Cell Stress & Chaperones最新文献

{"title":"Hsp90: Bringing It All Together.","authors":"Georgios Ioannis Karras, Giorgio Colombo, Andrea N Kravats","doi":"10.1016/j.cstres.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.cstres.2025.01.002","url":null,"abstract":"<p><p>Heat-shock protein 90 (Hsp90) is an ancient and multifaceted protein-folding machine essential for most organisms. The past 40 years have uncovered remarkable complexity in the regulation and function of Hsp90, which dwarfs in sophistication most other machines in the cell. Here, we propose four analogies to illustrate Hsp90's sophistication: a multifunctional Swiss Army knife, an automobile engine and its controls, a switchboard acting as a hub and directing signals, and an orchestra conductor setting the tempo of a symphony. Although each of these analogies represents some key Hsp90 activities, none of them captures the entirety of Hsp90's complexity. Together, these roles enable Hsp90 to support both homeostasis and differentiation, both cellular stability and adaptability. At the 11th International Conference on the Hsp90 Chaperone Machine, the consensus was that to understand this major guardian of proteostasis, we need to study how the many facets of Hsp90's function influence each other. We hope that these analogies will help to conceptually integrate the many roles of Hsp90 in proteostasis and help the field develop the practical applications of Hsp90 modulators.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073987","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":"LARGE SCALE ENERGY DECOMPOSITION FOR THE ANALYSIS OF PROTEIN STABILITY.","authors":"Samman Mansoor, Elena Frasnetti, Ivan Cucchi, Andrea Magni, Giorgio Bonollo, Stefano A Serapian, Luca F Pavarino, Giorgio Colombo","doi":"10.1016/j.cstres.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.cstres.2025.01.001","url":null,"abstract":"<p><p>To carry out their functions in cells, proteins are required to fold into well-defined three-dimensional conformations. The stability of the folded state dictates several aspects of protein life, such as their evolution, interactions, and selection of structures that are ultimately linked to activity. Sequence mutations may change the stability profile and consequently impact structure and function. Here we use a simple, molecular dynamics-based energy decomposition approach to map the response to mutations of each aminoacid in the sequences of a set of five test proteins with different lengths, folds, and topologies. To this end we make use of the decomposition of the residue-pair nonbonded energy matrix. We show that parameters obtained from this analysis, namely the main eigenvalue reporting on the most stabilizing energy contributions and the spectral gap of the matrix (ENergy Gap (ENG)), reproduce experimentally determined stability trends. At the same time, our approach identifies the residue-pair couplings that play key roles in defining the 3D properties of a certain fold. We discuss the relevance of these results for the design of protein mutants for experimental applications and the possibility for our energy decomposition approach to complement other computational and experimental analyses of conformational stability. Keywords.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063936","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":"Secreted extracellular heat shock protein gp96 and inflammatory cytokines are markers of severe malaria outcome.","authors":"Fatou Thiam, Djibaba Djoumoi, Mame Ndew Mbaye, Aminata Fall, Abou Abdallah Malick Diouara, Mamadou Diop, Cheikh Momar Nguer, Babacar Mbengue, Gora Diop, Evelyne Kohli, Alioune Dieye","doi":"10.1016/j.cstres.2024.12.004","DOIUrl":"10.1016/j.cstres.2024.12.004","url":null,"abstract":"<p><p>Malaria caused by Plasmodium spp., is a major public health issue in sub-Saharan Africa. The fight against malaria has stalled due to increasing resistance to treatments and insecticides. There is an urgent need to focus on new therapeutic targets to combat malaria effectively. This study aimed to measure the secreted heat shock protein gp96 levels in both malaria patients and controls. Indeed, gp96 plays a crucial role in parasite survival within the host and in establishing a successful infection. Therefore, gp96 could be a promising target for antimalarial drugs. In our study, we included 60 malaria patients, 30 with severe malaria (SM) and 30 with uncomplicated malaria (UM). Additionally, 28 controls were included. Using the ELISA method, we measured gp96 levels in the participants' blood samples. We then used the Mann-Whitney or analyse of variance tests to calculate descriptive statistics and determined the correlation between gp96 level and parasitemia using Spearman's rank correlation test. The study found that gp96 levels in the plasma significantly increased in malaria patients (23.86 ng/mL) compared to control (5.88 ng/mL), with a P < 0.0001. Interestingly, there was a significant difference between SM (27.56 ng/mL) and UM (13.9 ng/mL), with a P-value of 0.001. These findings are accompanied by significantly higher parasitemia and elevated proinflammatory cytokines such as IL-17A and IL-1β levels in SM patients compared to UM and controls. Furthermore, there was no significant positive correlation between gp96 levels and parasitemia/proinflammatory cytokines. Our research has revealed, for the first time, that individuals with SM have significantly higher levels of gp96 in the context of high parasitemia and proinflammatory cytokines. Our preliminary results will be taken further to evaluate gp96 as a valuable biomarker for the diagnosis of SM and a potential target for antimalarial drug discovery.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"48-56"},"PeriodicalIF":3.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HSP mRNA sequences and their expression under different thermal oscillation patterns and heat stress in two populations of Nodipecten subnodosus.","authors":"Axel Bonesteve, Salvador E Lluch-Cota, Maria Teresa Sicard, Ilie S Racotta, Miguel A Tripp-Valdez, Liliana Rojo-Arreola","doi":"10.1016/j.cstres.2024.12.002","DOIUrl":"10.1016/j.cstres.2024.12.002","url":null,"abstract":"<p><p>Understanding the molecular mechanisms underlying thermal acclimation and heat shock responses in marine ectotherms is critical for assessing their adaptive capacity in the context of climate change and climate extremes. This study examines the expression dynamics of heat shock proteins (HSPs) in the scallop Nodipecten subnodosus, shedding light on their role in thermal adaptation. Our analysis revealed the presence of several conserved functional signatures in N. subnodosus HSPs deduced amino acid sequences. Comparative gene expression profiling between two populations of N. subnodosus, maintained for 15 days under constant and oscillatory thermal regimes and then exposed to acute heat stress, revealed conserved adaptive traits. The heat-inducible nature of N. subnodosus HSP70 (HSPA8) gene expression highlights its potential as a stress marker, in contrast to its human homolog, which is constitutively expressed. Furthermore, the identification of HSP90 (HSPC3) and its overexpression during acute heat stress underscores its critical role in initiating a protective stress response. Population-specific responses in the magnitude of gene expression were observed; however, both populations exhibited similar overall patterns of HSP induction, suggesting a shared adaptive response mechanism. This study also elucidated the diversity and expansion of members of the HSP70 family members, specifically the HSPA12 subfamily, in N. subnodosus. This characteristic, previously observed in other bivalves, underscores the role of HSPA12 in environmental adaptation, providing molecular plasticity to withstand varying environmental pressures. These findings offer valuable insights into the molecular basis of thermal adaptation in N. subnodosus, highlighting the importance of HSPs in coping with environmental stochasticity under climate change scenarios.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"33-47"},"PeriodicalIF":3.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FKBP51 overexpression in the corticolimbic system stabilizes circadian rhythms.","authors":"Niat T Gebru, David Beaulieu-Abdelahad, Danielle Gulick, Laura J Blair","doi":"10.1016/j.cstres.2024.12.003","DOIUrl":"10.1016/j.cstres.2024.12.003","url":null,"abstract":"<p><p>Circadian rhythm disruptions have been associated with a wide range of health issues and complications, including an increased risk of circadian rhythm sleep disorders (CRSDs). CRSDs are common among individuals who have been through a traumatic event, particularly in those who have post-traumatic stress disorder (PTSD). Allelic variations in the gene encoding for FK506-binding protein 51 (FKBP51) can increase the susceptibility for PTSD and other stress-related disorders following trauma. At least one of these variants increases the levels of FKBP51 following stress through a glucocorticoid receptor-mediated process. Here, we used a mouse model that overexpresses human FKBP51 throughout the forebrain, rTgFKBP5, to investigate if elevated FKBP51 contributes to circadian rhythm disruption. Surprisingly, our findings indicate a greater rhythm amplitude and decreased rhythm fragmentation in rTgFKBP5 mice, particularly females, compared to controls. Female rTgFKBP5 mice also showed higher corticosterone levels basally and following stress exposure. Overall, this study associates FKBP51 overexpression with beneficial circadian rhythm outcomes.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"22-32"},"PeriodicalIF":3.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular response of canine testis to GnRH agonist: Insights into AR, HIF-1α, and HSPs expression during arrest and recovery of spermatogenesis.","authors":"Anastasiia Vasetska, Eva-Maria Packeiser, Hanna Körber, Selim Aslan, Serhan Ay, Murat Findik, Firdevs Binli, Murat Selçuk, Christelle Speiser-Fontaine, Sandra Goericke-Pesch","doi":"10.1016/j.cstres.2024.11.007","DOIUrl":"10.1016/j.cstres.2024.11.007","url":null,"abstract":"<p><p>Slow-release gonadotropin-releasing hormone (GnRH) agonist implants are frequently used for contraception in male dogs. Although the effects are fully reversible, there is still concern about the safety of the implant's mode of action. Addressing this, we investigated cellular stress and androgen receptor (AR) signaling during downregulation and recovery. Testicular tissues were sampled from dogs castrated at different time points after GnRH implant removal and compared with untreated controls. AR, hypoxia-inducible factor 1 (HIF1A), heat shock proteins heat shock protein 72 (HSP72), heat shock protein 73 (heat shock cognate, HSPA8) (HSP73), heat shock protein A2 (HSPA2), heat shock protein 90 alpha (inducible isoform) (HSP90AA1), and heat shock protein 90 beta (constitutive isoform) (HSP90AB1) were investigated by quantitative real-time polymerase chain reaction and AR, HSP72, HSP73, and HSP90 immunohistochemically. While AR, HIF1A, and HSP70 were upregulated at gene expression level, HSPA8, HSPA2, and HSP90AA1 expression were downregulated during spermatogenic arrest; HSP90AB1 expression did not change. Immunohistochemistry verified AR-expression in Sertoli, peritubular, and Leydig cells, occasionally also in spermatogonia. Stress-inducible HSP72 was occasionally detected, while constitutive HSP73 and HSP90 were abundantly expressed by germ cells. Our results were similar to studies on seasonal breeders such as pine voles, geese, fish, and soft-shelled turtles. Accordingly, GnRH implants did not impose additional cellular stress on testicular cells when compared with natural recrudescence. Since comparative data on HIF1α are scarce, we cannot draw conclusions about hypoxic conditions.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"9-21"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceapin-A7 suppresses the protective effects of Octreotide in human and bovine lung endothelial cells.","authors":"Saikat Fakir, Madan Sigdel, Md Matiur Rahman Sarker, Joy T Folahan, Nektarios Barabutis","doi":"10.1016/j.cstres.2024.12.001","DOIUrl":"10.1016/j.cstres.2024.12.001","url":null,"abstract":"<p><p>Endothelial injury can be the cause and consequence of severe inflammation and injury. Synthetic somatostatin analogs-which suppress Growth Hormone-are clinically-approved drugs associated with anti-inflammatory activities. In the present study, we suggest that the protective activities of Octreotide in human and bovine endothelial cells are mitigated by Ceapin-A7, which is an activating transcription factor 6 inhibitor. To study endothelial function, we assessed protein expression levels of key cytoskeletal proteins, as well as paracellular permeability. To evaluate inflammation, we measured factors that promote vascular leak, as well as reactive oxygen species generation. Collectively, our study supports the involvement of activating transcription factor 6 in the protective effects of Octreotide in endothelial barrier function.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"1-8"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: From molecular mechanisms to therapeutic applications.","authors":"Yifan Lu, Jing Zhou, Hong Wang, Hua Gao, Eryu Ning, Zhiqiang Shao, Yuefeng Hao, Xing Yang","doi":"10.1016/j.cstres.2024.11.005","DOIUrl":"10.1016/j.cstres.2024.11.005","url":null,"abstract":"<p><p>Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response, ER-associated degradation, and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"805-830"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the FKBP51-Hsp90 complex in Alzheimer's disease: An emerging new drug target.","authors":"Xavier Jeanne, Zsolt Török, László Vigh, Chrisostomos Prodromou","doi":"10.1016/j.cstres.2024.11.006","DOIUrl":"10.1016/j.cstres.2024.11.006","url":null,"abstract":"<p><p>With increasing age comes the inevitable decline in proteostasis, where chaperone and co-chaperone activity becomes imbalanced. These changes lead to global disturbances and pathogenic rewiring of the chaperone system into epichaperones consisting of protein networks that are ultimately dysfunctional. Such imbalances in proteostasis may favor mechanisms that can lead to neurological diseases, such as Alzheimer's disease (AD). Consequently, there has been an increase in research activity toward finding small molecules that can re-balance the chaperone and co-chaperone machinery to counter the effects of disease resulting from old age. The Hsp90 co-chaperone FKBP51 has recently been identified as a protein whose induction not only increases with age but is elevated further in AD cells. Significantly, FKBP51 plays a role in the Hsp90-dependent isomerization of tau, which in turn influences its phosphorylation and susceptibility to aggregation. We hypothesize that FKBP51 is a major player that is able to elicit tauopathy in response to amyloid-beta senile plaques that damage the brain. We propose that elevated FKBP51 levels result in an abnormal FKBP51-Hsp90 activity that alters the normal processing of tau, which manifests as hyperphosphorylation and oligomerization of tau. Thus, the Hsp90-FKBP51 complex is emerging as a drug target against AD. In support of this idea, the structure of the FKBP51-Hsp90 complex was recently described, and significantly, the small-molecule dihydropyridine LA1011 was shown to be able to disrupt the Hsp90-FKBP51 complex. LA1011 was previously shown to effectively prevent neurodegeneration in the APPxPS1 AD transgenic mouse model. This review looks at the role of Hsp90 and its co-chaperones in AD with a focus on FKBP51.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"792-804"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrotinib induces cell death in HER2-positive breast cancer via triggering HSP90-dependent HER2 degradation and ROS/HSF-1-dependent oxidative DNA damage.","authors":"Xiaomin Gao, Xu Guo, Wenbo Yuan, Sunmin Jiang, Zihong Lu, Qing Luo, Yuan Zha, Ling Wang, Shu Li, Ke Wang, Xue Zhu, Ying Yao","doi":"10.1016/j.cstres.2024.11.004","DOIUrl":"10.1016/j.cstres.2024.11.004","url":null,"abstract":"<p><p>HER2-positive breast cancer (HER2+ BC) is distinguished by its poor prognosis, propensity for early onset, and high risk of recurrence and metastasis. Consequently, anti-HER2-targeted therapy has emerged as a principal strategy in the treatment of this form of breast cancer. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor, has brought fresh hope to patients with advanced HER2+ breast cancer. In this study, we conducted a comprehensive exploration of pyrotinib's antitumor mechanism. The in vitro results showed that pyrotinib significantly inhibited SKBR3 cells viability and induced apoptosis by promoting HER2 endocytosis and ubiquitylation, leading to HER2 degradation through the displacement of HSP90 from HER2. Beyond targeting the HER2 signaling pathway, pyrotinib also induced DNA damage, which was mediated by the activation of the reactive oxygen species/heat shock factor 1 signaling pathway and the downregulation of proliferating cell nuclear antigen expression. Furthermore, the in vivo results demonstrated a pronounced anticancer effect of pyrotinib in the SKBR3 xenograft mouse model, concomitant with a reduction in HER2 expression. In summary, our findings provide novel insights into the mechanism of pyrotinib in the treatment of HER2+ BC.</p>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":" ","pages":"777-791"},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}