Luiza B C T Coimbra, Andrea Pinto-Martinez, Isadora C B Pavan, Everton G Melo, Thaís L S Araujo
{"title":"Dynamics of heat shock protein 70 kDa in heat-shocked and hypoxic human endothelial cells.","authors":"Luiza B C T Coimbra, Andrea Pinto-Martinez, Isadora C B Pavan, Everton G Melo, Thaís L S Araujo","doi":"10.1016/j.cstres.2025.100085","DOIUrl":"https://doi.org/10.1016/j.cstres.2025.100085","url":null,"abstract":"<p><p>Heat shock proteins (HSPs) play crucial roles in human endothelial cell functions such as migration and angiogenesis. However, human heat shock protein dynamics under stress conditions such as heat shock and hypoxia in human endothelial cells (ECs) are enigmatic, and the characteristics of HSPs in endothelial cells after exposure to thermal stress and a low-oxygen environment are unknown. We hypothesized that endothelial cells (ECs) adapt to heat shock (HS) and hypoxia by modulating chaperome oligomerization and that HSP70 is a major determinant of the endothelial phenotype. HSP70 inhibition with VER-155008 or YM-1 in primary human endothelial cells decreases EC proliferation, migration and angiogenesis at baseline and after heat shock recovery. We showed that vascular-independent HSC/P70 multimeric complexes in primary human veins (HUVECs) and coronary artery ECs (HCAECs) accumulate after HS and are decreased by hypoxia. Heat shock recovery increases the number of HSP90 dimers, inducible HSP70, and HSP40 macromolecular complexes, whereas HSC70 returns to baseline. We demonstrated that the heat shock response and hypoxia regulate HSPs through a new layer of complexity, oligomerization, in addition to classical cochaperone/NEF interactions. The biphasic temporal oligomerization of molecular chaperones in the recovery phase provides a novel face of the heat shock response. In addition, shifts in the subcellular location and upregulation of HSP70 were also observed here. The decrease in HSP expression caused by hypoxia raises the possibility that decreased chaperone power contributes to the endothelial dysfunction found in atherosclerosis, thrombosis and cancer. Together, these results show that HSP70 is pivotal to the healthy endothelial response in veins and coronary arteries, and we revealed human HSP dynamics in the vascular response to proteotoxic stress.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"100085"},"PeriodicalIF":3.3,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157196","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}
Thiago J Borges, Karina Lima, Ayesha Murshid, Isadora T Lape, Maurício M Rigo, Benjamin J Lang, Thais J Teani, Shoib S Siddiqui, Leonardo V Riella, Cristina Bonorino, Stuart K Calderwood
{"title":"Innate extracellular mouse Hsp70 inflammatory properties are mediated by the interaction of Siglec-E and LOX-1 receptors.","authors":"Thiago J Borges, Karina Lima, Ayesha Murshid, Isadora T Lape, Maurício M Rigo, Benjamin J Lang, Thais J Teani, Shoib S Siddiqui, Leonardo V Riella, Cristina Bonorino, Stuart K Calderwood","doi":"10.1016/j.cstres.2025.100083","DOIUrl":"10.1016/j.cstres.2025.100083","url":null,"abstract":"<p><p>Innate immune responses to cell damage-associated molecular patterns induce a controlled degree of inflammation, ideally avoiding the promotion of intense unwanted inflammatory adverse events. When released by damaged cells, Hsp70 can stimulate different responses that range from immune activation to immune suppression. The effects of Hsp70 are mediated through innate receptors expressed primarily by myeloid cells, such as dendritic cells (DCs). The regulatory innate receptors that bind to extracellular mouse Hsp70 (mHsp70) are not fully characterized, and neither are their potential interactions with activating innate receptors. Here, we show that extracellular mHsp70 interacts with a receptor complex formed by both inhibitory Siglec-E and activating LOX-1 on DCs. We also find that this interaction takes place in lipid microdomains within the plasma membrane, and that Siglec-E acts as a negative regulator of LOX-1-mediated innate activation upon mHsp70 or oxidized LDL binding. Thus, Hsp70 can both bind to and modulate the interaction of inhibitory and activating innate receptors on the cell surface. These findings add another dimension of regulatory mechanism to indicate how self-molecules contribute to dampening of exacerbated inflammatory responses.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"100083"},"PeriodicalIF":3.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141453","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}
Emily E. Fink , Yi Zhang , Briana Santo , Anwita Siddavatam , Rosie Ou , Vishal Nanavaty , Byron H. Lee , Angela H. Ting
{"title":"Heat shock induces alternative polyadenylation through dynamic DNA methylation and chromatin looping","authors":"Emily E. Fink , Yi Zhang , Briana Santo , Anwita Siddavatam , Rosie Ou , Vishal Nanavaty , Byron H. Lee , Angela H. Ting","doi":"10.1016/j.cstres.2025.100084","DOIUrl":"10.1016/j.cstres.2025.100084","url":null,"abstract":"<div><div>Alternative cleavage and polyadenylation (APA) is a gene regulatory mechanism used by cells under stress to upregulate proteostasis-promoting transcripts, but how cells achieve this remains poorly understood. Previously, we elucidated a DNA methylation-regulated APA mechanism, in which gene body DNA methylation enhances distal poly(A) isoform expression by blocking CCCTC-binding factor (CTCF) binding and chromatin loop formation at APA control regions. We hypothesized that DNA methylation-regulated APA is one mechanism cells employ to induce proteostasis-promoting poly(A) isoforms. At the <em>DNAJB6</em> cochaperone locus, acute heat shock resulted in binding of stress response transcription factors heat shock factor 1, ATF6, and YY1 at the APA control region and an increase in the expression of the proximal poly(A) isoform known to prevent protein aggregation. Furthermore, TET1 was recruited to rapidly demethylate DNA, facilitating CTCF binding and chromatin loop formation, thereby reinforcing preferential proximal poly(A) isoform expression. As cells recovered, the transcription factors vacated the APA control region, and DNMT1 was recruited to remethylate the region. This process resolved chromatin looping and reset the poly(A) isoform expression pattern. Our findings unveil an epigenetic mechanism enabling cells to dynamically modulate poly(A) isoforms in response to stress while shedding light on the interplay between DNA methylation, transcription factor binding, and chromatin looping.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100084"},"PeriodicalIF":3.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141512","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}
P Gopikrishnan, Roshin Anie Jose, John Abraham, D K Deepak Mathew, K Raji, N P Sakkariya Ibrahim, P Valavan, T S Nisha, Varun Vijayan
{"title":"The effect of heat stress on the physiological parameters and blood biomarkers in Malabari goats.","authors":"P Gopikrishnan, Roshin Anie Jose, John Abraham, D K Deepak Mathew, K Raji, N P Sakkariya Ibrahim, P Valavan, T S Nisha, Varun Vijayan","doi":"10.1016/j.cstres.2025.100082","DOIUrl":"https://doi.org/10.1016/j.cstres.2025.100082","url":null,"abstract":"<p><p>Heat stress poses a great challenge to livestock health, productivity and adaptability especially in tropical climates. Under the scenario of climate change and rising global temperatures, understanding the physiological, haematological, biochemical and molecular responses to heat stress in livestock is crucial. The present study was designed to assess the physiological, haematological, biochemical and molecular responses to heat stress in Malabari goat breed, originated in South India. The gene expression patterns of heat shock proteins (HSP) HSP27, HSP70 and HSP90 were also assessed. Twelve adult does were divided into grazing and non-grazing groups and the study was conducted for two months during winter and summer seasons. Higher ambient temperature and solar radiation were recorded in summer with a higher temperature humidity index (THI) indicating heat stress (77.50±0.27). Significant increases in respiratory rate, rectal temperature, and surface body temperature were detected in goats indicating that the animals were under physiological stress especially during the summer season. The seasonal changes in theses parameters differed between grazing and non-grazing goats. The pulse rate was significantly influenced by both season and grazing patterns. The haematological parameters like monocyte count, mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC) in Malabari goats were mainly influenced by seasonal variations. However, the seasonal shift in haematocrit (HCT) levels was not uniform across the grazing strategies. Biochemical parameters, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels exhibited significant seasonal variations. Additionally, ALT and total protein concentrations differed between the grazing groups. The impact of seasonal variations on glucose concentration varied between grazing and non-grazing goats. HSP70 and HSP90 gene expression increased over the summer, but HSP27 gene expression did not show any difference in our study. As a stress response mechanism, these results show that Malabari goats experience physiological, hematological, biochemical and molecular changes in response to heat stress, including the upregulation of important heat shock proteins.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"100082"},"PeriodicalIF":3.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076224","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}
Gaozhong Sun , Yanzhe Wang , Kewei Ni , Jian Shen , Dongdong Liu , Haitao Wang
{"title":"COL5A2-mediated endoplasmic reticulum stress promotes macrophage M2 polarization in lung adenocarcinoma","authors":"Gaozhong Sun , Yanzhe Wang , Kewei Ni , Jian Shen , Dongdong Liu , Haitao Wang","doi":"10.1016/j.cstres.2025.100081","DOIUrl":"10.1016/j.cstres.2025.100081","url":null,"abstract":"<div><div>Collagen is a major component of the extracellular matrix. Type V collagen α2 (COL5A2), a common collagen subtype, plays a crucial role in immune regulation, angiogenesis, and tumor metastasis. It is highly expressed in various malignancies, but its mechanistic role in lung adenocarcinoma (LUAD) remains unclear. Therefore, this study aims to investigate the regulatory mechanism of COL5A2 in mediating macrophage M2 polarization in LUAD. We analyzed COL5A2 expression in LUAD samples from the TCGA-LUAD database. Using GSEA, we sought to identify the signaling pathways influenced by COL5A2 expression. mRNA levels of COL5A2, TGF-β, and IL-10 were quantified via qPCR analysis, and protein levels of COL5A2, PD-L1, and endoplasmic reticulum (ER) stress-related proteins (GRP78 and CHOP) were assessed using western blot. Immunofluorescence assay detected the fluorescence signal of CD206 in M2 macrophages, while flow cytometry assessed the M2 macrophage marker CD206, flow cytometry determined the positive rates for CD68 and CD206. Exosome uptake by macrophages was examined using confocal microscopy, and cell viability was measured with cell counting kit-8. KI-67 protein expression was analyzed by immunohistochemistry, and in vivo assays in animals verified our findings. The results showed that elevated COL5A2 levels in LUAD were found to correlate with a shift toward M2 macrophage polarization. Specifically, the overexpression of COL5A2 amplified ER stress, which led to an increase in PD-L1 exosome release and macrophage uptake of PD-L1, thus driving the M2 phenotype. In conclusion, COL5A2 in LUAD induces ER stress, which is associated with elevated PD-L1 exosome secretion and macrophage PD-L1 uptake, ramping up M2 polarization in macrophages.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100081"},"PeriodicalIF":3.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965775","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":"JNK signaling dominance in hyperthermia","authors":"Atsushi Enomoto , Takemichi Fukasawa","doi":"10.1016/j.cstres.2025.100080","DOIUrl":"10.1016/j.cstres.2025.100080","url":null,"abstract":"<div><div>Hyperthermia is a promising anticancer treatment that induces heat stress, stimulating various signal transduction pathways to maintain cellular homeostasis. Mitogen-activated protein kinases (MAPKs) link various extracellular stimuli with cytoplasmic and nuclear mediators through a three-tiered cascade of kinases, including MAPKs, MAP2Ks, and MAP3Ks. In mammals, three major groups of MAPKs have been characterized: extracellular signal-regulated protein kinases (ERK), p38 MAPKs, and c-Jun NH<sub>2</sub>-terminal kinases (JNK). Each group of MAPKs is heat-activated and exhibits distinct biological functions. However, the differences and advantages of the regulation of each MAPK with temperature changes remain unknown. Our results demonstrated that JNK was activated in a temperature-dependent manner, with degradation of the JNK phosphatases despite transient phosphorylation of ERK with induction of the ERK phosphatases. This brief insight deepens our current understanding of the deregulation of the ERK and JNK cascades in hyperthermia.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100080"},"PeriodicalIF":3.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955159","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}
Kevin Daupin , Véronique Dubreuil , Johanna K. Ahlskog , Annalisa Verrico , Lea Sistonen , Valérie Mezger , Aurélie de Thonel
{"title":"HDAC1 is involved in the destabilization of the HSF2 protein under nonstress and stress conditions","authors":"Kevin Daupin , Véronique Dubreuil , Johanna K. Ahlskog , Annalisa Verrico , Lea Sistonen , Valérie Mezger , Aurélie de Thonel","doi":"10.1016/j.cstres.2025.100079","DOIUrl":"10.1016/j.cstres.2025.100079","url":null,"abstract":"<div><div>Heat shock transcription factors 1 and 2 (HSF1 and HSF2) are the major regulators of the cellular response to stressors, notably to heat shock and to oxidative stress. HSF1 and HSF2 are also important contributors in devastating human pathologies like cancer, neurodegenerative disorders, and neurodevelopmental disorders. Under physiological conditions, nuclear HSF2 is detected in only a few cell types in human adult healthy tissues. In contrast, HSF2 protein levels are elevated at some embryonic stages, but greatly vary among cell types and fluctuate during the cell cycle in diverse cell lines. HSF2 is a short-lived protein whose rapid turnover is controlled by the components of the ubiquitin-proteasome degradation pathway, and the stabilization of HSF2 constitutes an important step that regulates its DNA-binding activity and mediates its roles in nonstress, physiological processes. The control of HSF2 abundancy is therefore critical for its regulatory roles in stress responses as well as under physiological conditions. In this regard, the fetal brain cortex is a singular context where HSF2 is strikingly abundant, exhibits constitutive DNA-binding activity and, by controlling a specific repertoire of target genes that play important roles at multiple steps of neurodevelopment. Recently, we showed that the lysine-acetyl-transferases CBP and EP300 stabilize the HSF2 protein under both unstressed and stressed conditions and that the integrity of the CBP/EP300-HSF2 pathway is important for neurodevelopment. Here, we identify the lysine-deacetylase histone-deacetylase 1 (HDAC1) as a novel HSF2-interacting protein partner and regulator, in an unbiased manner, and show that HSF2 and HDAC1 localize in the same cells in the developing mouse cortex and human cerebral organoids. We also demonstrate that HDAC1, through its catalytic activity, destabilizes the HSF2 protein, through HSF2 poly-ubiquitination and proteasomal degradation, under both normal and stress conditions.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 4","pages":"Article 100079"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968527","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}
Ting Liu , Lu Li , Meixia Meng , Ming Gao , Jinhua Zhang , Yuan Zhang , Yukun Gan , Yangjie Dang , Limin Liu
{"title":"The protective role of the IRE1α/XBP1 signaling cascade in autophagy during ischemic stress and acute kidney injury","authors":"Ting Liu , Lu Li , Meixia Meng , Ming Gao , Jinhua Zhang , Yuan Zhang , Yukun Gan , Yangjie Dang , Limin Liu","doi":"10.1016/j.cstres.2025.02.004","DOIUrl":"10.1016/j.cstres.2025.02.004","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a common and serious complication resulting from ischemia and hypoxia, leading to significant morbidity and mortality. Autophagy, a cellular process for degrading damaged components, plays a crucial role in kidney protection. The unfolded protein response pathway, particularly the inositol-requiring enzyme 1 (IRE1α)/X-box binding protein 1 (XBP1) signaling cascade, is implicated in regulating autophagy during renal stress. To elucidate the role of the IRE1α/XBP1 pathway in autophagy during hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) injury, renal tubular epithelial cells (TECs) were subjected to H/R conditions, and I/R injury was induced in mice. The expression of autophagy-related and endoplasmic reticulum stress markers (IRE1α, XBP1, GRP78, Beclin1, LC3I/II, and P62) was assessed using immunoblotting and immunofluorescence. Additionally, the impacts of IRE1α overexpression and pharmacological agents, IXA6 (IRE1α agonist), and STF083010 (IRE1α inhibitor) were evaluated on autophagy regulation. H/R injury significantly increased mitochondrial damage and the formation of autophagic vesicles in TECs. Key markers of autophagy were elevated in response to H/R and I/R injury, with activation of the IRE1α/XBP1 pathway enhancing autophagic processes. IXA6 treatment improved renal function and reduced injury in I/R models, while STF083010 exacerbated kidney damage. The IRE1α/XBP1 pathway is a critical regulator of autophagy in renal TECs during ischemic stress, suggesting that pharmacological modulation of this pathway may offer therapeutic avenues for preventing or mitigating AKI. Enhanced understanding of these mechanisms may lead to novel strategies for kidney disease management.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"30 3","pages":"Pages 160-171"},"PeriodicalIF":3.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472193","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}