bims-proteo 2026-07-12 papers

bims-proteo

Biomed News

on Proteostasis

Issue of 2026–07–12
43 papers selected by
Eric Chevet, INSERM

Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.
Structural proteomics reveals that misfolded nascent proteins expose buried lysines for ubiquitination and rapid proteasomal degradation.
Lectins of the Emp47/ERGIC-53 family target misfolded O-mannosylated ER proteins to ER-associated degradation.
Profiling of terminating ribosomes reveals translational control at stop codons.
The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.
Mechanosensing at the endoplasmic reticulum by IRE1.
OPTN (optineurin)-mediated selective substrate recognition in Golgi membrane-associated degradation.
Bioinformatic pipeline to identify candidate mRNA transcripts targeted by the putative Regulated Ire1-Dependent Decay pathway of Dictyostelium discoideum .
Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.
Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.
Wanted and unwanted modifications of mRNA, and their effect on gene expression and signaling.
Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.
UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice.
Targeting endoplasmic reticulum export disrupts metabolic resilience in multiple myeloma.
Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.
UbiDash: A UPS proteomic atlas for tissue-aware degrader design.
Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin.
Stress granules as RNA triage hubs suppress extracellular vesicle secretion under oxidative stress in cancer.
A detailed molecular picture of protein folding during active translation.
Pep2Mol: 3D Molecule Generation Targeting Protein-Protein Interfaces with Diffusion Models.
A comprehensive benchmark of sequence-based subcellular localization predictors for human proteins.
Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease.
Hypoxia rescues complex 1-associated disease caused by proteostatic defects.
Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.
Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.
Evolution of the ribosomal exit tunnel through the eyes of the nascent chain.
The Calcium-Calpain-ALIX Axis is the Major Link Between Gasdermin-D Membrane Pores and Terminal Membrane Damage in Pyroptosis.
TRIM21 induces selective autophagy of viruses and bacteria.
RIMTAC: A Novel Degrader Design Platform by Indirect VHL-Recruitment via RIPK1.
The Plant RABC1 GTPase Coordinates with Exocyst Component SEC5A in Regulating ER-phagy under Endoplasmic Reticulum Stress.
ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.
Elongationless start-stop elements are stress-resilient translation gates that are more repressive than uTranslons.
Inhibition of elastin degradation alleviates joint degeneration in aging mice, dogs, and human models.
Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.
Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer's disease.
Intrinsically disordered regions in eukaryotic mRNA decay pathways.
Resolving cellular signaling in space and time: From organelle proteomics to spatial phosphoproteomics.
Molecular mechanism of IF1- and IF2-driven translation initiation in bacteria.
Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.
Immunoglobulin binding protein (BiP) forms two types of dimers.
Benzoxaboroles Are Structurally Unique Binders of Eukaryotic Translation Initiation Factor 4E.
Proteome-scale quantification of the interactions driving condensate formation of intrinsically disordered proteins.
RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer.

Res Sq. 2026 Jul 01. pii: rs.3.rs-9933879. [Epub ahead of print]

Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.

Zhen Lu, Rumeysa Ozyurt, Gamze Bildik, Weiqun Mao, Hailing Yang, Robert Bast.

Cancer cells depend on protein quality control pathways to survive intrinsic and microenvironmental stress. Endoplasmic reticulum (ER)-selective autophagy (ER-phagy) maintains ER homeostasis by eliminating damaged ER and misfolded protein aggregates during ER stress. How ER stress-induced ER-phagy is regulated in cancer remains poorly understood. Salt-inducible kinases SIK2 and SIK3 (SIK2/3) are serine/threonine kinases implicated in metabolic regulation and cancer cell survival, but their roles in ER stress signaling and ER-phagy have not previously been studied. Here, we show that genetic or pharmacologic inhibition of SIK2/3 induces proteotoxic stress and activates the unfolded protein response through the PERK and IRE1 pathways, with predominant engagement of PERK and its downstream effector ATF4. SIK2/3 inhibition promotes ER-phagy by upregulating the ER-phagy receptor CCPG1 in an ATF4-dependent manner and increasing autophagic flux, thereby enabling cancer cell survival under stress. Disruption of this adaptive response results in the accumulation of polyubiquitinated protein aggregates, induction of CHOP, and apoptotic cell death in ovarian cancer cells. Importantly, combined treatment with the dual SIK2/3 inhibitor GRN-300 and the autophagy inhibitor chloroquine synergistically enhanced proteotoxic stress, reduced cell viability (combination index < 0.9), and triggered CHOP-dependent apoptosis. In ovarian cancer xenograft models, GRN-300 plus chloroquine markedly suppressed tumor growth and significantly prolonged survival compared with either monotherapy. Together, these findings identify SIK2/3 as key regulators of ER stress-induced ER-phagy and reveal a targetable stress-adaptation pathway that can be exploited therapeutically in ovarian cancer.

DOI: https://doi.org/10.21203/rs.3.rs-9933879/v1
Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00698-4. [Epub ahead of print]45(7): 117620

Structural proteomics reveals that misfolded nascent proteins expose buried lysines for ubiquitination and rapid proteasomal degradation.

Anushka Jain, Naiyareen F Mayeen, Michael E Meadow, Nino Kalandadze, Kyle Swovick, Kevin A Welle, Jennifer R Hryhorenko, Sina Ghaemmaghami.

  The proteasome maintains the integrity of eukaryotic proteomes by selectively degrading ubiquitinated protein substrates. Ubiquitination targets a wide range of substrates for degradation, including translationally stalled nascent chains, misfolded proteins, and properly folded but short-lived proteins destined for regulatory degradation. Distinct structural features and ubiquitination patterns across these classes of substrates remain largely undefined. In this study, we combine structural proteomics and time-resolved isotopic labeling to profile the modification sites, dynamics, and conformational properties of the human ubiquitinome. We show that proteins undergoing rapid proteasomal degradation are ubiquitinated at lysine residues that are normally buried within structured regions of their native conformations. We provide proteome-wide evidence that this high-flux subset of the ubiquitinome is enriched in newly synthesized proteins that have non-native conformations. Together, our findings demonstrate how the lack of structural integrity of misfolded nascent proteins influences their ubiquitination patterns and leads to rapid proteasomal degradation.

Keywords:  CP: molecular biology; mass spectrometry; protein folding; proteomics; proteostasis; ubiquitin proteasome system; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2026.117620
Cell Rep. 2026 Jul 07. pii: S2211-1247(26)00704-7. [Epub ahead of print]45(7): 117626

Lectins of the Emp47/ERGIC-53 family target misfolded O-mannosylated ER proteins to ER-associated degradation.

Leticia Lemus, Veit Goder.

  O-mannosylation of misfolded endoplasmic reticulum (ER) proteins in Saccharomyces cerevisiae by the bifunctional O-mannosyltransferase complex Pbn1-Gpi14 generates signals for ER-associated degradation (ERAD), but how these signals are recognized remains unknown. To address this question, we identify the binding partners of Pbn1 and find that the ER lectins Emp47 (ERGIC-53 in mammals) and Emp46 are among the strongest interactors. Simultaneous deletion of Emp46 and Emp47, but not of the lectin Yos9, impairs ERAD of an O-mannosylated, N-glycan-deficient CPY∗ variant. ERAD is restored by plasmid-expressed Emp47 or Emp46, but not by an Emp47 mutant lacking its carbohydrate-recognition domain (CRD). Furthermore, Emp47 interacts physically with the Hrd1 complex, suggesting that lectins of the Emp47/ERGIC-53 family recognize O-mannosylated misfolded proteins and target them for ERAD.

Keywords:  CP: cell biology; CP: molecular biology; ER lectins; ER quality control; ER-associated protein degradation; ERAD; Pbn1; emp46; emp47; protein O-mannosylation

DOI:  https://doi.org/10.1016/j.celrep.2026.117626
Elife. 2026 07 07. pii: RP109257. [Epub ahead of print]14

Profiling of terminating ribosomes reveals translational control at stop codons.

Longfei Jia, Yuanhui Mao, Saori Uematsu, Xinyi Ashley Liu, Leiming Dong, Leonardo Henrique França de Lima, Shu-Bing Qian.

  Accurate termination of protein synthesis is paramount for the integrity of the cellular proteome, yet the dynamics and fidelity of ribosome termination remain poorly understood. Here, we establish a profiling strategy to capture terminating ribosomes in mammalian cells and reveal a substantial heterogeneity in ribosome pausing at individual stop codons. We identify a sequence motif upstream of the stop codon that promotes termination pausing, a finding supported by massively parallel reporter assays. Unexpectedly, reduced termination pausing increases the likelihood of stop codon slippage, giving rise to proteins with heterogeneous C-terminal extensions. Mechanistically, we show that sequence-dependent termination pausing is consistent with post-decoding mRNA scanning by the 3' end of 18 S rRNA. We further uncover tissue-specific patterns of termination pausing that correlate with the stoichiometry of Rps26, which potentially modulates mRNA:rRNA interactions. Together, these results suggest termination pausing as a distinct translational signature shaped by mRNA sequence contexts, ribosome heterogeneity, and cell type-specific translational control.

Keywords:  biochemistry; chemical biology; human; ribosome; stop codon; translation

DOI:  https://doi.org/10.7554/eLife.109257
Mol Cell. 2026 Jul 09. pii: S1097-2765(26)00415-6. [Epub ahead of print]

The UFSP2-ODR4 complex spatially confines and dynamically controls UFM1 deconjugation to safeguard neuronal proteostasis.

Gaoxin Mao, Sota Ito, Ryosuke Ishimura, Jun-Ichi Sakamaki, Ryohei Sasaki, Takefumi Uemura, Kei-Ichi Ishikawa, Satoko Komatsu-Hirota, Wado Akamatsu, Manabu Abe, Satoshi Waguri, Sunita Bijarnia-Mahay, Nobuo N Noda, Toshifumi Inada, Masaaki Komatsu.

  The ubiquitin-fold modifier 1 (UFM1) pathway is essential for endoplasmic-reticulum-associated ribosome quality control (ER-RQC) through UFMylation of the 60S ribosomal protein RPL26, but the regulation and physiological significance of UFM1 deconjugation remain poorly understood. Here, we identify the ER-anchored UFSP2-ODR4 complex as a spatially confined deUFMylation module critical for neuronal proteostasis. Structural modeling and biochemical analyses show that ODR4 recruits UFSP2 to the ER, enabling efficient deUFMylation of RPL26. Disruption of the UFSP2-ODR4 interaction causes the accumulation of UFMylated RPL26 and defective ER-RQC. Neural progenitor-specific knockin mice expressing a catalytically inactive UFSP2 mutant exhibit perinatal lethality, microcephaly, and neuronal apoptosis. We also identify a patient with biallelic UFC1 mutations that enhance UFL1 binding and induce hyper-UFMylation of RPL26 in patient-derived neurons. These findings establish spatially confined deUFMylation as a critical mechanism for safeguarding neuronal proteostasis.

Keywords:  ER-RQC; ODR4; UFC1; UFM1; UFSP2; endoplasmic-reticulum-ribosome quality control; neurodevelopmental disorders; neuronal proteostasis; ribosomal protein RPL26

DOI:  https://doi.org/10.1016/j.molcel.2026.06.026
Res Sq. 2026 Jul 01. pii: rs.3.rs-10144286. [Epub ahead of print]

Mechanosensing at the endoplasmic reticulum by IRE1.

Hesso Farhan, Michaela Mayr, Luiz Garcia-Souza, Murphy McDermott, Utku Horzum, Yannick Frey, Margot Haun, Stephan Geley, Chao Jiang, Mattias Luber, Anush Bakunts, Camilla Pirolo, Alesia Yakimchyk, Klaus Liedl, Wylie Stroberg, Timo Betz, Liam Holt.

Sensing and integration of mechanical forces in eukaryotic cells have largely been attributed to the plasma membrane and the nucleus. Here, we identify the endoplasmic reticulum (ER) as an autonomous mechanosensitive organelle and uncover IRE1 as an ER-resident mechanosensor. We show that applying mechanical forces to ER membranes increases lateral tension, which is sensed by the transmembrane domain of IRE1. Mechano-activation of IRE1 was unrelated to its canonical role in the unfolded protein response and occurred independently of nuclear mechanosensing. Instead, mechanically activated IRE1 triggered JNK signaling and increased global protein synthesis independently of XBP1 splicing. In engineered skeletal muscle tissue, both electrical stimulation and passive stretch similarly activated IRE1, increased translation, and contributed to training-induced increases in contractile force. Collectively, our results uncover a non-canonical role for IRE1 as an ER-based mechanosensor that couples mechanical forces to the regulation of protein translation.

DOI: https://doi.org/10.21203/rs.3.rs-10144286/v1
Autophagy. 2026 Jul 08. 1-2

OPTN (optineurin)-mediated selective substrate recognition in Golgi membrane-associated degradation.

Yoichi Nibe-Shirakihara, Shigeomi Shimizu.

  Golgi membrane-associated degradation (GOMED) is a protein degradation pathway that primarily targets proteins transiting through the trans-Golgi cisternae, and functions constitutively or in response to abnormalities in Golgi-trafficked cargos. Although GOMED is morphologically similar to macroautophagy/autophagy, its substrate recognition mechanism has remained unclear to date. In this study, we identified OPTN (optineurin) as an essential receptor protein for selective cargo recognition in GOMED. We found that OPTN binds K33-linked polyubiquitinated proteins that have passed through the Golgi apparatus and delivers them to GOMED structures for degradation. In vivo, OPTN-dependent GOMED is required for mitochondrial clearance during erythrocyte maturation, and Optn-deficient mice have erythrocytes that retain mitochondria. Taken together, our findings define the molecular basis of selective cargo recognition in GOMED.

Keywords:  Golgi membrane-associated degradation (GOMED); K33-linked polyubiquitin; OPTN (optineurin); organelle quality control; selective GOMED

DOI:  https://doi.org/10.1080/15548627.2026.2698749
MicroPubl Biol. 2026 ;2026

Bioinformatic pipeline to identify candidate mRNA transcripts targeted by the putative Regulated Ire1-Dependent Decay pathway of Dictyostelium discoideum .

Connor Bingham, Elias Taylor-Cornejo.

Inositol-requiring protein 1 (Ire1) is a eukaryotic stress sensor that counteracts the buildup of unfolded proteins in the endoplasmic reticulum (ER) by activating the Unfolded Protein Response (UPR) via a specific ribonuclease (RNase) activity. The amoeba Dictyostelium discoideum relies on an ire1 ortholog, ireA , to survive ER stress, but the mRNA transcripts targeted by the IreA ribonuclease remain unknown. In this work, we developed a bioinformatic pipeline that identified 21 mRNA transcripts of D. discoideum that contain a consensus Ire1 cut site found within a secondary mRNA hairpin loop structure and have the potential to be cut by IreA.

DOI: https://doi.org/10.17912/micropub.biology.002098
Science. 2026 Jul 09.

Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion.

Caleb R Glassman, Kheewoong Baek, Gaopeng Hou, Qiru Zeng, Christopher Nardone, Kate B Juergens, Eric Fujimura, Colin N O'Leary, Mamie Z Li, Joao A Paulo, Eric S Fischer, Siyuan Ding, J Wade Harper, Stephen J Elledge.

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of ~10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and non-canonical ligases that rewire Cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1β-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.

DOI: https://doi.org/10.1126/science.aec6299
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2531623123

Interleukin-6 is critical in the development of pulmonary vascular disease in Gcn2-deficient mice.

Max Schwiening, Qingyue Gao, Mark Southwood, Alexi Crosby, Stephen Moore, Jose A Valer, Niki Veale, Benjamin J Dunmore, Paul D Upton, A A Roger Thompson, Nicholas W Morrell, Stefan J Marciniak, Elaine Soon.

  Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.

Keywords:  GCN2; interleukin-6; pulmonary veno-occlusive disease

DOI:  https://doi.org/10.1073/pnas.2531623123
J Biol Chem. 2026 Jul 06. pii: S0021-9258(26)02186-1. [Epub ahead of print] 113314

Wanted and unwanted modifications of mRNA, and their effect on gene expression and signaling.

Ankanahalli N Nanjaraj Urs, Animesh Dali, Hani S Zaher.

  RNA plays essential roles in transmitting and decoding genetic information, as well as carrying out enzymatic functions during transcription and translation. The function of the polymer is determined by the unique structures of its four nucleobases, which dictate how the molecule interacts with itself, other RNAs, and proteins. As a result, modifications to the bases often impact RNA function by altering these interactions. While we have known for decades that tRNA, rRNA and mRNA are modified, recent research has shed more light on the functional importance of these internal modifications in mRNAs. In addition to enzyme-mediated modifications, mRNA is also susceptible to damage-induced alterations. These arise from endogenous and exogenous alkylating, oxidizing, and cross-linking agents, as well as exposure to UV radiation. Many of these modifications severely disrupt tRNA-mRNA interactions, often leading to ribosome stalling. An integrating theme of this review is that both enzymatic and damage-induced modifications are actively sensed by the cell, with damage-induced modifications in particular engaging dedicated quality control pathways and stress-response programs that regulate gene expression and cellular fate. We begin this review by discussing the most abundant enzymatic mRNA modifications and focus on their impact on translation before turning to damage-induced lesions and the ribosome-based quality control machinery that resolves them. We conclude by discussing the remarkable discovery that damaged mRNA, through its impact on ribosome collisions, activates the integrated stress response (ISR) and ribotoxic stress response (RSR) to reprogram gene expression and, under severe conditions, determine cell fate.

Keywords:  RNA damage; collided ribosomes; gene expression; mRNA modification; ribosome; ribosome quality control; ribotoxic stress signaling; the integrated stress response; translation; translational control

DOI:  https://doi.org/10.1016/j.jbc.2026.113314
Aging Cell. 2026 Jul;25(7): e70620

Proteostasis Rebalancing by LET-607 Deficiency Promotes Longevity.

Haixiang Tong, Wei Li, Pangui Yuan, Feng Li, Qin Liu, Shanshan Pang, Haiqing Tang.

  Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPRER) and the cytosolic UPR (UPRcyto) in C. elegans that influences lifespan. We find that wild-type animals maintain high UPRER activity but low UPRcyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPRER activity decreases while UPRcyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPRcyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPRcyto genes, a process involving the regulators and readers of this histone mark, leading to UPRcyto activation. Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.

Keywords:  HSF‐1; longevity; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1111/acel.70620
Dis Model Mech. 2026 Jul 06. pii: dmm.052935. [Epub ahead of print]

UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice.

Michelle Curley, Flavia A Graca, Anna Stephan, Wei Wang, Vishwajeeth R Pagala, Yong-Dong Wang, Anthony A High, Fabio Demontis.

  UBA1 is the primary ubiquitin-activating enzyme that initiates ubiquitination, which regulates protein function and turnover. While UBA1 loss is cell lethal, silent mutations that reduce UBA1 mRNA levels cause spinal muscular atrophy X-linked 2 (SMAX2), a disorder marked by skeletal muscle weakness and wasting. However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle. Here, we examined Drosophila and mice with muscle-targeted UBA1 knockdown and found that this intervention reduces protein ubiquitination, muscle function, and lifespan. Integrated transcriptomic and proteomic analyses indicate that a limited set of proteins is modulated post-transcriptionally by UBA1RNAi, suggesting that these UBA1-sensitive proteins may rely on optimal UBA1 levels for degradation (UBA1RNAi-upregulated proteins) and stability (UBA1RNAi-downregulated proteins). Therefore, despite its general function in ubiquitination, UBA1 knockdown alters the levels of relatively few critical proteins, which may contribute to muscle weakness and SMAX2 pathogenesis. Moreover, although SMAX2-linked UBA1 mutations occur ubiquitously, experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2.

Keywords:  Muscle function; Proteostasis; SMAX2; Skeletal muscle; UBA1; Ubiquitination

DOI:  https://doi.org/10.1242/dmm.052935
Signal Transduct Target Ther. 2026 Jul 07. pii: 262. [Epub ahead of print]11(1):

Targeting endoplasmic reticulum export disrupts metabolic resilience in multiple myeloma.

Utku Horzum, Herbert Oberacher, Margot Haun, Stephan Geley, Monica Roman-Trufero, Holger Auner, Agnieszka Martowicz, Gerold Untergasser, Eberhard Gunsilius, Wolfgang Willenbacher, Hamdullah Yanik, Gunes Esendagli, Dominik Wolf, Hesso Farhan.

Multiple myeloma (MM) is characterized by the production and secretion of large quantities of immunoglobulins, making this malignancy highly dependent on mechanisms that maintain cellular proteostasis. While significant clinical progress has been made by targeting the degradative branch of proteostasis, much less attention has been given to the biosynthetic branch. In this study, we demonstrated that inhibiting COPII-dependent endoplasmic reticulum (ER) export induces cell death in several MM cell lines and primary patient-derived cells. The induction of cell death was dependent on the secretory status of MM cells. Blocking ER export in secretory MM cells caused the accumulation of misfolded proteins, which activated ER-associated degradation (ERAD). Consequently, we observed an ERAD-dependent increase in the levels of free cytosolic amino acids and a subsequent activation of mTORC1 signaling. Simultaneously, we observed mitochondrial dysfunction. These alterations resulted in a mismatch between the increased energy demand due to mTORC1 activation, and the disrupted energy supply from mitochondrial impairment. This energetic imbalance results in homeostatic collapse and cell death of secretory MM cells. The therapeutic potential of the concept was demonstrated in two in vivo myeloma models. These findings suggest that the ER export machinery could be a promising therapeutic target in multiple myeloma.

DOI: https://doi.org/10.1038/s41392-026-02833-y
J Mol Cell Biol. 2026 Jul 07. pii: mjag021. [Epub ahead of print]

Cytosolic transmembrane helices enter the ER membrane through EMC6-driven electrostatic interactions.

Hongyan Zheng, Wenxue Gu, Tong Zhou, Cecilia M Canessa.

  The endoplasmic reticulum membrane protein complex (EMC) facilitates transmembrane domain (TMD) insertion and translocation of small terminal domains. Here, we identify EMC as a critical determinant of epithelial sodium channel (ENaC) biosynthesis. EMC loss reduces ENaC expression without affecting surface trafficking, indicating a biosynthetic stabilizing role. We demonstrate that electrostatic interactions between the negatively charged distal segment of ENaC's TMD2 and a positively charged patch on EMC6 are essential for ENaC-EMC association. We propose a 'semi-insertase' mechanism wherein the Sec61 translocon partially inserts TMD2, leaving its hydrophilic distal segment exposed to the cytosol. EMC captures this segment through electrostatic attraction and completes membrane integration. Bioinformatic analysis identified a group of non-canonical EMC clients including >200 multipass proteins with similarly charged TMDs, suggesting that electrostatic capture may represent a solution for inserting unconventional hydrophilic transmembrane segments. Additionally, we demonstrate that EMC8 plays an essential role in stabilizing the EMC-a function that cannot be compensated by its homolog EMC9 due to lower expression and absence of compensatory upregulation in EMC8-deficient cells. These results reveal a multifaceted EMC mechanism coupling insertase activity with chaperone-like stabilization to facilitate biogenesis of multipass membrane proteins containing highly hydrophilic TMDs.

Keywords:  EMC; EMC8-KO; EMC9-KO; ENaC; TM2b hydrophilicity

DOI:  https://doi.org/10.1093/jmcb/mjag021
Cell Death Differ. 2026 Jul 10.

UbiDash: A UPS proteomic atlas for tissue-aware degrader design.

Tania J González-Robles, Paul Sastourné, Marisa Triola, Maha Khan, Áron Bartha, Jeffrey Estrada, Yadira M Soto-Feliciano, Benjamin G Neel, David Fenyö, Michele Pagano, Kelly V Ruggles.

Targeted protein degradation repurposes endogenous E3 ubiquitin ligases to eliminate disease-driving proteins, yet the ligase toolkit deployed clinically remains narrow and largely tissue-agnostic. To support rational expansion of this toolkit, we built a harmonized pan-tissue proteomic atlas of the ubiquitin-proteasome system (UPS) by integrating four major resources: (1) CPTAC tumor and normal-adjacent tissues, (2) PRIDE healthy tissues, (3) the Pan-Cancer Proteome Atlas (TPCPA), and (4) the Cancer Cell Line Encyclopedia (CCLE). The resulting atlas spans 20 distinct tissue contexts and quantifies 5998 proteins, including 473 UPS components and 181 E3 ligases. Cross-resource validation confirmed successful harmonization while maintaining biological signal. We then derived a sample-level relative rank score (RRS) for every quantified UPS protein and identified 139 E3 ligases (of 181 detected) as being significantly tissue- or tumor-specific, including XIAP in lung cancer, KLHL7 in female-specific malignancies, and FBXL18 in head-and-neck and brain tumors. To enable broad accessibility, we developed UbiDash ( https://ruggleslab.shinyapps.io/UbiDash/ ), an interactive R Shiny platform that supports queries of UPS expression, mutation effects, protein co-regulation, and clinical associations. Together, the atlas and UbiDash provide a tissue-aware framework for ligase prioritization and rational degrader design that complements the mechanistic mutation- and lineage-driven UPS analyses described in our companion manuscript [1].

DOI: https://doi.org/10.1038/s41418-026-01791-w
Mol Cell. 2026 Jul 07. pii: S1097-2765(26)00417-X. [Epub ahead of print]

Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin.

Dazhi Li, Xinbo Wang, Hongyan Hao, Jessica Eden, Bodan Hu, Emma E Walsh, Matthew A H Parson, Stephanie Hamill, Yuting Li, Guochao Chen, John E Burke, Pietro De Camilli, Karin M Reinisch.

  Bridge-like lipid transfer proteins (BLTPs) play fundamental roles in cellular lipid redistribution between organellar membranes. They comprise bridge domains spanning organelles at contact sites that allow lipids to transit through the cytosol between adjacent membranes. The assembly of BLTPs into complexes with adaptor proteins enables lipid transfer. To address the mechanisms underlying the assembly and regulation of BLTP complexes, we used cryo-EM to resolve the structure of one such BLTP, the Parkinson's disease protein VPS13C, at near-atomic resolution. The structure identifies a lipid-transfer-nonpermissive conformation, in which the built-in C-terminal VAB adaptor module blocks the end of the lipid transfer bridge, interfering with lipid delivery. We also identify calmodulin (CaM), central to calcium signaling, as a constitutive VPS13C interactor. Calcium induces conformational changes in the VPS13C-CaM complex, suggesting calcium regulation of VPS13 function. Altogether, this structure of intact VPS13C serves as a starting point for understanding its regulation and that of other VPS13 proteins.

Keywords:  lipid transport; lysosomes, PARK23, Parkinson's disease, BLTP; membrane homeostasis

DOI:  https://doi.org/10.1016/j.molcel.2026.06.028
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2533990123

Stress granules as RNA triage hubs suppress extracellular vesicle secretion under oxidative stress in cancer.

Yue Dong, Takeshi Yoshida, Mitsuyo Maeda, Haruki Adachi, Asami Eguchi, Emi Mishiro-Sato, Daisuke Okuzaki, Yosky Kataoka, Takuya Yoshida, Chitose Oneyama.

  Cancer cells confronting oxidative stress must coordinate their extracellular vesicle (EV) secretion to balance intercellular signaling with the intracellular programs required for survival, yet how these decisions are integrated remains poorly understood. Here, we identify a stress-adaptive mechanism in which stress granules (SGs) selectively suppress CD63+ EV release. Using a bioluminescent EV-reporter screen, we found that the clinical compound YM155 selectively inhibits CD63+ EV secretion across diverse tumor cells. Mechanistically, YM155 rapidly inactivates the antioxidant transcription factor FOXO3a, diminishing expression of key detoxifying enzymes and leading to delayed but sustained accumulation of reactive oxygen species (ROS). Elevated ROS drives SG formation, and these SGs function not as passive storage sites but as RNA triage hubs that exclude and destabilize a subset of transcripts. Among them, Rab27A mRNA-encoding a GTPase essential for multivesicular-body docking to the plasma membrane-is selectively excluded and degraded, resulting in loss of Rab27A protein and suppression of CD63+ EV secretion. Forced Rab27A expression restores EV release but paradoxically reduces proliferation under oxidative stress, indicating that EV suppression is prosurvival. The same FOXO3a-ROS-SG-Rab27A axis operates during physiological glucose deprivation and is evident in vivo, where SGs form in xenograft tumors and circulating CD63+ EVs decline. Pancancer transcriptomic analyses further show that Rab27A expression correlates with FOXO3a-dependent antioxidant programs, underscoring clinical relevance. These findings reveal that SGs actively reprogram RNA fate to tune vesicle output, establishing a redox-responsive mechanism by which cancer cells transiently suppress EV secretion to enhance survival.

Keywords:  Rab27A; cancer progression; extracellular vesicle; reactive oxygen species; stress granule

DOI:  https://doi.org/10.1073/pnas.2533990123
bioRxiv. 2026 Jul 04. pii: 2026.07.03.736445. [Epub ahead of print]

A detailed molecular picture of protein folding during active translation.

Amir Bitran, Carlos Bustamante, Susan Marqusee.

All proteins can begin to fold on the ribosome, and many proteins critically rely on co-translational folding to attain their native conformation. The molecular details underlying this crucial process, however, remain largely unknown and are not accounted for by structure predictions such as AlphaFold. To probe high-resolution folding during active translation, we develop a novel application of hydrogen-deuterium pulse labeling. We show that two proteins sequentially adopt stable structure during elongation, while a third protein only has time to loosely fold during active elongation. This loose folding kinetically traps the N-terminus and alters the post-translational folding pathway, allowing it to circumvent an aggregation-prone intermediate. These results highlight the crucial non-equilibrium coupling between translation and folding and reveal diverse strategies to promote robust co-translational folding.

DOI: https://doi.org/10.64898/2026.07.03.736445
bioRxiv. 2026 Jun 29. pii: 2026.06.28.734975. [Epub ahead of print]

Pep2Mol: 3D Molecule Generation Targeting Protein-Protein Interfaces with Diffusion Models.

Rongting Yue, Zekun Yang, Gustavo Seabra, Chenglong Li, Yanjun Li.

Protein-protein interactions (PPIs) are central to biological processes. Designing small molecules that modulate dysregulated PPIs holds strong promise for targeting undruggable proteins. However, existing structure-based drug design approaches focus on well-defined small-molecule binding pockets and struggle to generalize to large, shallow, and chemically complex PPI interfaces. Here, we introduce Pep2Mol, a diffusion-based generative model for 3D molecule design that targets orthosteric PPI sites by explicitly incorporating binding peptides or proteins as structural guidance, moving beyond conventional pocket-conditioned generation. To enable model development and benchmarking, we curate a large-scale, high-quality dataset of 10,956 experimentally resolved protein complex structure pairs, each pairing an orthosteric competitive ligand with a protein binder at overlapping receptor interfaces. Pep2Mol integrates two SE(3)-equivariant graph neural networks that encode protein-ligand and protein-peptide interactions respectively, and fuses these representations via attention-based conditioning to jointly guide the diffusion trajectory. Extensive evaluations demonstrate that Pep2Mol generates chemically valid ligands with state-of-the-art binding affinities, providing a strong foundation for small-molecule inhibitor design against challenging PPI interfaces.

DOI: https://doi.org/10.64898/2026.06.28.734975
Nat Methods. 2026 Jul;23(7): 1458-1469

A comprehensive benchmark of sequence-based subcellular localization predictors for human proteins.

Zoe Wefers, Ankit Gupta, Noorsher Ahmed, Xikun Zhang, Emma Lundberg.

Computational sequence-based predictors of protein localization have the potential to accelerate the discovery of protein functions and interactions, thereby advancing our understanding of human biology and disease. While many methods have been proposed, evaluations remain limited by small test sets, coarse-grained cellular compartment labels and single-label classification, despite the fact that nearly half of human proteins localize to multiple compartments. Here we integrate annotations from major protein databases to construct a highly validated, twofold larger benchmark test set of 3,814 human proteins. Using this dataset, we systematically evaluate existing sequence-based predictors and compare combinations of protein language models and aggregation strategies. We find that current models underperform on fine-grained compartments, multilocalizing proteins and pathogenic variants known to mislocalize. Our results reveal fundamental limitations of existing approaches and underscore the need for improved models, standardized benchmark datasets and more rigorous evaluation in subcellular localization prediction.

DOI: https://doi.org/10.1038/s41592-026-03142-6
bioRxiv. 2026 Jun 30. pii: 2026.06.25.734545. [Epub ahead of print]

Mitochondrial Hsp60/10 Client Protein Decline Reveals Braak/Tau- and Cognition-Linked Proteostasis Vulnerabilities in Alzheimer's Disease.

Ashlyn Sloane, Varunya M Kattunga, Julie K Andersen.

Background: Alzheimer's disease (AD) is classically defined by amyloid and tau pathology and is accompanied by broad disruptions in proteostasis. Heat shock proteins (HSPs) help maintain proteostasis, yet mitochondrial chaperone systems remain comparatively underexplored in AD. Hsp60 and Hsp10 form a mitochondrial chaperonin complex that folds dozens of AD-implicated mitochondrial proteins, but this client network has not been evaluated as an integrated proteostasis axis in AD. It remains unknown whether Hsp60/10 client proteins are selectively vulnerable across AD severity.
Methods: We analyzed transcriptomic, proteomic, neuropathological, and cognitive data from the Religious Order Study and Memory and Aging Project (ROSMAP) to evaluate Hsp60/10 client proteins in AD. We compared Hsp60/10 clients with abundance-matched non-client mitochondrial proteins and tested differences across AD diagnostic groups and associations with Braak/tau burden, cognitive outcomes, and network centrality. These evidence layers were integrated into a candidate prioritization framework.
Results: Hsp60/10 client abundance declined more strongly at the protein level than at the RNA level in late-stage AD. Compared with abundance-matched non-client mitochondrial proteins, Hsp60/10 clients showed stronger late-stage protein abundance decline. Greater late-stage client decline was associated with higher Hsp60/10 network centrality, defining a selectively vulnerable client subnetwork. Lower client abundance was associated with greater Braak/tau burden and greater cognitive impairment. Integrated prioritization nominated mitochondrial translation and TCA/pyruvate/redox clients as high-priority candidates for mechanistic follow-up.
Conclusions: Together, these findings identify an Hsp60/10 client-centered mitochondrial proteostasis axis spanning mitochondrial translation and TCA/pyruvate/redox metabolism that is associated with AD severity. These findings identify a novel potential axis warranting further investigation as a mechanistic link between mitochondrial dysfunction, proteostasis, and AD.

DOI: https://doi.org/10.64898/2026.06.25.734545
Nat Metab. 2026 Jul 08.

Hypoxia rescues complex 1-associated disease caused by proteostatic defects.

Ankur Garg, Brandon R Desousa, Raju Roy, Amy Flis, Skyler Y Blume, Yohei Abe, Arthur A Melo, Ryan R Cupo, Gabriela Grigorean, Daniel R Southworth, James Shorter, Isha H Jain.

Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy. Using an Htra2 mutant mouse model that displays severe neurodegeneration and early lethality, we find that continuous hypoxia rescues striatal degeneration and extends lifespan. Mechanistically, we demonstrate that HTRA2 forms a functional complex with the disaggregase CLPB. Loss of function of either protein drives aggregation of intermembrane space-facing subunits of complex I of the electron transport chain, resulting in secondary complex I dysfunction. These changes impair tissue oxygen consumption and probably cause pathological hyperoxia, which is corrected by hypoxia. Together, these findings define a proteostasis pathway linking intermembrane space quality control to complex I function and expand the potential of hypoxia therapy to secondary complex I disease.

DOI: https://doi.org/10.1038/s42255-026-01566-0
Science. 2026 Jul 09. 393(6807): 188-194

Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.

Samuel Ojeda, Meng Wang, Kheewoong Baek, Wallace Bourgeois, Alba Sommerschield, Hong Yue, Rebecca J Metivier, Panos Karagiannis, Talya S Levitz, Yuan Xiong, Katherine A Donovan, Scott A Armstrong, Eric S Fischer.

Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)-based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.

DOI: https://doi.org/10.1126/science.aef5391
Aging Cell. 2026 Jul;25(7): e70624

Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.

Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda.

  Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.

Keywords:  age‐related diseases; aging; inter‐organelle communication; metabolic kinases; mitochondrial quality control

DOI:  https://doi.org/10.1111/acel.70624
Nucleic Acids Res. 2026 Jul 03. pii: gkag689. [Epub ahead of print]54(13):

Evolution of the ribosomal exit tunnel through the eyes of the nascent chain.

Tomasz Włodarski.

The exit tunnel is a universally conserved feature of the ribosome that directs the nascent polypeptide into the cellular environment and is involved in co-translational folding, stalling, and antibiotic binding. While cryogenic electron microscopy has revealed variations in ribosome structure, tunnel definition and comparative analyses have largely relied on geometric algorithms. Here, we present a functional, nascent chain (NC)-centric characterization of the exit tunnel across the tree of life, derived from molecular dynamics simulations of 64 cytoplasmic ribosome structures. By mapping steric accessibility through the "eyes" of the NC at five distinct stages of translation, we reveal a topological and stage-dependent complexity invisible to geometric approaches, demonstrating how tunnel accessibility dynamically changes during biosynthesis. We identify transient, bacteria-specific lateral branches that, in archaeal and eukaryotic ribosomes, are structurally occluded by the eL39 protein and N-terminal extensions of the uL24 protein. These evolutionary "plugs" seal the tunnel wall and decrease its functional width. Collectively, our results demonstrate that the ribosome exit tunnel has a branched, lineage-specific topology where accessibility is temporally gated by NC length. This functional definition provides a new framework for understanding how ribosomal architecture modulates the early stages of protein biogenesis.

DOI: https://doi.org/10.1093/nar/gkag689
Res Sq. 2026 Jun 29. pii: rs.3.rs-10100112. [Epub ahead of print]

The Calcium-Calpain-ALIX Axis is the Major Link Between Gasdermin-D Membrane Pores and Terminal Membrane Damage in Pyroptosis.

Gergely Imre, Sylvia Otchere, Himesh Parmar, Kushagra Singh, Lauren Tereshisnki, Natalie Thiex, Adam Hoppe.

Pyroptosis is an inflammatory form of regulated cell death driven by gasdermin-mediated membrane pore formation. Although gasdermin D (GSDMD) pores are widely regarded as the executioners of pyroptosis, recent studies demonstrate that pore formation is not necessarily lethal because cells can actively repair membrane damage through the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. The molecular mechanism that converts reversible GSDMD pore formation into irreversible membrane rupture and cell death remains unknown. Here, we identify a calcium-calpain-ALIX signaling axis that mechanistically links GSDMD pore formation to catastrophic membrane damage. Using primary macrophages, THP-1 monocytes, and HCT-116 epithelial cells, we show that depletion of the ESCRT adaptor ALG-2-interacting protein X (ALIX) abolishes membrane repair, promotes GSDMD accumulation, and markedly increases susceptibility to pyroptotic death. We further demonstrate that GSDMD pores trigger calcium influx, which induces proteolytic cleavage of ALIX. Preventing calcium influx or chelating intracellular calcium blocks ALIX cleavage, reduces GSDMD accumulation, and markedly improves cell survival. Mechanistically, we identify calpains as the calcium-dependent proteases responsible for ALIX cleavage and establish ALIX as a previously unrecognized calpain substrate. Pharmacologic inhibition or genetic depletion of calpains significantly reduces membrane permeabilization and pyroptotic cell death. Mapping of calpain cleavage sites localizes the major cleavage site within the ALIX V-domain. Importantly, calpain-mediated cleavage disrupts ALIX interaction with the ESCRT-III component CHMP4B, thereby preventing ESCRT assembly and membrane repair. In contrast, calcium depletion or calpain knock down restores CHMP4B recruitment and ESCRT activation Collectively, these findings reveal the first mechanistic pathway linking reversible membrane GSDMD pore formation to irreversible membrane rupture. We propose that GSDMD pore-induced Ca2+ influx activates calpains, disables ALIX-dependent ESCRT repair, and drives the transition from repairable membrane injury to terminal pyroptotic lysis. This pathway represents a potential therapeutic target for inflammatory diseases driven by excessive pyroptosis.

DOI: https://doi.org/10.21203/rs.3.rs-10100112/v1
Autophagy. 2026 Jul 08.

TRIM21 induces selective autophagy of viruses and bacteria.

T Rhinesmith, A Albecka, L C James.

  Antibodies are known to prevent infection by binding to pathogens extracellularly and blocking their entry into cells. What is less well known is that a proportion of pathogens, called the persistent fraction, still succeed in entering cells despite the antibodies bound to their surface. Fortunately, all mammalian cells express a dedicated cytosolic antibody receptor called TRIM21 that intercepts these incoming antibody-bound pathogens as soon as they enter the cytosol. Once it has detected an infection event, TRIM21 uses its E3 ubiquitin ligase activity to target pathogens for degradation. Our early work showed that TRIM21-mediated neutralization was both a fast and efficient process, capable of causing the degradation of incoming viral particles within hours. What was less clear was how TRIM21 achieves this degradation. In a recent study, we reveal that TRIM21 mediates a system of selective autophagy to direct incoming pathogens into the lysosome.Abbreviations:TRIM21:Tripartite-motif containing protein 21; VCP: Valosin-Containing Protein. CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; FACS: fluorescence activated cell sorting; GFP: green fluorescent protein; LC3: Microtubule-associated Protein 1 Light Chain 3; TBK1: TANK-binding kinase 1; FIP200: FAK family kinase-interacting protein of 200 kDa; ULK1: Unc-51-like autophagy activating kinase 1; PI3K: Phosphoinositide 3-Kinase; ATG: autophagy-related gene; TMEM41B: transmembrane protein 41B; VPS37A: Vacuolar Protein Sorting-Associated Protein 37A; RBSN: Rabenosyn-5; EPG5: Ectopic P-Granules 5 Autophagy Tethering Factor; NDP52: Nuclear Dot Protein 52; ADX: antibody-dependent xenophagy; p62/SQSTM1: Protein 62/ Sequestosome 1; LPS: Lipopolysaccharide.

Keywords:  Antibodies; TRIM21; bacteria; viruses; xenophagy

DOI:  https://doi.org/10.1080/15548627.2026.2701600
J Med Chem. 2026 Jul 08.

RIMTAC: A Novel Degrader Design Platform by Indirect VHL-Recruitment via RIPK1.

Chang Shen, Hanyin Sun, Ruining Li, Raghupathi Mutyala, Xinjian Tian, Chaoqun Huang, Jinglei Hu, Jie An, Lin Li, Tao Zhang, Xufen Yu, Bo Zhao, Mingyan Zhu, Yudao Shen.

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach for targeted protein degradation (TPD). However, their therapeutic potential is limited by the scarcity of diverse E3 ligase ligands. Only a small fraction of more than 600 human E3 ligases are currently amenable to functional PROTAC development. To expand the E3 ligase toolbox, we developed RIPK1-Mediated Targeting Chimeras (RIMTAC). Rather than directly inhibiting VHL, RIMTAC employs a RIPK1 inhibitor to hijack the endogenous RIPK1-VHL complex, recruiting VHL indirectly for TPD. As a proof of concept, we designed RIMTACs targeting BRD4, AKT, and JAK1. These molecules induced potent, concentration- and time-dependent degradation of their targets. Mechanistically, degradation was confirmed to be UPS-dependent and required a quaternary complex of VHL, RIPK1, the target protein, and the RIMTAC molecule. RIMTAC expands the TPD toolbox and offers a promising synergistic strategy for anti-inflammatory therapy.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00897
Plant Cell. 2026 Jul 06. pii: koag208. [Epub ahead of print]

The Plant RABC1 GTPase Coordinates with Exocyst Component SEC5A in Regulating ER-phagy under Endoplasmic Reticulum Stress.

Shuai Hu, Dongmei Zhu, Xiaohui Ma, Linjuan Shi, Wenze Zhang, Mei Huang, Youshun Lin, Baiying Li, Yonglun Zeng, Liwen Jiang, Jinbo Shen.

Small GTPase proteins regulate intracellular transport between endomembrane compartments, yet their roles in endoplasmic reticulum (ER) stress responses and selective autophagy remain poorly understood. Here we characterize the plant RAB GTPase RABC1 as a regulator of ER-phagy during ER stress. Our results demonstrate that rabc1 mutants are hypersensitive to heat shock and ER stress inducers dithiothreitol and tunicamycin. RABC1 localizes primarily to the ER and Golgi with partial trans-Golgi network (TGN) association. Upon ER stress, RABC1 is recruited to autophagosomes and subsequently delivered into the vacuole. Autophagic turnover of the ER chaperone Calnexin (CNX1)-GFP is impaired in the rabc1 mutant after DTT and TM treatments. Additionally, RABC1 interacts with the exocyst subunit SEC5A in planta, and this interaction is required for SEC5A recruitment to autophagosomes, promoting autophagosome formation. Double-mutant analysis indicates an additive genetic interaction between RABC1 and SEC5A in ER stress sensitivity. Taken together, our results suggest that RABC1 coordinates with SEC5A to promote autophagosome formation and ER-phagy during ER stress, revealing a novel mechanism by which a plant RAB GTPase regulate ER-phagy.

DOI: https://doi.org/10.1093/plcell/koag208
Cell Death Dis. 2026 Jul 07.

ACSL3 inhibits ferroptosis in gastric cancer through the activation of unfolded protein response following endoplasmic reticulum stress.

Honglei Wang, Jie Jiao, Wenshuo Yang, Danping Sun, Meng Wei, Guorui Sun, Zhibo Yan, Yize Liang, Zewei Cheng, Yongqi Yan, Menghui Wang, Yangjia Li, Xiaohan Cui, Wenbin Yu.

The long-chain acyl-CoA synthetase (ACSL) family has been associated with tumor progression across various cancer types. However, the function of the ACSL family in gastric cancer (GC) remains poorly understood. Comprehensive investigations employing in vivo and in vitro experiments demonstrate that ACSL3 suppresses ferroptosis and drives GC progression. Mechanistically, ACSL3 facilitated YY1 nuclear translocation, triggering endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR). Genome-wide binding analysis revealed that YY1 directly binds to the USP37 promoter, enhancing its transcriptional activation. Furthermore, a novel interaction was identified between USP37 and PERK, a pivotal UPR regulator, wherein USP37 mediates K29-linked deubiquitination of PERK. PERK stabilization upregulated SLC7A11 expression, thereby inhibiting ferroptosis and promoting tumor progression. Collectively, the findings establish a molecular cascade wherein ACSL3 mediates ER stress-mediated UPR activation through the YY1/USP37/PERK axis, suppressing ferroptosis and accelerating GC progression, identifying ACSL3 as a potential therapeutic target for GC treatment.

DOI: https://doi.org/10.1038/s41419-026-09068-3
Nucleic Acids Res. 2026 Jul 03. pii: gkag627. [Epub ahead of print]54(13):

Elongationless start-stop elements are stress-resilient translation gates that are more repressive than uTranslons.

Justin Rendleman, Solomon A Haizel, Shaohuan Wu, Laurelle Lee Young, Junjie Liu, Xinyi Ge, Huijing Zou, Mahabub Pasha Mohammad, Matthew Pressler, Shuvadeep Maity, Vladislava Hronová, Zhaofeng Gao, Anna Herrmannová, Anna Smirnova, Amy Lei, Kristina Allgoewer, Daniel Sultanov, Will Edward Hinckley, Ziyue Cheng, Lauren Shelby, Tanubrata Dey, Krzysztof J Szkop, Ivan Topisirovic, Ola Larsson, Maria Hatzoglou, Leoš Shivaya Valášek, Christine Vogel.

Start-stop elements are translation regulatory elements in 5' untranslated regions (UTR) of eukaryotic transcripts, consisting of a start codon immediately followed by a stop codon. In contrast to canonical upstream Translons (uTranslons), they exclude elongation which creates unique properties. We conducted a comprehensive, carefully controlled comparison of human start-stop elements and uTranslons both at a genome-wide level and with targeted reporter assays. We found that start-stops and uTranslons were similar with respect to their presence in the 5' UTRs of hundreds of genes, in particular transcription factors and signaling molecules, the low transcript levels of the corresponding genes, short RNA half-lives, and the negative effect on downstream translation. However, start-stop containing genes were translationally even more repressed than genes with uTranslons. Analysing the start-stop architecture and diverse ribosome footprinting datasets, we found evidence for a start-stop-specific mechanism that involves repeat cycling between initiation, termination, ribosome splitting, and 60S rejoining-a process possibly modulated by ASCC3 and eIF1. This cycling explained increased ribosome retention at start-stops and was-in contrast to ribosome retention at uTranslons-independent of the global initiation state. Finally, we showed that the start-stop element in human ATF4 augments the core regulatory model by controlling translation of the uTranslons.

DOI: https://doi.org/10.1093/nar/gkag627
Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2537622123

Inhibition of elastin degradation alleviates joint degeneration in aging mice, dogs, and human models.

Junzhi Yi, Xiao Xiao, Hui Zhang, Xinjie Xu, Keyu Chen, Xinqi Cai, Yutao Zhu, Xianan Mo, Shihan Xiong, Zhichu Chen, Hairu Sui, JiaChun Wu, Jiaqi Xu, Xuri Chen, Yan Wu, Zi Yin, Youzhi Cai, Xianzhu Zhang, Jing Zhou, Hua Liu, Hongwei Ouyang.

  Extracellular matrix degradation is a fundamental pathological feature of osteoarthritis, while the roles of degraded matrix remain largely unknown. We previously showed that serum elastin fragments were a systemic aging driver. Here, we found that elastin fragments were upregulated in synovial fluid in dual-center osteoarthritis patients. Elastin fragments actively impaired joint tissue in mice and human explants. Mechanistically, a specific elastin motif containing Valine-Glycine-Valine-Alanine-Proline-Glycine (VGVAPG) oligopeptide (E-motif) promoted macrophage secretion of inflammatory factors via the neuraminidase-1, a component of the elastin receptor complex. These inflammatory factors, together with the E-motif, upregulated serum amyloid A3 protein in chondrocytes, accelerating cartilage degeneration. Therapeutically, both the myeloid-specific knockout of neutrophil elastase and the pharmacological inhibition using a clinically applied drug (sivelestat) alleviated joint degeneration in naturally aging mice partly by reducing elastin fragments levels. The pharmacological inhibitor exhibited 1-y systemic safety in dogs and alleviated osteoarthritis-like phenotypes in naturally aging dogs and human explants. Finally, several matrix fragments, including the fragments of type II collagen, fibronectin, hyaluronic acid, and aggrecan, were demonstrated to universally induce cartilage degeneration. Conclusively, this study identifies degraded matrix, especially elastin fragments, as one of the drivers of joint degeneration via pathological macrophage-chondrocyte crosstalk, suggesting elastase inhibitors as a potential therapeutic strategy for aging-related osteoarthritis.

Keywords:  elastase inhibitor; joint degeneration; macrophage; matrix fragments; preclinical research

DOI:  https://doi.org/10.1073/pnas.2537622123
Mol Biol Cell. 2026 Jul 08. mbcE26060256

Integrative Chemical Genetics Platform Identifies Condensate Modulators Linked to Neurological Disorders.

Dylan Poch, Chandrayee Mukherjee, Sunanda Mallik, Vanessa Todorow, E F Elsiena Kuiper, Nalini Dhingra, Yulia V Surovtseva, Christian Schlieker.

Dysregulation of biomolecular condensates is implicated across multiple neurological disorders. However, approaches to systematically identify their modulators remain limited. Here we expand the utility of MLF2 as a versatile condensate biomarker and develop CondenScreen, an integrated high-content screening and bioinformatic pipeline enabling identification of condensate modulators across chemical and genetic space. Screening 1,760 bioactive compounds in a cellular DYT1 dystonia model, we validate the platform for condensate-targeted drug discovery, identifying drugs that prevent accumulation of the MLF2 reporter into nuclear envelope condensates. In parallel, a genome-wide CRISPR/Cas9 screen correlates nuclear condensate abundance with genes implicated in microcephaly and over eight additional neurodevelopmental disorders. Machine learning and confocal imaging resolve distinct condensate phenotypes, with RNF26-deletion provoking nuclear envelope condensates that phenocopy hallmarks of torsin deficiency. Our study provides a scalable platform for identifying modulators of condensates and establishes a correlative connection between nuclear condensate accumulation and genes implicated in neurodevelopmental disorders.

DOI: https://doi.org/10.1091/mbc.E26-06-0256
Neurobiol Dis. 2026 Jul 09. pii: S0969-9961(26)00273-1. [Epub ahead of print] 107528

Local translation controls early reactive changes in perisynaptic astrocyte processes at pre-symptomatic stages of Alzheimer's disease.

Katia Avila-Gutierrez, María Ángeles Carrillo de Sauvage, Noémie Depret, Marc Oudart, Robin Thompson, Rodrigo Alvear-Perez, Yiannis Poulot-Becq-Giraudon, Esther Kozlowski, Heloïse Monnet, Philippe Mailly, Valentin Garcia, Laurent Jourdren, Alexandre Lucas, Alexis Bemelmans, Helene Hirbec, Carole Escartin, Martine Cohen-Salmon.

  Early synaptic dysfunction is a hallmark of Alzheimer's disease (AD), yet the astrocytic mechanisms underlying these alterations remain poorly defined. Here, we identify astrocyte perisynaptic processes (PAPs) as subcellular hotspots of early translational dysregulation in AD. Soluble Aβ₁-₄₂ rapidly enhanced global and local protein synthesis in primary astrocytes. In 5.5-month-old APP/PS1-dE9 (APP) mice, translating ribosome affinity purification (TRAP) revealed widespread remodeling of the PAP translatome, while whole-astrocyte translation remained largely unchanged. Dysregulated mRNAs were linked to neuroinflammation, synaptic remodeling, and endoplasmic reticulum stress, and alterations emerged prior to amyloid plaque deposition. Among them, Serpina3n encoding α1-antichymotrypsin exhibited increased mRNA abundance in PAPs, uncovering spatially restricted translational control. Mechanistically, early Serpina3n upregulation was partially driven by JAK-STAT3 signaling, with preferential effects in astrocyte processes. These findings provide a conceptual advance by demonstrating that local translation in astrocyte PAPs is an early and compartment-specific mechanism that may contribute to synaptic dysfunction and disease initiation in AD.

Keywords:  Alzheimer's disease; Astrocyte reactivity; Astrocytes; FISH; Glia; Inflammation; JAK-STAT3; Local translation; Neurodegenerative disorders; Perisynaptic astrocyte process; SOCS3; Serpina3n; Synapse; TRAP; mRNA distribution

DOI:  https://doi.org/10.1016/j.nbd.2026.107528
Trends Biochem Sci. 2026 Jul 07. pii: S0968-0004(26)00178-7. [Epub ahead of print]

Intrinsically disordered regions in eukaryotic mRNA decay pathways.

Sarah Lewandowski, Lea Sophie Pommerening, Sutapa Chakrabarti.

  Regulation of gene expression in cells is mediated by RNA-binding proteins (RBPs), which act as adaptors connecting messenger RNA (mRNA) to enzymatic and structural components to achieve a distinct functional outcome. RBPs are enriched in intrinsically disordered regions (IDRs). These regions mediate multivalent interactions that lead to the expansion of a physical and functional network in cells and, therefore, play a pivotal role in mRNA processing. In this review, we highlight the role of IDRs in eukaryotic mRNA decay. IDRs drive the assembly of transient mRNA-protein complexes essential for mRNA degradation and regulate the catalytic activities of enzymes involved therein. Beyond these functions, IDRs connect different pathways of targeted mRNA decay, building a global functional network that dictates gene expression.

Keywords:  CCR4–NOT; Dcp2; SLiMs; UPF1; conformational flexibility; networks

DOI:  https://doi.org/10.1016/j.tibs.2026.06.002
Curr Opin Chem Biol. 2026 Jul 09. pii: S1367-5931(26)00073-6. [Epub ahead of print]94 102724

Resolving cellular signaling in space and time: From organelle proteomics to spatial phosphoproteomics.

Alejandro Matía, Ruth Hüttenhain.

Cellular signaling is inherently organized in space and time, requiring coordinated control of protein localization, molecular interactions, and enzymatic activity across subcellular compartments. Recent advances in chemical biology, protein engineering, and quantitative proteomics have made it possible to interrogate these dimensions in an integrated manner. Here, we highlight emerging strategies to resolve signaling organization across three interconnected dimensions: organelle-resolved proteome mapping to define spatial context, proximity labeling to capture local protein interaction networks, and spatially resolved phosphoproteomics to quantify signaling outputs. Developments in proximity labeling, including split, conditionally activated and light-gated enzymes, enable temporally controlled, context-dependent profiling of transient protein assemblies in living cells. Advances in high-throughput and low-input phosphoproteomics, together with improved computational frameworks for kinase activity inference and subcellular enrichment strategies, are enabling spatially resolved measurement of signaling activity. Together, these approaches are shifting the field from static localization maps toward dynamic models of signaling networks.

DOI: https://doi.org/10.1016/j.cbpa.2026.102724
bioRxiv. 2026 Jun 29. pii: 2026.06.26.734871. [Epub ahead of print]

Molecular mechanism of IF1- and IF2-driven translation initiation in bacteria.

Gabriel Soares Guerra, Hassan Zafar, Xueliang Ge, Ritwika S Basu, Chenhui Huang, Ahmed H Hassan, Nicolette A Valdez, Sylva Brabencova, Lucie Slamova, Chandra Sekhar Mandava, Howard Gamper, Ya-Ming Hou, Matthieu G Gagnon, Suparna Sanyal, Gabriel Demo.

Bacterial translation initiation is a highly regulated process essential for accurate start codon selection and the assembly of an elongation-competent ribosome. Two initiation factors, 1 (IF1) and 3 (IF3), contribute to quality control for formation of 30S preinitiation complex (30S PIC), while the GTPase IF2 facilitates stable initiator tRNA binding and promotes subunit association. However, the molecular mechanism of IF1 action and the regulatory role of IF2-mediated GTP hydrolysis and inorganic phosphate (Pi) release remain poorly understood. Using ensemble cryo-EM integrated with fast-kinetics, we delineate the translation initiation pathway involving IF1 and IF2. We show that IF1 transiently associates with the 30S subunit and interferes with the formation of multiple inter-subunit bridges. IF2 promotes subunit association by stabilizing the 30S PIC through interactions mediated by its N-terminal domains. IF1 departure happens after or concomitant with GTP hydrolysis, following which the inter-subunit bridges establish. Then Pi release triggers remodeling of IF2 followed by its departure from the 70S initiation complex. These findings reveal how the coordinated interplay of IF1 and IF2 with the ribosome ensures translational fidelity and plays crucial role for formation of elongation-competent 70S.

DOI: https://doi.org/10.64898/2026.06.26.734871
J Cell Biol. 2026 Sep 07. pii: e202511211. [Epub ahead of print]225(9):

Intercellular mitochondrial transfer and trans-mitophagy in response to protein import dysfunction.

Emily Glover, Beth Wiseman, Celyn Dugdale, Charlie Humphery, Lorena Sueiro Ballesteros, Lorna Hodgson, Kevin Wilkinson, Ian Collinson.

Mitochondrial protein import is critical for organelle biogenesis, maintenance, and regeneration-essential for cellular homeostasis. Import dysfunction compromises cellular energy supplies, which is damaging to cells, particularly those with high energetic demands like neurons. Previously, we have shown that import failure is rescued by intercellular mitochondrial transfer (IMT) via tunnelling nanotubes (TNTs) however, the fate of the transferred mitochondria and the mechanistic basis for rescue were unresolved. Here, we show that bidirectional mitochondrial trafficking between cells harboring import-defective and import-competent mitochondria is distinct in terms of their regulation and ensuing consequences. Transferred import-defective mitochondria are highly fragmented and destined for canonical lysosomal degradation. In contrast, reactive oxygen species (ROS)-producing mitochondria at the periphery of cells with import-competent mitochondria are transferred into neighboring cells undergoing import failure. These new arrivals then accumulate within previously uncharacterized "mitochondrial degradation bodies" (MDBs). We speculate that the cooperation of these distinct cases of TNT-mediated conventional and noncanonical "trans-mitophagy" instigates mitochondrial regeneration, and thereby rescues mitochondrial function.

DOI: https://doi.org/10.1083/jcb.202511211
Protein Sci. 2026 Aug;35(8): e70690

Immunoglobulin binding protein (BiP) forms two types of dimers.

Karina New, Miguel I A Lagos-Espinoza, Nathalie Casanova-Morales, Roi Asor, John William Young, Zahra Alavi, Christian A M Wilson.

  Immunoglobulin binding protein (BiP) is a chaperone protein that plays crucial roles in protein folding and transport by binding unfolded proteins in the substrate binding domain (SBD), an interaction allosterically linked to the nucleotide occupancy of the nucleotide binding domain (NBD). BiP also forms oligomers that influence its activity, particularly in binding polypeptide clients. Using single-molecule approaches and mechanical and enzymatic activity assays, BiP monomer stability and oligomerization were analyzed both alone and in response to nucleotides and peptides. We find that the formation of BiP dimers exhibits biphasic behavior as a function of BiP concentration, suggesting concentration-dependent changes in dimer dissociation constants. At low BiP concentrations, dimers were disrupted by peptide substrate and adenosine triphosphate (ATP) but remained unaffected by ADP or Adenosine 5'-O-(3-thio)triphosphate (ATPγS). At high concentrations, dimers are unaffected by peptides, but their assembly is inhibited by ATP and ATPγS to the same degree. These results suggest the formation of two distinct BiP dimers exhibiting unique binding affinities, kinetics, and potentially structures. We propose the existence of a high-affinity dimer binding site within the SBD of BiP, while the formation of a low-affinity dimer involves interactions between the lid and NBD of each protomer. Our findings demonstrate the importance of considering single-molecule characteristics when interpreting bulk studies on protein function and regulation.

Keywords:  Hsp70; chaperone protein; dimerization; endoplasmic reticulum; mass photometry; protein–protein interactions; proteostasis; unfolded protein response

DOI:  https://doi.org/10.1002/pro.70690
J Am Chem Soc. 2026 Jul 09.

Benzoxaboroles Are Structurally Unique Binders of Eukaryotic Translation Initiation Factor 4E.

Joshua B Combs, D Matthew Peacock, Gregory B Craven, Sungwon Jung, Ying Chen, Sang M Le, Jack Taunton, Kevan M Shokat.

Benzoxaboroles offer unusual reactivity and protein recognition for the development of small molecule drugs. Despite this potential, they are uncommon in drug discovery or in fragment screening libraries. We synthesized a series of structurally related benzoxaboroles containing a diazirine/alkyne tag to enable in-cell photoaffinity labeling experiments. A subset of this library was found to have high selectivity for eukaryotic translation initiation factor 4E (eIF4E). The benzoxaborole-eIF4E interaction was found to be stereoselective in nature and competitive with the 7-methylguanosine cap of mRNA. Site of labeling experiments revealed that the benzoxaborole fragment interacts with the cap binding pocket of eIF4E. In silico modeling of the modified protein suggests that H-bonding interactions between the main chain of Trp102 and the side chain of Asn155 to the amide carbonyl and anionic boronate of the benzoxaborole, respectively, drive affinity for this challenging to drug pocket.

DOI: https://doi.org/10.1021/jacs.6c04291
Nat Commun. 2026 Jul 09.

Proteome-scale quantification of the interactions driving condensate formation of intrinsically disordered proteins.

Rasmus K Norrild, Sören von Bülow, Baptiste Zanchet, Einar Halldórsson, Kresten Lindorff-Larsen, Joseph M Rogers, Alexander K Buell.

Cellular organization in the form of biomolecular condensates is a fundamental regulatory mechanism across all forms of life. Formation of condensates relies on multivalent interactions that are often weak and transient, making them challenging to study experimentally. We have developed Condensate Partitioning by mRNA-Display (CPmD) to measure these interactions from the partition free energies of peptides and nucleic acids into reconstituted condensates. CPmD increases experimental throughput by several orders of magnitude, and we apply it to reveal the interactions driving condensate formation of intrinsically disordered proteins. We show that the partition free energies of about one hundred thousand peptides derived from the disordered proteome into a model condensate directly reflect their intrinsic propensity to form condensates. We reveal that amino acid content, linked to hydrophobicity, is the primary determinant of phase behavior. Additionally, CPmD uniquely resolves subtle sequence-dependent contributions that can encode specificity. CPmD thus provides a powerful tool to decipher how weak interactions between protein and RNA regulate biological function through condensate formation.

DOI: https://doi.org/10.1038/s41467-026-74825-z
Cell Rep. 2026 Jul 03. pii: S2211-1247(26)00728-X. [Epub ahead of print]45(7): 117650

RelB drives integrin-mediated stress tolerance and relapse in high-grade serous ovarian cancer.

Omar Lujano-Olazaba, Mikella Robinson, Gregory J Jordan, Sofia Howe, Anna Platen, Cassidy Lucht, Dishant Vandra, Cecilia Gallo, Mena Shammas, Katelyn Shelby, Nathan Wong, Ingrid R Niesman, David D Schlaepfer, David A Cheresh, Christina M Annunziata, Carrie D House.

  High-grade serous ovarian cancer (HGSOC) often relapses after chemotherapy due to chemoresistant cancer stem-like cells (CSCs). NF-κB signaling, previously shown to enhance stemness traits, was investigated for its role in post-treatment tumor regrowth. Here, we found that NF-κB subunits RelA and RelB jointly regulate extracellular matrix genes but differentially control integrin subunits: RelA regulates ITGAV (αV) and RelB regulates ITGB3 (β3). Integrin αVβ3 expression is upregulated on CSCs, and this is partially driven by NF-κB activation. In vivo models demonstrate that αVβ3+ cells have higher tumor-initiating capacity and comprise over 90% of cells from relapsed tumors. Cells expressing RelB and αVβ3 preferentially grow on mesentery at relapse. Targeting this pathway, combined RelB knockdown and inhibition of αVβ3 eliminated stress-tolerant CSCs, reduced tumor burden, and extended survival. These findings highlight integrins as promising therapeutic targets and reveal distinct roles for NF-κB subunits in regulating metastasis and relapse in HGSOC.

Keywords:  CP: cancer; NF-κB; cancer stem-like cell; integrins; metastasis; ovarian cancer; stress tolerance; αVβ3

DOI:  https://doi.org/10.1016/j.celrep.2026.117650