{"title":"The heat shock factor code: Specifying a diversity of transcriptional regulatory programs broadly promoting stress resilience","authors":"Milad J. Alasady , Marc L. Mendillo","doi":"10.1016/j.cstres.2024.10.006","DOIUrl":"10.1016/j.cstres.2024.10.006","url":null,"abstract":"<div><div>The heat shock factor (HSF) family of transcription factors drives gene expression programs that maintain cytosolic protein homeostasis (proteostasis) in response to a vast array of physiological and exogenous stressors. The importance of HSF function has been demonstrated in numerous physiological and pathological contexts. Evidence accumulating over the last two decades has revealed that the regulatory programs driven by the HSF family can vary dramatically depending on the context in which it is activated. To broadly maintain proteostasis across these contexts, HSFs must bind and appropriately regulate the correct target genes at the correct time. Here, we discuss “the heat shock factor code”—our current understanding of how human cells use HSF paralog diversification and interplay, local concentration, post-translational modifications, and interactions with other proteins to enable the functional plasticity required for cellular resilience across a multitude of environments.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 6","pages":"Pages 735-749"},"PeriodicalIF":3.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495872","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}
Brenda A. Schilke , Thomas Ziegelhoffer , Przemyslaw Domanski , Jaroslaw Marszalek , Bartlomiej Tomiczek , Elizabeth A. Craig
{"title":"Functional similarities and differences among subunits of the nascent polypeptide-associated complex (NAC) of Saccharomyces cerevisiae","authors":"Brenda A. Schilke , Thomas Ziegelhoffer , Przemyslaw Domanski , Jaroslaw Marszalek , Bartlomiej Tomiczek , Elizabeth A. Craig","doi":"10.1016/j.cstres.2024.10.004","DOIUrl":"10.1016/j.cstres.2024.10.004","url":null,"abstract":"<div><div>Protein factors bind ribosomes near the tunnel exit, facilitating protein trafficking and folding. In eukaryotes, the heterodimeric nascent polypeptide-associated complex (NAC) is the most abundant—equimolar to ribosomes. <em>Saccharomyces cerevisiae</em> has a minor β-type subunit (Nacβ2) in addition to abundant Nacβ1, and therefore two NAC heterodimers, α/β1 and α/β12. The additional beta NAC gene arose at the time of the whole genome duplication that occurred in the <em>S. cerevisiae</em> lineage. Nacβ2 has been implicated in regulating the fate of messenger RNA encoding ribosomal protein Rpl4 during translation <em>via</em> its interaction with the Caf130 subunit of the regulatory CCR4-Not complex. We found that Nacβ2 residues just C-terminal to the globular domain are required for its interaction with Caf130 and its negative effect on the growth of cells lacking Acl4, the specialized chaperone for Rpl4. Substitution of these Nacβ2 residues at homologous positions in Nacβ1 results in a chimeric protein that interacts with Caf130 and slows the growth of ∆<em>acl4</em> cells lacking Nacβ2. Furthermore, alteration of residues in the N-terminus of Nacβ2 or chimeric Nacβ1 previously shown to affect ribosome binding overcomes the growth defect of ∆<em>acl4</em>. Our results are consistent with a model in which Nacβ2’s ribosome association <em>per se</em> or its precise positioning is necessary for productive recruitment of CCR4-Not <em>via</em> its interaction with the Caf130 subunit to drive Rpl4 messenger RNA degradation.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 6","pages":"Pages 721-734"},"PeriodicalIF":3.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459007","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":"In memoriam James S. Clegg (1933–2024)","authors":"Lawrence E. Hightower","doi":"10.1016/j.cstres.2024.10.003","DOIUrl":"10.1016/j.cstres.2024.10.003","url":null,"abstract":"","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 6","pages":"Pages 718-719"},"PeriodicalIF":3.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459008","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}
Rebecca A. Sager , Sarah J. Backe , Jennifer Heritz , Mark R. Woodford , Dimitra Bourboulia , Mehdi Mollapour
{"title":"Flow cytometry FRET reveals post-translational modifications drive Protein Phosphatase-5 conformational changes in mammalian cells","authors":"Rebecca A. Sager , Sarah J. Backe , Jennifer Heritz , Mark R. Woodford , Dimitra Bourboulia , Mehdi Mollapour","doi":"10.1016/j.cstres.2024.10.002","DOIUrl":"10.1016/j.cstres.2024.10.002","url":null,"abstract":"<div><div>The serine/threonine Protein Phosphatase-5 (PP5) plays an essential role in regulating hormone and stress-induced signaling networks as well as extrinsic apoptotic pathways in cells. Unlike other Protein Phosphatases, PP5 possesses both regulatory and catalytic domains, and its function is further modulated through post-translational modifications (PTMs). PP5 contains a tetratricopeptide repeat (TPR) domain, which usually inhibits its phosphatase activity by blocking the active site (closed conformation). Certain activators bind to the PP5–TPR domain, alleviating this inhibition and allowing the catalytic domain to adopt an active (open) conformation. While this mechanism has been proposed based on structural and biophysical studies, PP5 conformational changes and activity have yet to be observed in cells. Here, we designed and developed a flow cytometry-based fluorescence resonance energy transfer (FC-FRET) method, enabling real-time observation of PP5 autoinhibition and activation within live mammalian cells. By quantifying FRET efficiency using sensitized emission, we established a standardized and adaptable data acquisition workflow. Our findings revealed that, in a cellular context, PP5 exists in multiple conformational states, none of which alone fully predicts its activity. Additionally, we have demonstrated that PTMs such as phosphorylation and SUMOylation impact PP5 conformational changes, representing a significant advancement in our understanding of its regulatory mechanisms.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 6","pages":"Pages 709-717"},"PeriodicalIF":3.3,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459006","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}
Chuanlan Liu , Xiaomu Zhu , Erbu Aga , Wai Ming Tse , Kathy Wai Gaun Tse , Yanyong Liu , Bengui Ye
{"title":"Ebeiedinone and peimisine inhibit cigarette smoke extract-induced oxidative stress injury and apoptosis in BEAS-2B cells","authors":"Chuanlan Liu , Xiaomu Zhu , Erbu Aga , Wai Ming Tse , Kathy Wai Gaun Tse , Yanyong Liu , Bengui Ye","doi":"10.1016/j.cstres.2024.10.001","DOIUrl":"10.1016/j.cstres.2024.10.001","url":null,"abstract":"<div><div>Ebeiedinone and peimisine are the major active ingredients of Fritillariae Cirrhosae Bulbus. In this study, we looked at how these two forms of isosteroidal alkaloids protect human bronchial epithelial BEAS-2B cells from oxidative stress and apoptosis caused by cigarette smoke extract (CSE). First, the cytotoxicity was determined using the CCK8 assay, and an oxidative stress model was established. Then the antioxidative stress activity and mechanism were investigated by ELISA, flow cytometry, and Western blotting. By the CCK-8 assay, exposure to CSE (20%, 40%, and 100%) reduced the viability of BEAB-2S cells. The flow cytometry findings indicated that CSE-induced production of ROS (0.5% to maximum) and treatments with 10 μM ebeiedinone and 20 μM peimisine attenuated the production of ROS. The western blot assay results indicate that ebeiedinone and peimisine reduce CSE-induced oxidative stress, DNA damage, apoptosis, and autophagy dysregulation by inhibiting ROS, upregulating SOD and GSH/GSSG, and downregulating MDA, 4-HNE, and 8-OHdG through the NRF2/KEAP1 and JNK/MAPK-dependent pathways, thereby delaying the pathological progression of COPD caused by CS.Our data suggest that CSE causes oxidative stress, DNA damage, and apoptosis in BEAS-2B cells, as well as the progression of COPD. Ebeiedinone and peimisine fight CS-induced COPD by suppressing autophagy deregulation and apoptosis.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 6","pages":"Pages 697-708"},"PeriodicalIF":3.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380110","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 mechanism and therapeutic strategies in doxorubicin-induced cardiotoxicity: Role of programmed cell death","authors":"Yanzhao Li , Jing Yan , Pingzhen Yang","doi":"10.1016/j.cstres.2024.09.001","DOIUrl":"10.1016/j.cstres.2024.09.001","url":null,"abstract":"<div><div>Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that programmed cell death plays a significant role in DOX-induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, oxidative stress, inflammation, and mitochondrial dysfunction are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathways of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including sirtuin deacetylase (silent information regulator 2 [Sir2]) 1 (SIRT1)/nuclear factor erythroid 2-related factor 2, SIRT1/Klotho, SIRT1/Recombinant Sestrin 2, adenosine monophosphate-activated protein kinase, AKT, and peroxisome proliferator-activated receptor. Heat shock proteins function as chaperones, which play an important role in various stressful situations, especially in the heart. Thus, some of heat shock proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 5","pages":"Pages 666-680"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342430","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}
Xinxu Min , Yunfan Li , Xiaojin Zhang , Shijiang Liu , Ziyang Chen , Qian Mao , Qiuyue Kong , Zhaohe Wang , Li Liu , Zhengnian Ding
{"title":"HSPA12A stimulates “Smurf1-Hif1α-aerobic glycolysis” axis to promote proliferation of renal tubular epithelial cells after hypoxia/reoxygenation injury","authors":"Xinxu Min , Yunfan Li , Xiaojin Zhang , Shijiang Liu , Ziyang Chen , Qian Mao , Qiuyue Kong , Zhaohe Wang , Li Liu , Zhengnian Ding","doi":"10.1016/j.cstres.2024.09.002","DOIUrl":"10.1016/j.cstres.2024.09.002","url":null,"abstract":"<div><div>Proliferation of renal tubular epithelial cells (TECs) is critical for the recovery after kidney ischemia/reperfusion (KI/R). However, there is still a lack of ideal therapies for promoting TEC proliferation. Heat shock protein A12A (HSPA12A) shows abundant expression in kidney in our previous studies. To investigate the role of HSPA12A in TEC proliferation after KI/R, an <em>in vitro</em> KI/R model was simulated by hypoxia (12 h) and reoxygenation (12 h) in human kidney tubular epithelial HK-2 cells. We found that, when hypoxia/reoxygenation (H/R) triggered HK-2 cell injury, HSPA12A expression was downregulated, and extracellular lactate, the readout of glycolysis, was also decreased. Loss and gain of functional studies showed that HSPA12A did not change cell viability after hypoxia but increased cell proliferation as well as glycolytic flux of HK-2 cells after H/R. When blocking glycolysis by 2-deoxy-D-glucose or oxamate, the HSPA12A promoted HK-2 cell proliferation was also abolished. Further analysis revealed that HSPA12A overexpression increased hypoxia-inducible factor 1α (Hif1α) protein expression and nuclear localization in HK-2 cells in response to H/R, whereas HSPA12A knockdown showed the opposite effects. Notably, pharmacological inhibition of Hif1α with YC-1 reversed the HSPA12A-induced increases of both glycolytic flux and proliferation of H/R HK-2 cells. Moreover, the HSPA12A increased Hif1α protein expression was not <em>via</em> upregulating its transcription but through increasing its protein stability in a Smurf1-dependent manner. The findings indicate that HSPA12A might serve as a promising target for TEC proliferation to help recovery after KI/R.</div></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 5","pages":"Pages 681-695"},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342429","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}
Cigdem Cicek , Pelin Telkoparan-Akillilar , Semra Sertyel , Cumhur Bilgi , Osman Denizhan Ozgun
{"title":"Investigation of endoplasmic reticulum stress-regulated chaperones as biomarkers in idiopathic nonobstructive azoospermia","authors":"Cigdem Cicek , Pelin Telkoparan-Akillilar , Semra Sertyel , Cumhur Bilgi , Osman Denizhan Ozgun","doi":"10.1016/j.cstres.2024.08.004","DOIUrl":"10.1016/j.cstres.2024.08.004","url":null,"abstract":"<div><p>Azoospermia is a condition in which sperm cells are completely absent in a male's ejaculate. Typically, sperm production occurs in the testes and is regulated by a complex series of cellular and molecular interactions. Endoplasmic reticulum (ER) stress arises when there is a deviation from or damage to the normal functions of the ER within cells. In response to this stress, a cascade of response mechanisms is activated to regulate ER stress within cells. This study aims to investigate the role of ER stress-regulated chaperones as potential biomarkers in male infertility. ER stress associated with azoospermia can manifest in cells such as spermatogonia in the testes and can impact sperm production. As a result of ER stress, the expression and activity of a variety of proteins within cells can be altered. Among these proteins are chaperone proteins that regulate the ER stress response. The sample size was calculated to be a minimum of 36 patients in each group. In this preliminary study, we measured and compared serum levels of protein disulfide-isomerase A1, protein disulfide-isomerase A3 (PDIA3), mesencephalic astrocyte-derived neurotrophic factor (MANF), glucose regulatory protein 78 (GRP78), clusterin (CLU), calreticulin (CRT), and calnexin (CNX) between male subjects with idiopathic nonobstructive azoospermia and a control group of noninfertile males. Serum PDIA1 (<em>P</em> = 0.0004), MANF (<em>P</em> = 0.018), PDIA3 (<em>P</em> < 0.0001), GRP78 (<em>P</em> = 0.0027), and CRT (<em>P</em> = 0.0009) levels were higher in the infertile group compared to the control. In summary, this study presents novel findings in a cohort of male infertile patients, emphasizing the significance of incorporating diverse biomarkers. It underscores the promising role of ER stress-regulated proteins as potential serum indicators for male infertility. By elucidating the impact of ER stress on spermatogenic cells, the research illuminates the maintenance or disruption of cellular health. A deeper understanding of these results could open the door to novel treatment approaches for reproductive conditions, including azoospermia.</p></div>","PeriodicalId":9684,"journal":{"name":"Cell Stress & Chaperones","volume":"29 5","pages":"Pages 654-665"},"PeriodicalIF":3.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1355814524001159/pdfft?md5=84713038e695926d42b7593588ba33b6&pid=1-s2.0-S1355814524001159-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139422","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}