Cell Stress & Chaperones最新文献

{"title":"Expanding the landscape of the unfolded protein response: The roles of secondary transcription factors in development and disease","authors":"Miguel Angel Jiménez-Beltrán ,&nbsp;Rocío Valle-Bautista ,&nbsp;Edgar Ricardo Vázquez-Martínez","doi":"10.1016/j.cstres.2025.100141","DOIUrl":"10.1016/j.cstres.2025.100141","url":null,"abstract":"<div><div>The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a classic cellular reaction to stress that helps restore ER homeostasis. However, growing evidence demonstrates that the main UPR effectors (Activating Transcription Factor 6 (ATF6), X-box Binding Protein 1 (XBP1s), and Activating Transcription Factor 4 (ATF4)) not only regulate canonical UPR target genes but also promote the transcription of genes encoding secondary transcription factors (TFs). These secondary TFs contribute to ER homeostasis maintenance and are involved in various physiological processes that extend beyond the traditional UPR. In this review, we examine the secondary TFs activated by UPR master regulators (UPR-TFs) and discuss their functional roles in different tissues and organs. We emphasize how these secondary TFs, controlled by their respective UPR-TFs, participate in stress responses, cell differentiation, embryonic development, circadian rhythms, metabolism, and other physiological processes. Furthermore, we explore common signaling pathways and tissue- and cell-specific regulatory mechanisms, highlighting convergence points where secondary TFs from different UPR branches intersect, indicating a more complex regulatory network. We also discuss the functions of these secondary TFs in the lungs, placenta, testis, uterus, pancreas, and liver, as well as during embryonic development and in pathological conditions. This study reveals biological activities that extend beyond the traditional roles of the UPR, providing a broader view of this signaling pathway and opening new avenues for future research.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 1","pages":"Article 100141"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800154","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 dihydropyridine LA1011 modulates multiple Hsp90—co-chaperone interactions relevant to Alzheimer’s disease","authors":"Xavier Jeanne ,&nbsp;Jasmeen Oberoi ,&nbsp;Mark S. Roe ,&nbsp;Matthias Baud ,&nbsp;John Spencer ,&nbsp;Zsolt Torok ,&nbsp;Laszlo Vigh ,&nbsp;Chrisostomos Prodromou","doi":"10.1016/j.cstres.2025.100131","DOIUrl":"10.1016/j.cstres.2025.100131","url":null,"abstract":"<div><div>LA1011 (dimethyl 4-(4-Trifluoro-methyl-phenyl)-2,6-bis(2-dimethylamino-ethyl)-1-methyl-1-4 dihydropyridine-3-5-dicarboxylate dihydrochloride) has been shown to improve the prognosis of Alzheimer’s disease (AD) in an APPxPS1 mouse model. The target for LA1011 is the C-terminal domain of Hsp90, where it was shown previously to reduce the interaction between FKBP51 and Hsp90. FKBP51 is a Hsp90 co-chaperone that promotes the <em>trans</em> to <em>cis</em> isomerization of proline at multiple tau pSer/pThr-pro sites, thus preventing their dephosphorylation. Potentially this leads to the hyperphosphorylation of tau and the formation of neurofibrillary tangles that eventually lead to the development of AD. In this study, we demonstrate that LA1011 affects the FKBP51-mediated regulation of Hsp90 but also potentially modulates the regulation Hsp90 by the co-chaperones FKBP52, CHIP, Aha1, Hch1 and PP5. We also show that the co-chaperones HOP, CDC37 and Sgt1 appear to enhance mildly the binding of LA1011. In contrast, nucleotide alone or nucleotide with Aha1 or p23, which promote the closed conformation of Hsp90, reduce the affinity for LA1011. We conclude that LA1011 can modulate the regulatory landscape of the Hsp90 co-chaperone network, which in turn appears to improve the prognosis of Alzheimer’s disease.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 1","pages":"Article 100131"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687170","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":"DNA damage-inducible transcript 3-mediated endoplasmic reticulum stress drives manganese-induced apoptosis in bovine testicular Leydig cells","authors":"Liwei Huang ,&nbsp;Yu Cheng ,&nbsp;Xiaolong Pan ,&nbsp;Hongxia Li ,&nbsp;Jia Liu ,&nbsp;Guoqing Zhao ,&nbsp;Lijuan Huang ,&nbsp;Lili Wang ,&nbsp;Chunying Song ,&nbsp;Pengkang Song ,&nbsp;Le Zhao ,&nbsp;Xuanqi Yu ,&nbsp;Juan Xiong ,&nbsp;Xiaoyu Li ,&nbsp;Qun Rao ,&nbsp;Xi Wang ,&nbsp;Ruigao Song","doi":"10.1016/j.cstres.2025.100144","DOIUrl":"10.1016/j.cstres.2025.100144","url":null,"abstract":"<div><div>Manganese (Mn) is an essential trace element, but it is also an environmental pollutant. Excessive Mn accumulation in animals induces toxic effects, particularly reproductive damage. The mechanism of Mn toxicity in ruminants is unclear. This study investigated the mechanism of Mn toxicity on bovine Leydig cells. Bovine Leydig cells were treated with Mn at a semi-inhibitory concentration of 70 μM for 24 h, and this concentration was subsequently set as the Mn-treated experimental group. Multiple analytical approaches were employed, including the examination of cellular ultrastructure, measurement of oxidative stress indicators, analysis of apoptosis-related genes, and RNA-Seq sequencing for the screening of differentially expressed genes. The results showed that Mn treatment led to abnormal damage to the ultrastructure of mitochondria and endoplasmic reticulum. An increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, along with a decrease in glutathione peroxidase (GSH-Px) activity, provided evidence of oxidative stress induction. Additionally, Mn exposure upregulated the expression of apoptosis-related genes <em>Caspase-3</em> and <em>BAX</em>, while downregulating the expression of <em>BCL-2</em>, indicating the initiation of apoptosis. RNA-Seq analysis revealed that the <em>DDIT3</em> gene, associated with endoplasmic reticulum stress, exhibited highly significant differential expression. Further experiments showed that knockdown of the <em>DDIT3</em> gene effectively alleviated Mn-induced apoptosis in bovine Leydig cells. In conclusion, Mn exposure promotes apoptosis in bovine Leydig cells, and interference with <em>DDIT3</em> can mitigate this apoptotic process, which provides valuable references for the prevention and control of Mn pollution in animal husbandry and the management of the reproductive health of breeding bulls.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 1","pages":"Article 100144"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877840","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)00011-8","DOIUrl":"10.1016/S1355-8145(26)00011-8","url":null,"abstract":"","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 1","pages":"Article 100155"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147395516","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)00010-6","DOIUrl":"10.1016/S1355-8145(26)00010-6","url":null,"abstract":"","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"31 1","pages":"Article 100154"},"PeriodicalIF":3.2,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147395515","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":"Ex vivo qualitative and quantitative analysis of fluorescently-labeled Hsp90 drug in human tumors","authors":"Sarah J. Backe ,&nbsp;Dimitra Bourboulia ,&nbsp;Mark R. Woodford ,&nbsp;Mehdi Mollapour","doi":"10.1016/j.cstres.2025.100129","DOIUrl":"10.1016/j.cstres.2025.100129","url":null,"abstract":"<div><div>Heat shock protein 90 (Hsp90) stabilizes numerous oncogenic proteins, making it a key therapeutic target in cancer. This protocol details an <em>ex vivo</em> method using freshly resected human renal cell carcinoma tissues to evaluate fluorescently labeled Hsp90 inhibitor ganetespib accumulation in tumor versus normal tissue. By preserving the native tumor architecture, this method offers a physiologically relevant alternative to xenograft models. This protocol combines flow cytometry and confocal microscopy to quantitatively and visually assess ganetespib uptake, providing insight into drug distribution and therapeutic response in human cancers. For complete details on the use and execution of this protocol, please refer to Dunn et al. and Woodford et al.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100129"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630397","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":"Signal relay in C. elegans: A tissue-perspective on coordinating organismal proteostasis and its impact on aging","authors":"Loren Cocciolone,&nbsp;Akhil Souparnika,&nbsp;Valeria Uvarova,&nbsp;Katie Kessler,&nbsp;Patricija van Oosten-Hawle","doi":"10.1016/j.cstres.2025.100127","DOIUrl":"10.1016/j.cstres.2025.100127","url":null,"abstract":"<div><div>As the global demographics shifts towards an increasingly aging population, understanding the effects and molecular mechanisms underlying aging becomes more and more important within biomedical research. A hallmark of aging is the progressive deterioration of protein homeostasis (proteostasis), characterized by the accumulation of misfolded protein aggregates within the cell. The proteostasis network is essential in mitigating the harmful effects of proteotoxic aggregates by activating stress response and degradation pathways. Significant discoveries in aging research are often inherently intertwined with proteostasis, many of which were made using the invertebrate <em>Caenorhabditis elegans</em>. Many longevity pathways, such as the insulin-like signaling pathway, initially identified in <em>C. elegans,</em> are mediated through inter-tissue stress signaling from the nervous system, intestine, or gonad. These cell nonautonomous signaling pathways not only enhance lifespan and stress resilience but also limit age-related accumulation of protein aggregates that exacerbate age-associated diseases. Thus, findings from aging research were often key to providing new insights into cell nonautonomous regulation of stress responses and organismal proteostasis. In this review, we outline key discoveries made using <em>C. elegans</em> as a model system and highlight their contributions that led to our current understanding of inter-tissue communication in organismal proteostasis regulation. We furthermore highlight emerging concepts and discuss the translational relevance of conserved cell nonautonomous proteostasis regulation in mammals. We emphasize the importance of mammalian research to support the research done in <em>C. elegans,</em> with the future goal of developing potential therapeutic interventions targeting these inter-tissue proteostasis signaling pathways to combat aging.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100127"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336508","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":"Hsp70 and Hsp90 post-translational modifications and translating the chaperone code","authors":"Sarah J. Backe ,&nbsp;Jennifer A. Heritz ,&nbsp;Mehdi Mollapour","doi":"10.1016/j.cstres.2025.100118","DOIUrl":"10.1016/j.cstres.2025.100118","url":null,"abstract":"<div><div>Molecular chaperones maintain proteostasis by assisting protein folding, stability, and activity. Heat shock protein 70 (Hsp70) and Hsp90 (Hsp90) are ATP-dependent chaperones essential for protein quality control, signaling, and stress adaptation. Their activities are controlled not only by co-chaperones, but also by dynamic post-translational modifications (PTMs). This review dissects phosphorylation, acetylation, methylation, ubiquitination, glycosylation, and other PTMs of Hsp70 and Hsp90 across systems. These PTMs regulate the ATPase activity, localization, and interactions of the molecular chaperones with major implications in health and disease. The term “chaperone code” describes the PTM landscape that fine-tunes chaperone function. This code governs client fate, drug sensitivity, and stress responses. Importantly, combinatorial PTMs introduce regulatory complexity and flexibility, especially in cancer, neurodegeneration, and inflammation. The crosstalk between various PTMs and feedback loops add new regulatory layers to chaperone function. Additionally, these PTMs impact the function of the clients that are central in regulating specific cellular processes or pathways, such as transcription, autophagy, metabolism, and immune regulation. These pathways are usually affected in different maladies, such cancer, neurodegenerative, infectious and chronic diseases. Unlocking the chaperone code is essential for directing chaperone activity toward therapeutic benefit. This can be achieved by targeting enzymes that write, erase, or read the chaperone code, thereby offering new therapeutic strategies.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100118"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111526","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 role of Atp2a2-mediated calcium imbalance and endoplasmic reticulum stress in hydrocortisone-induced neurotoxicity","authors":"Weihua Kong ,&nbsp;Pei Jiang ,&nbsp;Xinglu Miao ,&nbsp;Ben Sang ,&nbsp;Shunxin Hu ,&nbsp;Lei Feng","doi":"10.1016/j.cstres.2025.100112","DOIUrl":"10.1016/j.cstres.2025.100112","url":null,"abstract":"<div><div>Glucocorticoids (GCs), as commonly used anti-inflammatory and immunosuppressive drugs, may induce neurotoxicity with long-term use, although the specific mechanisms remain unclear. This study utilized zebrafish as a model to investigate the mechanisms and potential intervention targets of hydrocortisone (HC)-induced neurotoxicity. Transcriptome analysis revealed that HC exposure significantly downregulated the expression of <em>Atp2a2</em> (encoding the endoplasmic reticulum calcium pump SERCA2). Functional experiments confirmed that HC disrupts cellular calcium homeostasis: endoplasmic reticulum Ca²⁺ levels decreased, mitochondrial Ca²⁺ accumulation occurred, accompanied by mitochondrial membrane potential depolarization, increased reactive oxygen species (ROS) generation, and cell apoptosis. Additionally, fluorescent signals in brain and spinal cord neurons were weakened, and significant decreases in movement distance, time, and average speed were observed. Intervention experiments with the GR antagonist RU486 and the SERCA2 activator demonstrated that both could partially restore calcium homeostasis, reduce ROS and apoptosis, and improve motor behavior. The findings revealed that HC disrupted calcium homeostasis by downregulating <em>Atp2a2</em>, activating endoplasmic reticulum stress, and triggering mitochondrial dysfunction, ultimately leading to neuronal damage and behavioral abnormalities. SERCA2 may serve as a potential target for alleviating GC-associated neurotoxicity, and this study provides experimental evidence for elucidating its mechanisms.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100112"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091162","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":"Autophagy in proteostasis and aging in Caenorhabditis elegans","authors":"Caitlin M. Lange ,&nbsp;Ryo Higuchi-Sanabria ,&nbsp;Caroline Kumsta","doi":"10.1016/j.cstres.2025.100115","DOIUrl":"10.1016/j.cstres.2025.100115","url":null,"abstract":"<div><div>Proteostasis (protein homeostasis), the balance of protein synthesis, folding, and degradation, is critical for cellular function and organismal health. Its disruption leads to the accumulation of misfolded and aggregated proteins, hallmarks of aging and age-related diseases, including neurodegeneration. Autophagy, a conserved lysosome-mediated degradation pathway, is central to proteostasis by clearing toxic proteins and damaged organelles. In <em>Caenorhabditis elegans</em>, studies across conserved longevity paradigms and models of neurodegenerative diseases have defined key mechanisms by which autophagy maintains proteostasis during aging and stress. Beyond its degradative functions, autophagy contributes to spatial quality control by promoting the formation of potentially protective protein inclusions and coordinating with the ubiquitin-proteasome system. Emerging evidence also points to noncanonical autophagy pathways, such as unconventional secretion and inter-tissue communication, that broaden its role in systemic proteostasis. Together, these advances underscore autophagy’s multifaceted contribution to protein quality control, with wide-ranging implications for aging, stress resistance, and neurodegenerative disease.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 6","pages":"Article 100115"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102573","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}