Cell Stress & Chaperones最新文献

{"title":"Nucleotide-dependent domain interactions of Aha1-type co-chaperones with Hsp90 reveal evolutionarily conserved binding determinants.","authors":"Desmond Prah Amoah, Rakesh Bhat, Malak Trad, Solomon K Hussein, Michael Overduin, Paul LaPointe","doi":"10.1016/j.cstres.2026.100179","DOIUrl":"10.1016/j.cstres.2026.100179","url":null,"abstract":"<p><p>Hsp90 is a dimeric molecular chaperone essential for the maturation, activation, stabilization, and folding of numerous clients required for cellular functions. Hsp90 progresses through a dynamic ATP-driven conformational cycle that is precisely regulated by accessory proteins known as co-chaperones. Here, we show that the isolated N-domain of Aha1 (Aha1N156) binds the apo state of Hsp90 but fails to associate with the closed, nucleotide-bound state. In contrast, the full-length Aha1 binds Hsp90 in both conformational states, suggesting a key role for the Aha1 C domain in binding to the nucleotide-bound, closed state of Hsp90. Surprisingly, the Aha1 paralogue Hch1, which corresponds to the Aha1 N domain, was capable of binding to Hsp90 in both the apo and nucleotide-bound states. Interestingly, the addition of a 14 amino acid residues section of the linker to the Aha1 N domain restores closed-state binding, indicating an unexpected role for the linker in stabilizing nucleotide-dependent interactions. Analysis of yeast-human Aha1 chimeras further demonstrates that the C-terminal domain of Aha-type co-chaperones serves as an evolutionarily conserved anchoring module, enabling stable engagement of the ATP-bound state despite significant sequence divergence. This work allows us to propose a model in which the Aha1 C domain allows for the repositioning of the Aha1 N domain that occurs during the transition from the apo to the ATP-bound state of Hsp90.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"100179"},"PeriodicalIF":3.2,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Human DBR1 Interactome Reveals Coupling Between Intron Lariat Turnover, Pre-mRNA Splicing and RNA Quality Control Pathways.","authors":"Tiffany Barwell, Dipendra Gautam, Nitika, Bo Zheng, Andrew W Truman, Kausik Chakrabarti","doi":"10.1016/j.cstres.2026.100178","DOIUrl":"https://doi.org/10.1016/j.cstres.2026.100178","url":null,"abstract":"<p><p>Pre-mRNA splicing produces intron lariats that must be cleaved at their internal 2'-5' phosphodiester bond by the debranching endonuclease DBR1. While human DBR1 (hDBR1) is established as the lariat debranching enzyme, how it interfaces with broader RNA-metabolc pathways is less clear. Using chemical inhibition of splicing, we show that DBR1 expression correlates with splicing activity. We then mapped the hDBR1 interactome by immunopurification coupled to mass spectrometry using complementary gel-based and on-bead workflows. hDBR1 associates with spliceosome and intron-turnover factors, and with RNA quality-control proteins including UPF1, XRN2, and the RNA helicase DHX29. RNase A treatment identifies an RNA-dependent subnetwork enriched for stress-granule proteins and hnRNPs, linking hDBR1 to RNA surveillance during stress. Comparison with BioGRID indicates that most detected associations were not previously reported. Finally, phosphoproteomic profiling reveals multiple hDBR1 phosphorylation sites, including four residues preferentially detected after RNase treatment, suggesting regulatory modifications that may tune hDBR1 interactions or activity. Together, these data expand the functional landscape of hDBR1 across splicing, intron turnover, and RNA quality control.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"100178"},"PeriodicalIF":3.2,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board Members/Copyright","authors":"","doi":"10.1016/S1355-8145(26)00024-6","DOIUrl":"10.1016/S1355-8145(26)00024-6","url":null,"abstract":"","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100168"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147540069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of host proteostasis by Prevotella corporis via induction of the heat shock response","authors":"Matthew F. Tibi ,&nbsp;Yoan M. Argote ,&nbsp;Alyssa C. Walker ,&nbsp;Swapnil Pandey ,&nbsp;Cristian Puente ,&nbsp;Garrett L. Ellward ,&nbsp;Anan Safwat ,&nbsp;Diego E. Rincon-Limas ,&nbsp;Daniel M. Czyż","doi":"10.1016/j.cstres.2026.100150","DOIUrl":"10.1016/j.cstres.2026.100150","url":null,"abstract":"<div><div>Neurodegenerative protein conformational diseases (PCDs) are progressive, currently incurable disorders driven by toxic protein aggregation that leads to neuronal death. Emerging evidence supports a microbial role in PCDs, including the most prevalent: Alzheimer’s and Parkinson’s disease. While metagenomic studies consistently associate gut dysbiosis with these disorders, the mechanisms by which microbes influence host proteostasis remain poorly understood. In particular, considerable attention has been given to proteotoxic bacteria, whereas the mechanisms by which commensal microbes confer proteoprotection have received comparatively little attention. We previously employed <em>Caenorhabditis elegans</em> models to characterize the role of over 220 bacterial isolates from the Human Microbiome Project on host proteostasis. Strikingly, members of the <em>Prevotella</em> genus exhibited proteoprotective effects. Most notably, transient exposure to <em>Prevotella corporis</em> uniquely induced Hsp70, a critical molecular chaperone that maintains proteostasis, and significantly reduced aggregation of polyglutamine (polyQ), A<span><math><mi>β</mi></math></span>42, and α-synuclein. In the present study, we expand on these findings, demonstrating that among 13 <em>Prevotella</em> species tested, <em>P. corporis</em> robustly activates the heat shock response (HSR) and confers conserved aggregate-suppressing activity in <em>Drosophila melanogaster</em>. We further demonstrate that transient exposure to <em>P. corporis</em> results in the activation of protective stress pathways and promotes disaggregation of existing intestinal polyQ aggregates in <em>C. elegans,</em> leading to a general enhancement of global proteostasis. This is supported by significantly improved survival and enhanced thermotolerance. Together, our findings reveal a beneficial niche for <em>P. corporis</em> in activating the HSR to enhance organismal proteostasis and support a microbe-mediated gut-proteostasis axis. This work underscores the therapeutic potential of targeting the gut microbiota for the management of PCDs, highlights the importance of species-level resolution in microbiome studies, and supports the emerging view of the intestine as a proteostasis-modulating organ.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100150"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High mobility group box 1: DAMPening the danger molecule in cardiovascular disease with exercise","authors":"Yu-Chieh Liao ,&nbsp;Jorming Goh","doi":"10.1016/j.cstres.2026.100161","DOIUrl":"10.1016/j.cstres.2026.100161","url":null,"abstract":"<div><div>High mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP). During cellular stress, it leaves the nucleus and moves into the extracellular space, where it modulates the development of cardiovascular diseases (CVDs), a leading global cause of age-related mortality. While evidence indicates that HMGB1 is associated with both the progression and severity of CVDs, it also has a paradoxically beneficial role in mitigating tissue repair. Exercise training improves cardiovascular function and modulates systemic concentrations of HMGB1. Acute exercise induces the release of HMGB1 into systemic concentration, whereas long-term exercise training appears to reduce its systemic levels. This paradoxical response of HMGB1 to either short-term or chronic exercise, alongside its complex role in the pathogenesis of age-associated CVDs, makes it an intriguing subject for research. A potential explanation for this paradox may lie in HMGB1’s capacity in regulating stem cell recruitment and tissue regeneration. This review explores the intricate interactions between HMGB1, exercise and CVDs, and discusses its potential both as a therapeutic target and a novel biomarker for tracking inflammatory signaling during exercise.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100161"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of α-1,3-mannosyltransferase sensitizes head and neck squamous cell carcinomas to cetuximab via endoplasmic reticulum stress","authors":"Yu Hao ,&nbsp;Guangchuan Deng ,&nbsp;Bolei Li ,&nbsp;Lei Cheng ,&nbsp;Shengguo Wang ,&nbsp;Zhenzhou Yang","doi":"10.1016/j.cstres.2026.100153","DOIUrl":"10.1016/j.cstres.2026.100153","url":null,"abstract":"<div><div>Developing effective therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) remains a considerable clinical challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. The aim of this study was to explore the potential of α-1,3-mannosyltransferase (ALG3) inhibition in augmenting the therapeutic efficacy of cetuximab. We first analyzed the Cancer Genome Atlas (TCGA) data and found that ALG3 was significantly overexpressed in HNSCC tissues, correlating with worse pathological features and lower overall and disease-specific survival. Functional studies using ALG3-knockdown cells and a subcutaneous tumor model demonstrated that ALG3 inhibition markedly suppressed HNSCC proliferation both <em>in vitro</em> and <em>in vivo</em>. Furthermore, combining ALG3 inhibition with cetuximab elicited potent anti-cancer effects <em>in vitro</em> and <em>in vivo</em>. Mechanistic investigations <em>via</em> quantitative polymerase chain reaction, western blotting, and transmission electron microscopy revealed that <em>ALG3</em> knockdown induced endoplasmic reticulum (ER) stress in HNSCC cells through the Bip/IRE1α axis. Finally, blocking N‑linked glycosylation synergistically enhanced cetuximab-mediated growth inhibition of HNSCC cells. In conclusion, ALG3 is a promising target to enhance the therapeutic efficacy of cetuximab in HNSCC.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100153"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover and caption","authors":"","doi":"10.1016/S1355-8145(26)00023-4","DOIUrl":"10.1016/S1355-8145(26)00023-4","url":null,"abstract":"","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100167"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147540070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional responses to proteotoxic stressors are profoundly diverse and tissue-specific","authors":"Adelina Rabenius,&nbsp;Intisar Salim,&nbsp;Hilmar Lindström,&nbsp;Anastasiya Pak,&nbsp;Serhat Aktay,&nbsp;Anniina Vihervaara","doi":"10.1016/j.cstres.2026.100146","DOIUrl":"10.1016/j.cstres.2026.100146","url":null,"abstract":"<div><div>Cells counteract proteotoxic conditions by launching transcriptional stress responses. While synthesis of heat shock proteins (HSPs) upon acute stress is well characterized, how distinct proteotoxic conditions reshape the transcriptome remains poorly understood. Here, we analyse polyA+ RNA expression under heat shock, HSP90 inhibition, and polyglutamine (polyQ) aggregation. We find fundamentally distinct transcriptional responses to proteotoxic stressors and a systemic deficiency of mice under chronic stress to launch acute responses. While heat shock and HSP90 inhibition induce chaperones, polyQ aggregation increases expression of RNAs linked to transcription repression, chromatin remodeling, and autophagy. Analysing wild-type and Huntington's Disease (HD) mice reveals tissue-specific transcriptional adaptations to polyQ, including repressed cell-type specific functions and altered energy metabolism. Despite profound reprogramming, remarkably few genes exhibit consistently increased (<em>Acy3</em>, <em>Abhd1</em>, <em>Tmc3</em>) or decreased (<em>Fos</em>) RNA levels across HD brain regions. These results emphasize cellular background in disease manifestation and support energy metabolism and detoxifying enzymes as therapeutic targets in late-stage HD. Moreover, the systemic deficiency of chronically stressed mice to launch responses challenges strategies that rely on induced transcription. Altogether, we characterize transcription signatures to proteotoxic stresses, identify key <em>trans</em>-activators driving proteotoxic stress responses, provide an interactive gene-by-gene viewer of global changes, and delineate tissue-specific transcription programs in HD mice.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100146"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leucine-rich repeats and immunoglobulin-like domains 3 suppresses hypoxia-induced vasculogenic mimicry in glioma by promoting the ubiquitination and degradation of Snail2","authors":"Yang Guo ,&nbsp;Dongsheng Guo ,&nbsp;Ran Xu ,&nbsp;Wenjin Qiu ,&nbsp;Chenghao Peng","doi":"10.1016/j.cstres.2026.100152","DOIUrl":"10.1016/j.cstres.2026.100152","url":null,"abstract":"<div><h3>Purpose</h3><div>Leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) functions as a tumor suppressor in glioma. Although our previous study demonstrated that LRIG3 inhibited angiogenesis via the PI3K/AKT/VEGFA pathway under normoxia, its impact on glioma vascularization under hypoxia remains elusive. Vasculogenic mimicry (VM), an alternative form of neovascularization, plays a pivotal role in glioma progression, particularly within hypoxic tumor microenvironments. This study aimed to investigate the effects of LRIG3 on hypoxia-induced VM in glioma and to elucidate the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>The effects of LRIG3 on VM were evaluated in vitro using tube formation and 3D spheroid invasion assays. Histological analysis of intracranial xenografts and glioblastoma specimens was performed to assess LRIG3's impact on glioma vascularization in vivo. The underlying mechanisms were investigated using western blot, quantitative real-time PCR (qRT-PCR), and ubiquitination assays.</div></div><div><h3>Results</h3><div>LRIG3 expression was inversely correlated with VM density in the central hypoxic regions of both xenografts and glioblastoma specimens. Under hypoxia, LRIG3 overexpression inhibited the invasion and tube formation capacities of glioma cells, whereas its knockdown promoted these activities. Mechanistically, LRIG3 suppressed VM phenotypes by downregulating Snail2 at the post-translational level, rather than affecting VEGFA. LRIG3 promoted the ubiquitination of Snail2, leading to its proteasomal degradation and destabilization under hypoxia.</div></div><div><h3>Conclusions</h3><div>LRIG3 inhibits hypoxia-induced VM in glioma by facilitating the proteasomal degradation of Snail2 via ubiquitination.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100152"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased FICD-mediated protein AMPylation triggers conserved endoplasmic reticulum stress signaling across species","authors":"Mirella A. Hernandez-Lima ,&nbsp;Blaise L. Mariner ,&nbsp;William Giblin ,&nbsp;Mark A. McCormick ,&nbsp;Matthias C. Truttmann","doi":"10.1016/j.cstres.2026.100149","DOIUrl":"10.1016/j.cstres.2026.100149","url":null,"abstract":"<div><div>Post-translational protein modifications (PTMs) are fundamentally important in regulating protein function across species. One such PTM, referred to as protein AMPylation, is increasingly recognized to fine-tune endoplasmic reticulum (ER) stress signaling in metazoans. Protein AMPylation in the ER is catalyzed by conserved fic-domain containing enzymes (fic AMPylases), including FICD (<em>Homo sapiens</em>) and FIC-1 (<em>Caenorhabditis elegans</em>). However, it remains unclear whether enhanced fic AMPylase-mediated protein AMPylation promotes a conserved cellular response. In this study, we determined the transcriptomic consequences of increased fic AMPylase-mediated protein AMPylation in mouse fibroblasts and young adult nematodes. We find that in <em>C. elegans</em>, FIC-1(E274G) over-expression (OE) triggers a unique transcriptional signature, leading to the marked upregulation of pathways involved in cellular stress signaling. We further show that FIC-1(E274G) OE upregulates genes involved in antibacterial innate immune responses and identify a potentially co-regulated gene cluster sensitive to changes in AMPylation levels. Intriguingly, we observe a similar transcriptomic signature in mouse fibroblasts in response to FICD(E234G) OE. A cross-species comparison of the transcriptomes of nematodes, yeast, and mouse fibroblasts enduring increased fic AMPylase-mediated protein AMPylation revealed a conserved transcriptional core response to enhanced AMPylation. Collectively, this study defines a conserved cellular stress response to enhanced fic AMPylase-mediated protein AMPylation.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 2","pages":"Article 100149"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}