TBC1D15 and Rab7A is disrupted, leading to decreased Rab7A GTPase activity and impaired STING degradation. Our findings reveal a mitochondria-controlled axis where Fis1 tunes Rab7A activity via TBC1D15, which is required to ensure proper STING degradation, directly linking mitochondria to lysosomal trafficking and the termination of innate immune signaling.
    Keywords:  CP: cell biology; CP: immunology; Fis1; Golgi; Rab-GAP; Rab7; STING; TBC1D15; innate immunity; lysosomal degradation; mitochondria; traffic
    DOI:  https://doi.org/10.1016/j.celrep.2026.117994
  11. Mol Cell. 2026 Sep 08. pii: S1097-2765(26)00561-7. [Epub ahead of print]
    Long-range mRNA folding shapes expression and sequence of bacterial genes.
    Manraj S Gill, Isabelle A Kim, James R Xue, Yashna Thappeta, James C Taggart, Gene-Wei Li.
      Bacterial gene expression is strongly influenced by local mRNA secondary structure, yet the impact of long-range folding remains poorly understood. Here, we show that sequences hundreds of nucleotides from the mRNA 5' end can act as potent repressors of gene expression through long-range base pairing to the ribosome binding site (RBS), subjecting anti-RBS sequences to negative selection. Using massively parallel reporter assays in Bacillus subtilis, we identify anti-RBS sequences as among the strongest determinants of reduced mRNA abundance across the transcript body. We demonstrate that distal anti-RBS elements engage in long-range folding with the Shine-Dalgarno sequence, blocking ribosome entry and promoting mRNA decay. Consistent with these repressive effects, anti-RBS-like sequences are depleted throughout diverse bacterial coding sequences but not from leaderless transcripts, and introducing distal anti-RBS to native genes reduces expression. Our findings establish that long-range mRNA folding is a conserved force shaping gene expression and constrains coding sequence evolution.
    Keywords:  RNA structure; bacterial coding sequence; bacterial mRNA; mRNA degradation; mRNA folding; mRNA stability; mRNA translation; ribosome binding site; sequence evolution; translation efficiency
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.014
  12. JCI Insight. 2026 Sep 08. pii: e199853. [Epub ahead of print]
    SMURF2 inhibits autophagic control of Mycobacterium tuberculosis in macrophages.
    Priscila C Campos, Kathryn C Rahlwes, Victoria A Ektnitphong, Beatriz Rs Dias, Kubra F Naqvi, Samuel Alvarez-Arguedas, Michael U Shiloh.
      Autophagy is a critical host defense mechanism that restricts intracellular pathogens such as Mycobacterium tuberculosis (Mtb). A key step in this process is the ubiquitination of Mtb or Mtb-associated structures. The E3 ligase SMURF1 catalyzes K48-linked ubiquitination, promoting bacterial clearance. However, the function of its homolog, SMURF2, in host defense remains undefined. Here, we demonstrate that Smurf2 deletion in murine macrophages increases SMURF1 levels, enhances LC3B lipidation, augments K48 ubiquitination of Mtb-associated structures, and reduces intracellular Mtb replication. These effects are reversed by Smurf1 deletion, supporting a role for SMURF1 in SMURF2-dependent control of Mtb. Mice with myeloid-specific Smurf2 deletion exhibit modestly prolonged survival following aerosol Mtb infection. In human macrophages, SMURF2 knockdown or its pharmacological inhibition with the HECT E3-ligase inhibitor Heclin reduces Mtb replication. Together, our findings identify SMURF2 as a negative regulator of macrophage control of Mtb and support further investigation of SMURF2 as a potential target for host-directed therapy in tuberculosis.
    Keywords:  Autophagy; Immunology; Infectious disease; Innate immunity; Microbiology; Tuberculosis
    DOI:  https://doi.org/10.1172/jci.insight.199853
  13. J Biol Chem. 2026 Sep 08. pii: S0021-9258(26)02412-9. [Epub ahead of print] 113540
    PARP16 is a Druggable Regulator of Ribosome MARylation and Protein Homeostasis in Ovarian Cancer Cells.
    Sridevi Challa, Morgan Dasovich, Jonathan C Abshier, Komal Pekhale, Lu Yang, Cristel V Camacho, W Lee Kraus.
      Cytosolic NAD+ synthesis supports ovarian cancer growth by enabling PARP16-dependent mono(ADP-ribosyl)ation (MARylation) of ribosomal proteins, thereby fine-tuning translation and maintaining protein homeostasis. While genetic depletion of PARP16 disrupts ribosome MARylation and impairs tumor cell growth, the therapeutic potential of pharmacologic PARP16 inhibition in this pathway remains unexplored. Here, we characterized the effects of DB008, a tool compound that functions as a selective inhibitor of PARP16, in ovarian cancer cells. Biochemical analyses demonstrated that PARP16 undergoes NAD+-dependent auto-MARylation and that NMNAT-2 supplies NAD+ to support this activity. DB008 potently inhibited PARP16 auto-MARylation in vitro. In ovarian cancer cells, DB008 engaged PARP16, reduced its MARylation, and decreased ribosome-associated MARylation. Consistent with PARP16 depletion, DB008 enhanced global protein synthesis, increased protein aggregation, and suppressed cell growth and anchorage-independent colony formation. CRISPR-mediated deletion of the PARP16 gene in ovarian cancer cells abolished the effects of DB008 on translation, protein aggregation, and proliferation, demonstrating on-target activity. Moreover, cells expressing a PARP16 mutant resistant to DB008 were unaffected by inhibitor treatment, further confirming that the cellular effects of DB008 require on-target inhibition. Finally, DB008 significantly inhibited tumor growth in OVCAR3 xenografts, with on-target engagement of PARP16 in the xenograft tumors. Collectively, these findings establish PARP16 as a druggable regulator of ribosome MARylation and protein homeostasis in ovarian cancer and provide pharmacologic proof-of-concept that disrupting ribosomal MARylation impairs tumor growth.
    Keywords:  ADP-ribosylation (ADPRylation); Cell growth; MARylation; Mono(ADP-ribosyl)ation; Ovarian cancer; PARP16; Ribosome; Xenograft
    DOI:  https://doi.org/10.1016/j.jbc.2026.113540
  14. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2617633123
    Ribosome stalling position, spacing, and A-site occupancy impact translation and cotranslational mRNA decay in plants.
    Sjors van der Horst, Joseph L Gage, Julia Bailey-Serres.
      Ribosomes can pause during mRNA translation, but what causes pausing, how pauses affect protein production, and whether they trigger cotranslational mRNA decay are poorly understood in plants. Here, we investigate the causes and consequences of ribosome pausing in Arabidopsis and maize. This is accomplished by sizing, mapping, and quantifying footprints of individual ribosomes (monosomes) and closely spaced ribosome pairs (disomes) at single-codon resolution on open reading frames (ORFs). Ribosome footprinting was combined with 5'P-degradome-seq to examine the coincidence of pausing with cotranslational decay under control conditions and brief hypoxia in Arabidopsis. The data resolve two monosome conformations and three disome configurations. These include monosomes with a vacant or occupied A-site and disomes that have collided or are separated by one or two codons. Pausing is prevalent at initiation, termination, and di-Proline codons. Di-Proline pauses do not trigger cotranslational decay but appear important in cotranslational protein processing. Brief hypoxia induces stalling of A-site vacant ribosomes at Aspartate codons, often coinciding with 5'P peaks, indicating that rate-limiting decoding can trigger cotranslational mRNA decay. Notably, actively transcribed and translated hypoxia-response mRNAs accumulate 1- to 2-codon-separated disomes and are actively degraded. Comparative analysis of footprints in the two species reveals ribosome conformations and codon-specific pausing can be conserved or lineage-specific, as exemplified by pausing at di-Prolines and on Conserved Peptide upstream ORFs. In sum, the stalling of ribosomes at specific codons, coupled with ribosome A-site occupancy and disome spacing, modulates protein production and cotranslational mRNA decay in plants.
    Keywords:  cotranslational mRNA turnover; ribosome collision; ribosome pausing; uORF
    DOI:  https://doi.org/10.1073/pnas.2617633123
  15. Nat Commun. 2026 Aug 13. pii: 9729. [Epub ahead of print]17(1):
    InsP3R signaling and actomyosin-dependent mitochondrial dynamics play essential roles in mitochondrial stress-induced longevity.
    Gaomin Feng, Elizabeth M Ruark, Alexandra G Mulligan, Eric K F Donahue, Anthony L Hoang, Brianne Jacquet-Cribe, Li Peng, Kristopher Burkewitz.
      Certain forms of mitochondrial impairment confer longevity, while disease-associated mitochondrial dysfunction triggers pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca2+ channel, InsP3R. To explain this connection, we test multiple candidate links between Ca2+ and mitochondrial homeostasis previously established in vitro, including mitochondrial calcium uniporter (MCU)-dependent stimulation of respiration and cytosolic pathways regulating mitochondrial dynamics. We find that MCU is dispensable for both respiration and longevity in Complex I mutants. Conversely, transcriptomic profiling and imaging reveal InsP3R impairment results in maladaptive expansion of compromised mitochondrial networks. We provide evidence that this aberrant mitochondrial expansion results from disruption of a conserved, InsP3R-dependent actin remodeling network centered on Arp2/3. Disruption of actin remodeling or autophagy mimics the mitochondrial expansion and longevity suppression of InsP3R mutants. Conversely, driving mitochondrial fragmentation ameliorates mitochondrial expansion and rescues longevity in InsP3R mutants, supporting a model in which InsP3R-dependent actin remodeling is required for segregation and clearance of mitochondria. These findings identify an inter-organelle signaling axis linking ER calcium release and cytoskeletal remodeling to adaptive mitochondrial responses associated with longevity.
    DOI:  https://doi.org/10.1038/s41467-026-76514-3
  16. Autophagy. 2026 Sep 09.
    Spatiotemporal control of Atg9 vesicle fusion in autophagosome formation.
    Takumi Kimura, Tetsuya Kotani, Hitoshi Nakatogawa.
      Atg9 vesicles serve as membrane seeds for autophagosome formation. These vesicles are derived from the Golgi/endosomes and localized to the pre-autophagosomal structure or phagophore assembly site (PAS) upon autophagy induction. How these vesicles are maintained as discrete membrane carriers while diffusing through the cytoplasm and subsequently become competent for downstream events at the PAS has remained unknown. Here, we show that the Atg9-interacting protein Atg23 remains associated with Atg9 vesicles following their formation and protects them from inappropriate fusion with endomembranes during their movement through the cytoplasm. Upon arrival at the PAS, Atg1-mediated phosphorylation of Atg9 triggers the dissociation of Atg23, thereby enabling efficient recruitment of the lipid-transfer protein Atg2. Collectively, these findings define a spatiotemporally regulated mechanism in which Atg23 preserves Atg9 vesicles during cytoplasmic transport, whereas its dissociation enables their productive utilization in autophagosome formation.
    Keywords:  Atg9; Phosphorylation-dependent regulation; autophagosome; membrane trafficking; vesicle coating; yeast
    DOI:  https://doi.org/10.1080/15548627.2026.2730073
  17. Nucleic Acids Res. 2026 Sep 07. pii: gkag880. [Epub ahead of print]54(17):
    Altered neuronal start codon stringency favors cap-independent repeat-associated non-AUG translation.
    Clare M Wieland, Shannon E Wright, Sydney Willey, Ishita Purwar, Samantha J Grudzien, Amy Krans, Erinn L Laimon, Melissa J Asher, Adrian M Isaacs, Amanda L Garner, Peter K Todd.
      Intronic GGGGCC repeat expansions in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This expansion supports a non-canonical form of translational initiation known as repeat-associated non-AUG (RAN) translation to produce toxic dipeptide repeat proteins that contribute to neurodegeneration. Here, we find that the efficiency of RAN translation and its dependency on the 5' 7-methylguanosine mRNA cap are variable across cell types, with both rodent neurons and human iNeurons favoring cap-independent RAN translation from two distinct repeats (CGG and GGGGCC) across multiple reading frames. Treatment with an eIF4E inhibitor that blocks cap-dependent translation enhances RAN translation specifically in neurons. Intriguingly, cap-independent RAN translation exhibits less reliance on near-cognate codons for initiation than cap-dependent RAN translation. This finding led us to identify a surprising global alteration in neuronal start codon stringency as a contributor to the relatively higher cap-independent RAN translation in this cell type. This effect correlates with cytoplasmic redistribution of eIF1 in neurons and is reversed with overexpression of the eukaryotic initiation factor eIF5, which relaxes start codon stringency and preferentially enhances cap-dependent RAN translation. Together, these findings reveal several neuron-specific features of translational regulation that favor cap-independent RAN translation with implications for nucleotide repeat expansion disorder pathogenesis.
    DOI:  https://doi.org/10.1093/nar/gkag880
  18. Adv Sci (Weinh). 2026 Sep 08. e77675
    Targeted Lysosomal Degradation of Extracellular and Membrane Proteins: From Receptor Hijacking to Programmable Endolysosomal Routing.
    Ke Liu, Xiyan Wang, Xiaozhen Liu, Chaoqi He, Da Qian, Xuli Meng, Liquan Zhu.
      Lysosome-targeting chimeras (LYTACs) have emerged as a strategy for eliminating secreted, extracellular, and plasma-membrane proteins by redirecting them to the endolysosomal system. By coupling target recognition to receptor-mediated uptake, LYTACs exploit endogenous trafficking pathways to access disease-associated proteins beyond the reach of conventional intracellular degradation mechanisms. Related target-intrinsic and cross-linking-driven strategies can likewise promote lysosomal target delivery without recruiting a separate clearance receptor. However, target internalization alone does not establish productive degradation. Following entry, target-containing complexes encounter a competitive endosomal network in which they may recycle, undergo retrograde transport or transcytosis, remain in non-degradative compartments, or proceed to lysosomes. Here, we present a routing-centered framework for understanding and designing extracellular and membrane-protein degradation. We discuss how target biology, receptor choice, tissue distribution, ligand competition, signaling liability, molecular architecture, and intracellular sorting shape degrader performance. We also outline evidence standards for distinguishing bona fide lysosome-dependent target loss from surface depletion, redistribution, epitope masking, shedding, secretion blockade, transcriptional effects, and nonspecific toxicity. Together, these principles define the transition from receptor hijacking to programmable endolysosomal routing.
    Keywords:  Internalization; axoplasmic transport; cell biology; endocytic cycle; extracellular; membrane protein; protein degradation; transport protein; vesicle
    DOI:  https://doi.org/10.1002/advs.77675
  19. Blood. 2026 Sep 09. pii: blood.2026033874. [Epub ahead of print]
    The stress-sensing MARCH5 axis governs blood cancer apoptotic resilience via tractable protein-protein interactions.
    Thomas E Lew, Mark F van Delft, Luuk Heitink, Simon A Cobbold, Christine Anne White, Jason Alfredo Randall Bong, Philip Hittmeyer, Amelia H Zhu, Vineet Vaibhav, Jumana Yousef, Laura F Dagley, Christopher D Riffkin, Angela Georgiou, Adrienne Hilton, Allan Shuai Huang, Yin Yuan, Miles B Horton, Mark A Dawson, Andrew W Roberts, David Ching Siang Huang.
      The mitochondrial E3 ligase MARCH5 has consistently emerged as a dependency in unbiased screens in acute myeloid leukemia and myeloma, yet the underpinning mechanism remains ill-defined. Here, we show that MARCH5 cooperates with UBE2J2 and MFN2, forming a stress-sensing complex at mitochondria-ER contact sites (MERCS) that restrains apoptosis in response to diverse organellar damage signals. Loss of MARCH5 potently sensitizes diverse blood cancer cell lines to BCL-2 and BCL-XL inhibition and compromises stress tolerance. By contrast, non-hematopoietic cell lines exhibit a phenotype largely restricted to BCL-XL dependence, permitting tissue-selective therapeutic synergy with venetoclax and other agents. Mechanistically, spatial organization underpins this specificity. The complex assembles at MERCS, where it co-localizes with BCL-2 and BCL-XL but not MCL-1. Upon organellar damage, it dissociates prior to BAX/BAK activation, lowering the apoptotic threshold and enforcing reliance on neighboring BCL-2 and BCL-XL. Consistent with its distribution, MARCH5 loss minimally alters MCL-1 dependence, revealing a spatially encoded mechanism integrating diverse stress signals into cell-death decisions. To guide future therapeutics, we demonstrate that disrupting key protein-protein interactions within this complex is sufficient to sensitize blood cancer cell lines, restoring venetoclax responsiveness and prolonging survival in a murine model of refractory lymphoma. Genetic deletion of MARCH5 or UBE2J2 restored BH3-mimetic sensitivity to primary chronic lymphocytic leukemia cells rendered resistant by cytokine stimulation. These findings establish the MERCS-resident MARCH5 complex as a central regulator of malignant cell stress tolerance and highlight tractable protein interfaces for therapeutic targeting.
    DOI:  https://doi.org/10.1182/blood.2026033874
  20. STAR Protoc. 2026 Sep 08. pii: S2666-1667(26)00473-9. [Epub ahead of print]7(3): 104820
    Protocol for fluorescence-activated mitochondria sorting in endoplasmic reticulum-mitochondria contact reporter cells.
    Drew C Stark, Brandon Chen, Kayla Hickman, Costas A Lyssiotis, Yatrik M Shah.
      Mitochondria exchange metabolites bidirectionally with the endoplasmic reticulum to maintain bioenergetic homeostasis and respond to cellular stress. Here, we describe a protocol for generating cells that contain a split-GFP contact-site reporter of ER-mitochondria interactions and the sorting of heterogeneous mitochondrial populations based on fluorescence intensity. This approach enables reproducible functional profiling of mitochondrial subpopulations, validated by proteomic analysis demonstrating the enrichment of endoplasmic reticulum-associated proteins in GFP-positive mitochondria. For complete details on the use and execution of this protocol, please refer to Chen et al.1.
    Keywords:  Cell Biology; Cell separation/fractionation; Flow Cytometry; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104820
  21. J Am Chem Soc. 2026 09 02. 148(34): 36392-36413
    Biomolecular Condensates Dictate the Folding Landscape of Protein Alpha-Helices.
    Nathaniel Hess, Jerelle A Joseph.
      Protein structure is exquisitely sensitive to the surrounding chemical environment, and many proteins encounter complex environments within cells. Importantly, numerous proteins organize into biomolecular condensates─dense macromolecular assemblies with distinct physicochemical properties. This raises a fundamental question: how do condensates reshape protein structure and dynamics? Here, we investigate how protein folding landscapes are altered inside condensates, using the protein α-helix as a model folded domain. Atomistic simulations suggest the helix-coil transition within condensates differs markedly from its behavior in dilute solution or in the presence of inert crowders. We then use Bayesian optimization to develop a chemically specific, residue-resolution model for quantification of α-helical folding and apply it to characterize diverse helices, including α-helical domains from the disease-associated proteins TDP-43, Annexin A11, and Androgen Receptor, within condensates of varying physicochemical properties. Our results support a framework in which multivalent interactions drive unfolding while crowding promotes folding, and α-helix conformational ensembles inside condensates emerge from this balance. Additionally, we show that helix folding transitions are kinetically frustrated inside condensates because they are coupled to the time scale of contact rearrangement with co-condensate proteins. As such, α-helix folding landscapes within condensates are dually sequence-dependent, informed by both the sequence of the α-helical domain and co-condensate proteins. Together, our work has implications for understanding condensate-mediated proteinopathies, targeting aberrant condensates, and designing condensates to program protein function across scales.
    DOI:  https://doi.org/10.1021/jacs.6c01403
  22. Angew Chem Int Ed Engl. 2026 Sep 08. e2233329
    Click-Activated Supramolecular Targeting Chimeras for Spatiotemporally Resolved Protein Degradation In Vivo.
    Yongsong Zhang, Ji Liu, Tianyu Ma, Ming Wang.
      Targeted protein degradation (TPD) holds enormous therapeutic potential, yet spatiotemporally controlled, tissue-selective protein degradation remains challenging. Herein, we report Click-activated Supramolecular TArgeting Chimeras (ClSupTAC), a multimodular platform leveraging bioorthogonal chemistry to realize spatially and temporally resolved TPD in vivo. ClSupTAC follows a two-step "click-to-activate" paradigm: self-assembled, functionally dormant tissue-targeting supramolecular nanoparticles presenting protein-binding ligands and trans-cyclooctene (TCO) moieties are locally activated upon inverse electron-demand Diels-Alder (IEDDA) cycloaddition with tetrazine-E3 ubiquitin ligase recruiter conjugates. The IEDDA chemistry of ClSupTAC delivers accelerated addition reaction and protein degradation kinetics compared to Staudinger reaction-mediated activation of TPD. Moreover, ClSupTAC achieves rapid, selective degradation of pathogenic proteins in vitro and enables lung-targeted protein degradation in vivo. In acute lung injury models, ClSupTAC effectively alleviates pulmonary inflammation and recovers vascular barrier integrity. This study establishes ClSupTAC as a versatile and programmable platform for spatiotemporally precise protein regulation and targeted therapeutic intervention.
    Keywords:  bioorthogonal chemistry; ferroptosis; organ selectivity; supramolecular targeting chimeras; targeted protein degradation
    DOI:  https://doi.org/10.1002/anie.2233329
  23. Biomol NMR Assign. 2026 Sep 11. pii: 28. [Epub ahead of print]20(1):
    Backbone and side chain 1H, 13C and 15N chemical shift assignment of the cargo-recognition domain MOTH of human TANGO1.
    Jelena Auch, Anna Carlotta Peddinghaus, Raphael Stoll.
      The cellular export of large-sized proteins, such as collagen or fibrillin, necessitates a specialized transport pathway tailored towards their size. For collagen and possibly also other bulky proteins, the Transport ANd Golgi Organization 1 (TANGO1) protein plays a substantial role in the transfer from the Endoplasmic Reticulum (ER) to the Golgi apparatus. TANGO1 and related proteins organize the ER exit sites and generate large export structures within the cytosol while anchored to the ER membrane. In contrast to other proteins involved, TANGO1 features a folded domain in the ER lumen, which seems to be central for detecting cargos. This cargo-recognition domain has been shown to bind the collagen-specific chaperone HSP47 (Ishikawa et al. 2016) as well as type IV collagen directly (Arnolds and Stoll 2023). However, the exact molecular mechanism of these interactions remains unknown. The resonance assignments presented here lay the foundation for the experiments studying the binding process on a molecular level and is designed to facilitate investigations into how TANGO1 detects and selects the cargos to be exported.
    Keywords:  Assignments; MOTH domains; NMR; Protein transport; TANGO1 protein
    DOI:  https://doi.org/10.1007/s12104-026-10278-1
  24. Cell Death Differ. 2026 Sep 08.
    Canonical lymphocyte chemokine receptors CXCR3 and CXCR5 modulate neuronal autophagy.
    Matea Rob, Farah H Siddiqi, Junrui He, Yoshinori Tanaka, David C Rubinsztein.
      Autophagy, a conserved cellular degradation process, plays a critical role in clearing toxic aggregate-prone proteins, which are characteristic pathological hallmarks of neurodegenerative diseases. As we previously found that microglia secreted factors impair neuronal autophagy and identified CCL3, CCL4 and CCL5 as causative chemokines, we screened the microglial secretome for soluble factors and neuronal cytokine receptors to identify candidates impacting autophagy in neuronal models. Against our expectations of identifying negative regulators, we found that two receptor-ligand pairs, CXCR3-CXCL10 and CXCR5-CXCL13, stimulated autophagy across several neuronal models, both in vitro (SH-SY5Y, i3Neurons) and in vivo. Mechanistically, CXCL10 and CXCL13 promoted autophagy through a shared mechanism: cognate receptor stimulation led to downstream activation of JNK, which in turn phosphorylates BCL-XL, promoting its disassociation from BECN1. The freed BECN1 interacts with VPS34 to form the autophagy initiation complex, enhancing autophagosome formation and flux. These findings reveal chemokine signalling as a targetable pathway for neuronal autophagy induction in neurodegeneration.
    DOI:  https://doi.org/10.1038/s41418-026-01865-9
  25. Nature. 2026 Sep 09.
    Proximity-guided graph learning reveals tumour-associated proximity antigens.
    Cody Scandore, Clare F Malone, Christopher K May, Anna K de Regt, Jeff Guernsey, Hayley Ma, Noah Dephoure, Ben Setter, Rebecca A Howell, Kendall R Johnson, Carol L Farr, Sophia Romero, Lydia Vignale, Tali Vittum, Emma Dawson, Tsadik Habtetsion, Francesca Nardi, Brian Woodruff, Martin Mathay, Julia Swanson, Mikaela Rusnak, Quynh Ton, Payam E Farahani, Robert W Gene, Jason Misurelli, Zach Caldwell, Hengyu Xu, Michael Hornsby, Marc A Gavin, Heath E Klock, Ertan Eryilmaz, Pamela M Holland, Scott A Lesley, Rob C Oslund, Olugbeminiyi O Fadeyi.
      The spatial organization of membrane proteins is an underexplored dimension of cell surface biology1,2. Spatial proximity shapes cellular function and therapeutic targetability2,3, yet efforts to identify tumour-associated antigens (TAAs) have largely focused on expression alone4. Here, we developed an industrialized surface protein proximity-mapping workflow to interrogate TAAs within their membrane microenvironments. Using this workflow, we generated 248 proximity maps across 12 receptor tyrosine kinases and 28 tumour cell systems. The resulting atlas enabled the development of MetaMap, a correlation-based analytical framework that defines spatial protein communities and infers conserved proximity relationships among non-targeted proteins, and establishes the concept of tumour-associated proximity antigens (TAPAs), a class of co-targets defined by disease-specific spatial proximity to TAAs rather than expression alone. Integrating these proximity-derived relationships within a multimodal prioritization framework, we identified and validated EGFR-CDCP1 as a TAA-TAPA pair that enhances tumour cell killing across therapeutic modalities. Together, this work advances disease-associated membrane proximity as a guiding principle for the design of precision multispecific therapeutics.
    DOI:  https://doi.org/10.1038/s41586-026-11003-7
  26. J Am Chem Soc. 2026 09 02. 148(34): 36338-36344
    Kinetic Frustration of Collagen Folding Drives Condensate-Mediated Fibrous Assembly.
    Debajit Kalita, Debashree Borah, Amar Ghosh, Kalpita Baruah, Rhea Gangamma, Bani Kanta Sarma.
      Collagen assembly is generally assumed to proceed hierarchically with rapid triple-helix folding preceding higher-order organization. Here, we show that this paradigm can break down when triple helix formation becomes kinetically frustrated. Using collagen-mimetic peptides containing cis-trans-isomerizing cationic and anionic peptoid residues, we selectively delay folding kinetics and demonstrate that liquid-liquid phase separation (LLPS) can occur prior to fibrous assembly. Delayed folding enables weak multivalent charge-pair interactions to become kinetically relevant, generating a phase-separated intermediate that subsequently matures into micrometer-scale fibrous architectures. Time-resolved spectroscopic, thermal, and microscopic analyses establish a condensate-mediated assembly pathway that is inaccessible under conventional rapid folding conditions. By demonstrating that kinetic frustration can redirect collagen-mimetic assembly through LLPS, this work identifies folding kinetics as a key determinant of the assembly pathway selection. Our findings expand the current framework of collagen-inspired self-assembly, reveal an alternative route to hierarchical collagen organization, and establish condensate-mediated growth as a strategy for programming the supramolecular architecture in collagen-inspired materials.
    DOI:  https://doi.org/10.1021/jacs.6c13610
  27. J Cell Biol. 2026 Nov 02. pii: e202605096. [Epub ahead of print]225(11):
    Nucleolar dynamics are determined by the ordered assembly of the ribosome.
    Jessica Sheu-Gruttadauria, Xiaowei Yan, Nico Stuurman, Riley O Ogrean, Sabrina Lin, Stephen N Floor, Ronald D Vale.
      Ribosome biogenesis occurs in the nucleolus, a biomolecular condensate whose material properties are thought to be important for function. However, the molecular basis of nucleolar dynamics and their relationship to ribosome assembly remain incompletely understood. We present a platform for high-throughput FRAP (HiT-FRAP) and use it to screen hundreds of genes for their impact on dynamics of the nucleolar scaffold nucleophosmin (NPM1). We find that NPM1 dynamics and nucleolar morphology are sensitive to ribosome assembly state: accumulation of early pre-ribosomal intermediates slows NPM1 dynamics and compacts the condensate, while accumulation of abortive late precursors accelerates dynamics and disrupts condensate integrity. These opposing biophysical states correlate with the strength of NPM1-pre-ribosome interactions. Importantly, mutations in the NPM1 intrinsically disordered region that alter pre-ribosome binding directly tune nucleolar dynamics. These results establish that ribosomal precursor assembly state determines nucleolar material properties through the strength of scaffold-pre-ribosome interactions and introduce HiT-FRAP as a platform for interrogating condensate dynamics broadly.
    DOI:  https://doi.org/10.1083/jcb.202605096
  28. RSC Med Chem. 2026 Aug 11.
    Covalent warheads as a versatile platform for molecular glue development.
    Bo Zhang, Shiji Zhang, Renshuai Liu, Xuben Hou, Hao Fang.
      Targeted protein degradation (TPD) has become a novel therapeutic modality for diseases in drug discovery. Most progress on TPD has focused on the ubiquitin proteasome system; however, only a handful of >600 human genome-encoded E3 ligases have been successfully applied. Expansion of the E3 ligase toolbox with novel E3 ligases and their ligands will broaden the potential applications of TPD. Besides that, covalent molecular glue degraders (MGDs) provide a promising direction for TPD. Covalent MGDs may offer several advantages, including increased selectivity, broad applicability to traditionally undruggable proteins, and efficient protein degradation. This review systematically summarizes the latest progress in the field of covalent MGDs, focusing on validated E3 ligases and their corresponding covalent warheads. Structural features, modes of action, and design strategies of covalent MGDs are discussed aiming to provide guidance for the development of novel covalent MGDs.
    DOI:  https://doi.org/10.1039/d6md00581k
  29. Cell Mol Immunol. 2026 Sep 07.
    p97-mediated proteostasis is a checkpoint for late-stage thymocyte positive selection.
    Ruixian Yu, Weihong Zhang, Yi Han, Wenjia Wang, Yan Meng, Pingping Nie, Cuiwei Zhang, Zaisheng Ye, Bin Yan, Zhaocai Zhou, Shi Jiao.
      AAA+ ATPase p97 is a central regulator of protein homeostasis, yet its role in late-stage thymocyte development remains undefined. Here, we demonstrate that T-cell-specific ablation of p97 in mice severely blocks the double-positive (DP) to single-positive (SP) transition, with a pronounced defect in CD8+ lineage commitment. Using both genetic deletion and acute pharmacological inhibition, we revealed a stage- and lineage-specific requirement for p97, with DP thymocytes being most sensitive to p97 loss. This failure in late-stage positive selection leads to intrathymic developmental arrest of immature DP cells and profound peripheral T-cell lymphopenia. Mechanistically, p97 deficiency results in the accumulation of ubiquitinated proteins, triggering the unfolded protein response and apoptosis in thymocytes. Furthermore, we identified a critical requirement for p97 in sustaining IL-7 receptor (IL-7R) expression and JAK signaling. Strikingly, pharmacological activation of JAK partially rescued SP thymocyte development in p97-deficient mice. Our findings establish p97-mediated protein homeostasis as a previously uncharacterized, cell-intrinsic checkpoint that is indispensable for late-stage positive selection by preventing proteostatic collapse and ensuring the fidelity of IL-7R signaling.
    Keywords:  IL-7R-JAK signaling; Positive selection; Protein homeostasis; Thymus; p97
    DOI:  https://doi.org/10.1038/s41423-026-01466-z
  30. Sci Adv. 2026 Sep 11. 12(37): eaeh2771
    Metabolic regulation of calcium homeostasis via SERCA succination.
    Su Jin Ham, Yena Kim, Sehyeon Kim, Sunhoe Bang, Young Hoon Koh, Soung-Hun Roh, Hyung Seo Park, Jongkyeong Chung.
      Although calcium homeostasis is disrupted in metabolic diseases, its metabolic regulation remains unclear. Here, we identify a mechanism by which fumarate suppresses sarco/endoplasmic reticulum (ER) calcium ion-adenosine triphosphatase (SERCA) activity via succination of a conserved cysteine residue, impairing ER calcium uptake and promoting metabolic dysfunction in Drosophila. In mammalian cells, high glucose or fumarate inhibits SERCA activity and increases ER calcium release and cytosolic and mitochondrial calcium levels. Mechanistically, we show that fumarate covalently modifies SERCA2b at Cys875 and that a Cys875Ser mutant resists fumarate-induced inhibition. In Drosophila, knock-in flies with the corresponding Cys875Ser mutation preserve ER calcium homeostasis and are protected from hyperglycemia, glucose intolerance, and reduced survival on a high-sugar diet. These effects are phenocopied by pharmacological fumarate reduction or allosteric SERCA activation. Collectively, these findings suggest that fumarate-mediated SERCA inhibition provides a mechanistic link between glucose metabolism and calcium homeostasis, with potential relevance to metabolic dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.aeh2771
  31. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2618090123
    The 4EHP/GIGYF2 translation repressor complex is co-opted by the vaccinia virus K3L protein as a potential mechanism of immunoevasion.
    Reese Jalal Ladak, Adrian Pelin, Haotian Zhuang, Chelsea Abboud, Niaz Mahmood, Jonathan Blanchet, Chenyue Wu, Huy-Dung Hoang, Tom McGirr, Andia Moshari, Mohamed Moustafa-Kamal, Patric Harris Snell, Stefan Düsterhöft, Albert M Berghuis, Jean-François Trempe, Michel L Tremblay, Jose G Teodoro, Arkady Khoutorsky, Tommy Alain, Nevan J Krogan, Jung-Hyun Choi, Seyed Mehdi Jafarnejad, Nahum Sonenberg.
      Poxviruses have evolved robust immunoevasion strategies to facilitate replication in the cytosol. We previously reported that like several RNA viruses, vaccinia virus replication is impaired in the absence of the host cap-binding translation repressor protein 4EHP (eIF4E2), implicating the latter in host antiviral defense regulation and immunosuppression. Here, we show that the vaccinia virus-encoded K3L protein interacts with 4EHP via its obligatory binding partner GIGYF2 to increase the stability of the 4EHP/GIGYF2 complex. Consequently, K3L bolsters 4EHP/GIGYF2-mediated mRNA translation repression. Thus, we demonstrate that a 4EHP/GIGYF2-mediated mechanism is exploited by and conserved among RNA and DNA viruses as a potential immunoevasion strategy. Our findings document a 4EHP/GIGYF2-dependent stringent regulation of infection by poxviruses, a clinically important family of viruses that are employed as vaccine vectors and in oncolytic viral therapy.
    Keywords:  4EHP; GIGYF2; K3L; poxvirus; vaccinia virus
    DOI:  https://doi.org/10.1073/pnas.2618090123
  32. Nucleic Acids Res. 2026 Sep 07. pii: gkag858. [Epub ahead of print]54(17):
    The alarmone pGpp inhibits translation through GTP depletion.
    Kevin A England, Aude Trinquier, Leah K McKinney, Jue D Wang, Heather A Feaga.
      Bacteria produce the alarmone nucleotides ppGpp and pppGpp during stress to affect replication, transcription, and metabolism. ppGpp and pppGpp also attenuate translation by competitively binding translational GTPases to conserve resources during stress. Recently, pGpp was identified as a third alarmone, and important pathogens like Clostridioides difficile exclusively produce pGpp in response to stress. Despite its abundance as an alarmone, the precise role of pGpp in mediating stress responses is poorly understood. Here, we show that, while pGpp is a weaker inhibitor of protein synthesis than ppGpp and pppGpp in vitro, pGpp production in the model Gram-positive bacterium Bacillus subtilis leads to faster translation inhibition in vivo. pGpp production leads to fewer ribosomes engaged in translation and more hibernating ribosome dimers than (p)ppGpp production, suggesting that translation initiation is strongly inhibited. Additionally, pGpp production depletes cellular GTP more rapidly than (p)ppGpp production, which we show is sufficient for translation inhibition. Faster GTP depletion during pGpp production is also accompanied by more robust transcriptome remodeling. This work expands the model by which alarmones inhibit translation to include GTP depletion and demonstrates how different alarmone species exert varying effects on physiology.
    DOI:  https://doi.org/10.1093/nar/gkag858
  33. Curr Biol. 2026 Sep 08. pii: S0960-9822(26)01082-1. [Epub ahead of print]
    Phosphorylation-dependent interaction between VAP proteins and INF2 influences ER morphology.
    Frieda Kage, Miriam Lee, Siddhi Bramhe, Alastair G McEwen, Fabien Alpy, Henry N Higgs.
      The endoplasmic reticulum (ER) interacts with virtually all other cellular organelles, and major players mediating these interactions are the ER-bound VAMP-associated protein (VAP) proteins VAPA and VAPB. Here, we show that VAP proteins interact with the actin polymerization factor INF2 in a phosphorylation-dependent manner. Similar to many other VAP-interacting proteins (the "VAPome"), an FFAT motif in INF2's C terminus interacts with the major sperm protein (MSP) domain of VAPs. Phosphorylation of a serine within the FFAT (S1100 in mouse; S1077 in human INF2) is necessary for high-affinity interaction both in cells and with purified proteins. The position of this phosphoserine, at position -1 of the FFAT consensus, is novel to the VAPome. Biochemical assays show that the phospho-FFAT binds both VAPA and VAPB, but not the related VAP family protein MOSPD2. Increased cytoplasmic calcium stimulates both INF2 phosphorylation and the INF2/VAP interaction. Amyotrophic lateral sclerosis (ALS)-associated mutations in the MSP disrupt the INF2/VAP interaction. Both major INF2 isoforms interact with VAPs: the INF2-CAAX isoform, which is constitutively ER-bound, and the INF2-nonCAAX isoform, which is predominantly cytosolic. For INF2-nonCAAX, VAP proteins cause ER recruitment in a phosphorylation-dependent manner. Disruption of INF2/VAP binding does not affect INF2-mediated actin polymerization but has a clear effect on ER morphology, causing the tubule/sheet balance to shift toward sheets. Cross-species evaluation suggests that only INF2 from placental mammals possesses an FFAT. These results suggest that interaction between VAP proteins and the actin polymerization factor INF2 plays a role in mediating ER morphology.
    Keywords:  CIA; calcium-induced actin polymerization
    DOI:  https://doi.org/10.1016/j.cub.2026.08.031
  34. Nat Chem Biol. 2026 Sep 07.
    Directed evolution of Lantern enables rapid RNA and protein proximity labeling.
    Yuxin Fang, Ziqi Ren, Fu Zheng, Ruixiang Wang, Songrui Zhao, Yihai Zhang, Wentao Wang, Chen Li, Luorong Liu-Yang, Chang Lin, Jun Liu, Peng Zou.
      In eukaryotic cells, the precise spatial localization of RNAs and proteins is essential for proper cellular function. Genetically encoded photocatalytic proximity labeling techniques have expanded our ability to map subcellular proteomes and transcriptomes, but their temporal resolution remains limited. Here we introduce Lantern, an engineered flavoprotein optimized via directed evolution, which enables sub‑minute, spatially resolved labeling of cellular biomolecules. Lantern is targetable to diverse subcellular compartments, including the endoplasmic reticulum (ER), mitochondria and stress granules (SGs), to map local transcriptomes (CAP-seq) and proteomes (CAP-MS). Using Lantern, we observed that N6-methyladenosine-rich RNAs are recruited to SGs within 10 minutes of stress induction, and ER‑proximal RNAs associate with G3BP1 during early SG assembly. Additionally, Lantern was adapted for cell surface tagging (CAP-CELL), enabling spatially resolved cell typing and identifying cell-cell interactions. Collectively, this study establishes Lantern as a powerful tool that offers unprecedented temporal resolution for investigating the dynamic organization of subcellular molecular networks.
    DOI:  https://doi.org/10.1038/s41589-026-02313-y
  35. Nat Commun. 2026 08 11. pii: 9623. [Epub ahead of print]17(1):
    ESMDynamic: Fast and accurate prediction of protein dynamic contact maps from single sequences.
    Diego E Kleiman, Jiangyan Feng, Zhengyuan Xue, Diwakar Shukla.
      Understanding conformational dynamics is essential for elucidating protein function, yet most deep learning models in structural biology predict only static structures. Here, we present ESMDynamic, a deep learning model that predicts residue-residue contact dynamics directly from protein sequence. Built on the ESMFold architecture and trained on conformational variability from experimental structure ensembles and molecular dynamics (MD) simulations, ESMDynamic predicts dynamic contact probabilities, contact occupancy fraction, and coarse-grained kinetics of contact formation and dissociation across multiple temperature conditions. On large-scale MD benchmarks (mdCATH and ATLAS), ESMDynamic matches or outperforms state-of-the-art ensemble prediction methods (AlphaFlow, ESMFlow, BioEmu) while requiring orders-of-magnitude less computation. We demonstrate generalization to diverse systems, including membrane transporters, a de novo designed protein, and a homodimer complex. We show that predicted dynamic contacts enable automated selection of collective variables for Markov state model construction. Applied to the human proteome, ESMDynamic generates predictions for over 18,000 proteins, enabling large-scale analysis of conformational variability. Overall, ESMDynamic provides a scalable, sequence-based representation of protein dynamics to inform simulation, analysis, and design workflows.
    DOI:  https://doi.org/10.1038/s41467-026-76361-2
  36. FEBS J. 2026 Sep 07.
    The E3 ubiquitin ligase WWP2 regulates the stability and tumor suppressive properties of the chromatin remodeler ARID1B.
    Pradipta Hore, Sandipkumar Bambhaniya, Murali Dharan Bashyam.
      ARID1B, a key subunit of the SWI/SNF (also known as BAF) chromatin remodeling complex, is characterized as a canonical tumor suppressor across various cancer types. Although the downregulation of ARID1B transcript levels has been observed in many cancers, its regulation at the protein level is comparatively less studied. Here, we identify WWP2, an E3 ubiquitin ligase, as a previously undescribed interaction partner of ARID1B. Our results show that WWP2 interacts with the PPxY motif located at the N terminus of ARID1B through its WW domains. We further demonstrate that wild-type WWP2, but not a catalytically inactive mutant counterpart, regulates ARID1B protein stability through ubiquitination-mediated proteasomal degradation. Interestingly, WWP2 appears to facilitate noncanonical K27- and K29-linked polyubiquitination of ARID1B. Additionally, silencing WWP2 expression results in a decrease in ubiquitination and a subsequent increase in ARID1B protein levels, indicating that WWP2 plays a crucial role in regulating ARID1B stability. Finally, based on several tumorigenic assays performed in cell lines and mouse xenograft models, we show that WWP2 may modulate ARID1B-mediated tumor suppression. Our results therefore highlight a new mechanism of post-translational regulation of ARID1B, which may have implications in ARID1B-mediated tumor suppression.
    Keywords:  ARID1B; WWP2; proteasomal degradation; tumor suppression; ubiquitination
    DOI:  https://doi.org/10.1111/febs.70721
  37. Drug Discov Today. 2026 Sep 07. pii: S1359-6446(26)00201-1. [Epub ahead of print] 104796
    Artificial intelligence-enabled induced-proximity drug discovery: Designing productive molecular associations.
    Haomin Wu, Yaxin Xu, Zhiwei Nie, Zhongyang Zhou, Zhengyu Ma, Zhixiang Ren.
      Induced proximity is changing drug discovery by turning molecular association into a therapeutic design principle. Rather than blocking a single active site, proximity-based agents can degrade, stabilize, relocalize or rewire disease-relevant proteins. This review examines how artificial intelligence is beginning to support that transition, from prioritizing target-effector pairs and modelling ternary or neo-interface assemblies to designing degraders, molecular glues and programmable systems and learning from experimental feedback. We discuss progress across degradative and nondegradative modalities and argue that future impact will depend less on larger models alone than on mechanism-resolved data, realistic benchmarks, interpretable failure analysis and developability-aware design.
    Keywords:  PROTACs; artificial intelligence; drug discovery; induced proximity; molecular glues; targeted protein degradation; ternary complex
    DOI:  https://doi.org/10.1016/j.drudis.2026.104796
  38. Am J Cancer Res. 2026 ;16(8): 3620-3643
    AI-assisted design and virtual profiling of targeted degraders for pancreatic cancer therapy via PROTAC technology.
    Bing Du, Kunjie Wang, Zhu Wu, Shaofan Qiu, Filippiadis Dimitrios Konstantinos, Shuo Yu.
      Pancreatic cancer remains one of the most lethal malignancies because of late diagnosis, aggressive progression, therapy resistance, and limited effective treatment options. Bromodomain-containing protein 4 (BRD4) is an important epigenetic regulator implicated in pancreatic cancer progression through its role in transcriptional control, cell proliferation, and survival signaling. Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a potential strategy for eliminating disease-associated proteins through ubiquitin-proteasome-mediated degradation rather than transient pharmacological inhibition. In this study, an AI-assisted and structure-guided computational workflow was used to design and virtually prioritize BRD4-targeting PROTAC candidates recruiting DCAF15 as the E3 ligase component. The workflow integrated protein-structure evaluation, pharmacophore-based ligand screening, ADMET and Lipinski filtering, binary protein-ligand docking, molecular-interaction analysis, rational linker selection, BRD4-DCAF15 protein-protein docking, PROTAC-mediated ternary-complex docking, and molecular dynamics simulation. The results identified CLTTMPBA-linker-E7820 as a computationally prioritized PROTAC architecture with favorable predicted binding behavior, residue-level interaction patterns, and simulated ternary-complex stability. Importantly, this study is entirely computational and should be interpreted as an early-stage in silico prioritization framework rather than experimental evidence of BRD4 degradation or anticancer efficacy. The proposed BRD4-DCAF15 PROTAC candidates represent lead hypotheses that require biochemical, cellular, pharmacological, and in vivo validation, including confirmation of target engagement, ternary-complex formation, proteasome-dependent BRD4 degradation, downstream transcriptional modulation, pancreatic cancer cell inhibition, selectivity, pharmacokinetics, toxicity, and antitumor efficacy.
    Keywords:  AI-assisted drug design; BRD4 oncogenic protein; PROTAC technology; Pancreatic cancer; targeted protein degradation
    DOI:  https://doi.org/10.62347/EKCM7279
  39. Mol Cancer. 2026 Aug 27. pii: 210. [Epub ahead of print]25(1):
    A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer.
    Lucia A Torres-Fernández, Volker Boehm, Joel Kaufmann, Jonas P Becker, Maria Garcia-Marquez, Beaunelle de Bruijn, Agnieszka Rumińska, Christian Müller, Graziella Bosco, Nazanin Alavinejad, Laura Lovric, Johanna I Bihler, Hanna Schulte, Poorya Davoodi, Anna Schöllhorn, Kian R Weihrauch, Laura Kaiser, Olta Ibruli, Fanyu Liu, Ariadne Androulidaki, Nina Wobst, Marcel Schmiel, Justinas Valiulis, Lukas Maas, Joshua D'Rozario, Vignesh Sakthivelu, Bianca Göbel, Marian Touet, Johannes Brägelmann, Katja Höpker, Felix John, Jürgen Wolf, Stefan Knapp, Alexander Quaas, Maria Cartolano, Silvia von Karstedt, Filippo Beleggia, Hans-Georg Rammensee, Cécile Gouttefangeas, Hans A Schlößer, Angelika B Riemer, Hans Christian Reinhardt, Niels H Gehring, Martin Peifer, Roman K Thomas, Julie George.
      Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.
    Keywords:  Cancer genomics; Cancer immunotherapy; Frameshift mutations; Genomic instability; Neoantigen; Nonsense mediated decay (NMD); Proteostasis; RNA surveillance; Small cell lung cancer (SCLC); Tumor mutational burden (TMB)
    DOI:  https://doi.org/10.1186/s12943-026-02750-2
  40. Toxicol In Vitro. 2026 Sep 06. pii: S0887-2333(26)00106-2. [Epub ahead of print] 106298
    Comparative toxicoproteomics reveals distinct proteostasis and ribosomal stress signatures of CMIT and PHMG.
    Ye-Eun Jeong, Min Jeong Jeon, Hyung-Sun Youn, Jiyou Han, Mi-Young Lee.
      Methylchloroisothiazolinone (CMIT) and polyhexamethylene guanidine (PHMG) are antimicrobial biocides associated with pulmonary toxicity, although their comparative cellular stress mechanisms remain unclear. Here, we investigated how CMIT and PHMG differentially alter the proteome of human alveolar epithelial A549 cells under subcytotoxic conditions. Cells were exposed to CMIT or PHMG, and global proteomic profiling was performed using label-free liquid chromatography-tandem mass spectrometry. Differentially expressed proteins (DEPs) were identified at a 1% false discovery rate with an absolute log2 fold change ≥1. Functional analyses were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis, and selected proteins were validated by western blotting. Comparative toxicoproteomics revealed distinct stress-response signatures induced by the two biocides. CMIT preferentially altered proteins associated with proteostasis, oxidative stress, and protein quality control, whereas PHMG was characterized by coordinated depletion of ribosome-associated and translation-related proteins. A total of 73 and 155 DEPs were identified in CMIT- and PHMG-treated cells, respectively, with 22 proteins shared between treatments. Western blotting confirmed PSMD3, TUBB2A, and GLRX1 as CMIT-responsive proteins and THRAP3, DHX15, and RPL4 as PHMG-responsive markers. These findings provide comparative mechanistic insight into how CMIT and PHMG induce distinct epithelial stress responses and identify candidate protein markers that may support future in vitro assessment of biocide-induced pulmonary toxicity.
    Keywords:  CMIT; PHMG; Proteomics; Proteostasis stress; Ribosomal stress
    DOI:  https://doi.org/10.1016/j.tiv.2026.106298
  41. Nat Chem Biol. 2026 Sep 08.
    Macrophages transfer functional proteins to their surface during live-cell uptake.
    Regan F Volk, Amy C Fan, Sara W Casebeer, Vishnu R Tejus, Andrew C Condon, Bahar Zirak, Nayelis A Manon, Iryna Irkliyenko, Danielle M Torralba, Shao Tao, Tommaso Pollini, Vijay Ramani, Ajay V Maker, Matthew F Krummel, Hani Goodarzi, Balyn W Zaro.
      A cell's proteome is assumed to reflect its transcriptional and translational activity. Macrophages regularly acquire xenobiotic material from neighboring cells, which is thought to result in degradation of the material. However, increasing lines of evidence suggest that not all taken up material is degraded and other transfer-like processes also occur. Field standard technologies are unable to rigorously report on precisely how and by whom the macrophage protein repertoire is altered during these interactions, leaving unresolved the extent to which nondegradative processes contribute to altered phenotypes. Here, we leveraged chemical tools and proteomics to show that intact target cancer cell surface proteins are transferred to the macrophage cell surface at functionally impactful levels in a manner associated with live-cell uptake. Widespread acquisition of proteins during cell uptake reengineers the macrophage cell surface proteome and is a transcriptionally silent, cell-nonautonomous process with the potential to alter metabolic uptake.
    DOI:  https://doi.org/10.1038/s41589-026-02292-0
  42. Nat Commun. 2026 Aug 11. pii: 9611. [Epub ahead of print]17(1):
    Adipocyte-derived β-hydroxybutyrate confers metabolic resilience in multiple myeloma.
    Chen Song, Peng Yang, Yu Li, Tao Xia, Rui Li, Mengmeng Guo, Wenjun Li, Chenfeng Liu, Tiantian Jia, Yansheng Wang, Xunxia Bao, Qi Wang, Yuan Yao, Qian Dai, Huan Liu, Zongwei Li.
      Multiple myeloma (MM) remains an incurable blood cancer. Obesity is a known risk factor, but how adipocytes promote MM progression is not fully understood. Here, we uncover a metabolic crosstalk between adipocytes and MM cells that promotes MM cell survival under glucose deprivation. We show that glucose restriction activates AMPK, disrupting HSP90-IRF4 binding and rendering IRF4 susceptible to TRIM21-mediated proteasomal degradation. Paradoxically, the same stress stimulates adipocytes to produce β-hydroxybutyrate (β-OHB). MM cells utilize β-OHB through OXCT1-mediated ketolysis, fueling NAT10-dependent acetylation of IRF4 at K87, which restores IRF4-HSP90 binding and sustains tumor cell survival. Genetic ablation of the rate-limiting ketogenic enzyme Hmgcs2 in adipocytes abrogates this protective effect. Importantly, combining an AMPK activator (metformin) with an OXCT1 inhibitor (pimozide) or a NAT10 inhibitor (remodelin) shows synergistic anti-tumor activity in vivo. Our findings position adipocyte-derived β-OHB as a critical metabolic adaptor and highlight a potential combination therapy for MM.
    DOI:  https://doi.org/10.1038/s41467-026-76595-0
  43. Mol Divers. 2026 Sep 09.
    Recent advances of dual PROTACs for potential therapeutic applications.
    Shun-Ran Li, Meng-Qian Yu, Bo-Qun Du, Ke-Jun Jin, Shu-Xun Chen, Zi Hui, Hang Zhang, Nian-Dong Mao, Yuan Gao, Xiang-Yang Ye.
      Targeted protein degradation (TPD) has revolutionized drug discovery, with PROTACs leading the charge by catalytically eliminating disease-causing proteins. While conventional PROTACs degrade a single target, the complexity of diseases like cancer and neurodegeneration-marked by redundant and compensatory signaling networks-has spurred the rapid development of dual/multi-target PROTACs capable of simultaneously degrading two or more pathogenic proteins. This review systematically surveys recent advances (2023-2026) in this area, categorizing them into two classes: those targeting homologous proteins (e.g., CDKs, BCL-2/BCL-xL, HDACs, BAZ2A/BAZ2B) and those targeting distinct proteins across interconnected pathways (e.g., ERα/ARO, α-Syn/tau, BET/HDAC, PI3K/mTOR, FLT3/CHK1, CBP/BRD4, and others). For each, we critically analyze design strategies, structure-activity relationships, linker optimization, and E3 ligase selection. Despite remarkable progress-including the first dual degraders for non-kinase epigenetic regulators and protein aggregates-challenges persist in pharmacokinetics, off-target toxicity, and limited E3 ligase diversity. By consolidating key breakthroughs and practical SAR insights, this review provides a valuable resource for advancing next-generation multi-target degraders toward clinical translation for complex diseases.
    Keywords:  Degradation; PROTACs; Simultaneously targeting; Therapeutic applications
    DOI:  https://doi.org/10.1007/s11030-026-11734-9
  44. Cell Rep. 2026 Sep 10. pii: S2211-1247(26)01031-4. [Epub ahead of print]45(9): 117953
    Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.
    Bingqing Zou, Qiuyun Chen, Junjun Zheng, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou.
      Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.
    Keywords:  CP: cell biology; CP: developmental biology; DLL4; ER stress; IL7; MSC; NOTCH3; PERK; bone marrow endothelium
    DOI:  https://doi.org/10.1016/j.celrep.2026.117953
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