Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"ATM kinase phosphorylates HSP90 on T297 changing its conformation dynamics and promoting its interaction with HER2 receptor tyrosine kinase","authors":"Giulia Fianco ,&nbsp;Irene Taddei ,&nbsp;Veronica Oropallo ,&nbsp;Claudia Contadini ,&nbsp;Alessandra Ferri ,&nbsp;Laura Coculo ,&nbsp;Stefano A. Serapian ,&nbsp;Giorgio Colombo ,&nbsp;Venturina Stagni ,&nbsp;Daniela Barilà","doi":"10.1016/j.bbamcr.2026.120110","DOIUrl":"10.1016/j.bbamcr.2026.120110","url":null,"abstract":"<div><div>Heat Shock Protein 90 (HSP90) is an essential molecular chaperone whose activity is regulated not only by co-chaperones but also by distinct post-translational modifications. Interestingly, its chaperone activity is essential for the stability of several oncogenes, among which the receptor tyrosine kinase HER2. HER2 is overexpressed in 20–30% of breast and ovarian cancers. Its overexpression triggers proliferative and transforming pathways aberrant activation and therefore frequently correlates with invasive and poor prognostic features, and associates with shorter patient survival. Of note, HSP90 inhibitors have been studied in HER2-positive breast cancer and have shown promising results. Unexpectedly, we previously reported that ATM promotes the interaction of HER2 with HSP90 therefore sustaining HER2 protein stability and tumorigenicity.</div><div>To further investigate the interplay between HER2-HSP90 and ATM, we tested the hypothesis that ATM could phosphorylate HSP90. We confirmed that ATM activation can induce the phosphorylation of HSP90 in HER2 positive breast cancer models. Point mutagenesis showed that T297 is the major site targeted by ATM kinase and importantly the unphosphorylatable mutant HSP90-T297A displays a reduced ability to interact with HER2, and to prevent its ubiquitination and degradation. Consistently, the overexpression of HSP90-T297A impinges on the viability of HER2-overexpressing cells, further supporting a role of this phosphorylation in the modulation of HER2 tumorigenicity. T297 is located in the middle domain of HSP90, a region that is involved in the interaction of HSP90 with clients. Consistently, structural studies indicate that T297 phosphorylation can indeed favor the chaperone's interaction with HER2, further supporting our hypothesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120110"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NSUN2 activated by KLF6 can mediate m5C modification of NCOA4 to enhance ferroptosis of OGD/R-induced SH-SY5Y cells in ischemic stroke","authors":"Genshan Gao ,&nbsp;Yue Xu ,&nbsp;Yao Liu,&nbsp;Shuqing Meng,&nbsp;Nannuan Liu","doi":"10.1016/j.bbamcr.2025.120102","DOIUrl":"10.1016/j.bbamcr.2025.120102","url":null,"abstract":"<div><div>Ischemic stroke (IS) constitutes the majority of stroke cases. Ferroptosis, a non-apoptotic form of programmed cell death, is an essential mechanism of IS. This study aimed to investigate a ferroptosis-related molecular mechanism in IS progression. IS model in vitro was induced by oxygen-glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells. RT-qPCR and Western blotting were performed for detection of NOP2/Sun RNA methyltransferase family member 2 (NSUN2), nuclear receptor coactivator 4 (NCOA4), and Krueppel-like factor 6 (KLF6). Cell functions were assessed by MTT assay, flow cytometry, and enzyme-linked immunosorbent assay. Mitochondrial membrane potential and other ferroptosis indicators were examined using kits. Molecular binding was detected using methylated RNA immunoprecipitation (MeRIP), RIP, dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. IS animal model was established by middle cerebral artery occlusion (MCAO). OGD/R-induced apoptosis, inflammation, and ferroptosis of SH-SY5Y cells were suppressed by NCOA4 knockdown. NSUN2 could promote NCOA4 mRNA stability by mediating 5-methylcytosine (m5C) methylation modification of NCOA4, and YBX1 served as a reader protein. NSUN2 contributed to OGD/R-induced SH-SY5Y cell injury via upregulating NCOA4. KLF6 acted as a transcription factor to activate NSUN2 transcription, and then facilitated nerve injury of OGD/R-induced SH-SY5Y cells. Animal assay showed that silencing NSUN2 inhibited infarct volume, tissue injury, neurological function, and neuroinflammation in MCAO rats. These current findings affirmed that KLF6-activated NSUN2 could contribute to ferroptosis of OGD/R-induced SH-SY5Y cells via inducing NCOA4 m5C modification, providing a novel insight into the mechanism of ferroptosis in IS.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120102"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevotella copri leads to colonic barrier dysfunction via the succinate receptor 1-FoxM1-IL-6 axis","authors":"Rui Li ,&nbsp;Shuang Liu ,&nbsp;Haiyan Zhang ,&nbsp;Xinglin Huang ,&nbsp;Wenchu Qian ,&nbsp;Daobin Han ,&nbsp;Fang Wang ,&nbsp;Zhonghui Feng ,&nbsp;Tongtong Zhang ,&nbsp;Hai Lin ,&nbsp;Haifang Li","doi":"10.1016/j.bbamcr.2025.120099","DOIUrl":"10.1016/j.bbamcr.2025.120099","url":null,"abstract":"<div><div><em>Prevotella copri</em>, a key commensal bacterium in the human gut microbiome, exhibits both positive and negative abundance correlations with various disorders. Although multiple studies have suggested an association between <em>P. copri</em> and intestinal pathologies, the mechanistic basis remains elusive. In this study, we examined <em>P. copri</em>'s effects on colonic physiology in healthy mice, revealing its capacity to compromise intestinal barrier integrity. This was demonstrated through downregulation of colonic tight junction proteins (Occludin and ZO-1) and elevated serum levels of gut permeability markers (LPS and D-LA). We identified succinate as the primary microbial metabolite mediating <em>P. copri</em>'s barrier-disrupting effects, with succinate receptor 1 (SUCNR1) being essential for this pathological process. Notably, both <em>P. copri</em> colonization and succinate administration activated the IL-6-STAT3 signaling pathway, leading to transcriptional suppression of the tight junction-related gene, <em>Occludin</em>. Through mechanistic studies, we identified Forkhead box M1 (FoxM1) as a crucial transcription factor regulating <em>P. copri</em>- or succinate-induced <em>Il-6</em> expression. Clinical relevance was established through human cohort analyses showing significant positive correlations between fecal succinate levels and plasma markers of gut permeability. These findings elucidate a novel mechanistic pathway through which <em>P. copri</em> impairs colonic function, suggesting therapeutic potential in colitis through strategies targeting either <em>P. copri</em> abundance or microbial succinate production.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 3","pages":"Article 120099"},"PeriodicalIF":3.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SPRED2 controls the severity of cisplatin-induced acute kidney injury by inhibiting ERK activation and TNFα production in mice","authors":"Xu Yang ,&nbsp;Jiali He ,&nbsp;Tong Gao ,&nbsp;Masayoshi Fujisawa ,&nbsp;Toshiaki Ohara ,&nbsp;Steven L. Kunkel ,&nbsp;Teizo Yoshimura ,&nbsp;Akihiro Matsukawa","doi":"10.1016/j.bbamcr.2025.120091","DOIUrl":"10.1016/j.bbamcr.2025.120091","url":null,"abstract":"<div><div>Cisplatin is an effective chemotherapeutic agent used to treat solid tumors, but its clinical use is limited by acute kidney injury (AKI), in which ERK signaling plays a crucial role. Here, we investigated whether Sprouty-related EVH1 domain-containing protein 2 (SPRED2), an endogenous inhibitor of the Ras/Raf/ERK pathway, protects against cisplatin-induced AKI. <em>Spred2</em>^{<em>−/−</em>} mice showed more severe renal injury and stronger ERK activation than wild-type (WT) mice, whereas pretreatment with the MEK inhibitor U0126 markedly attenuated the injury. In HK-2 cells (proximal tubular cells), SPRED2 knockdown enhanced cisplatin-induced apoptosis and caspase-3 activation, accompanied by decreased Bcl-2 expression. <em>Spred2</em>^{<em>−/−</em>} kidneys displayed increased macrophage infiltration and elevated <em>Tnfα</em>, <em>Il1b</em>, and <em>Ccl2</em> expression. Neutralization of TNFα with anti-TNFα antibody ameliorated renal injury and reduced the levels of <em>Il1b</em> and <em>Ccl2</em> mRNA in <em>Spred2</em>^{<em>−/−</em>} mice. In vitro, TNFα slightly decreased the viability of control and SPRED2 knockdown HK-2 cells without cisplatin treatment, but the decreased viability was augmented in SPRED2 knockdown cells by cisplatin. Immunohistochemistry revealed that macrophages were the predominant TNFα-positive cell population. Bone marrow–derived macrophages from <em>Spred2</em>^{<em>−/−</em>} mice produced higher levels of TNFα in response to cisplatin compared with control cells, and this increase was markedly suppressed by U0126.</div><div>These findings indicate that endogenous SPRED2 protects kidneys from cisplatin-induced AKI by limiting ERK activation, tubular apoptosis, and TNFα-mediated inflammation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120091"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the involvement of tumor-secreted factors in the inhibition of muscle differentiation","authors":"Miranda van der Ende ,&nbsp;Xiaolin Li ,&nbsp;Mieke Poland ,&nbsp;Fleur Jansen ,&nbsp;Jocelijn Meijerink ,&nbsp;Jaap Keijer ,&nbsp;Renger F. Witkamp ,&nbsp;Sander Grefte ,&nbsp;Klaske van Norren","doi":"10.1016/j.bbamcr.2025.120093","DOIUrl":"10.1016/j.bbamcr.2025.120093","url":null,"abstract":"<div><div>Cancer cachexia is a multifactorial syndrome characterized by involuntary and pathological weight loss, predominantly caused by muscle wasting. While tumors can elicit detrimental effects on skeletal muscle function, the contribution of specific tumor-derived mediators remains elusive. To explore this, we investigated the impact of conditioned media (CM) from four cachexia-inducing tumor cell lines (KPC, 4662, LLC, and C26) on muscle differentiation using C2C12 cells. Creatine kinase (CK) activity was measured as an indicator of muscle wasting, and global gene expression changes in C2C12 cells were analyzed via RNA sequencing. Cytokine profiling of the CM identified 111 immune factors, and mimic combinations of the most abundant cytokines from KPC CM were tested for their effects on CK activity. Additionally, the involvement of tumor-derived PGE2 was assessed via CRISPR/Cas9-mediated knockout of the <em>Ptgs2</em> gene in KPC cells. CM from all tumor cell lines significantly reduced CK activity in C2C12 cells, consistent with downregulation of <em>CKm</em> gene expression. Global gene expression profiles revealed upregulation of immune-related pathways in C2C12 cells exposed to KPC CM. However, mixtures of the 14 most abundant cytokines in CM had minimal effects on CK activity, and tumor-derived PGE2 showed no significant effect on CK activity or muscle cell differentiation. These findings suggest that the observed muscle-wasting effects of cachexia-inducing tumor cells cannot be replicated by the most abundant cytokines present in CM alone, highlighting the need for further research to identify the key tumor-derived factors responsible for cancer-induced muscle wasting.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120093"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming is implicated in the differential response of the CAL-1 plasmacytoid dendritic cell line to autophagy inhibitors","authors":"Carlota Ramalhinho ,&nbsp;Paulo Antas ,&nbsp;Philippe Pierre ,&nbsp;Iola F. Duarte ,&nbsp;Catarina R. Almeida","doi":"10.1016/j.bbamcr.2025.120090","DOIUrl":"10.1016/j.bbamcr.2025.120090","url":null,"abstract":"<div><div>Plasmacytoid dendritic cells (pDCs) produce large amounts of type I Interferons (IFN) and pro-inflammatory cytokines, playing crucial roles in antiviral and anticancer immunity as well as in autoimmune diseases. Understanding the mechanisms that regulate pDC function is therefore essential. Autophagy, a process responsible for recycling intracellular components, influences cellular metabolism and modulates immune responses. Here, we used the human CAL-1 pDC cell line, a validated model for primary pDCs, to investigate the functional impact of autophagy inhibition and the contribution of metabolism to these effects. CAL-1 cells were treated with two autophagy inhibitors, Spautin-1 and VPS34-IN1, and cytokine production was assessed by RT-qPCR and ELISA, while cellular metabolism was analysed by untargeted metabolomics of cell extracts and of medium supernatants. VPS34-IN1, but not Spautin-1, induced robust expression of IFN-β and TNF-α. The two inhibitors also elicited distinct metabolic responses: Spautin-1 enhanced glycolysis, promoted an anabolic phenotype with increased utilization of amino acids, and upregulated mTOR signaling. In contrast, VPS34-IN1 decreased glycolysis, increased intracellular amino acids, reduced TCA intermediates, and induced energy stress, reflected by an increased AMP/(ADP + ATP) ratio and decreased NAD⁺. These changes were consistent with AMPK activation, and pharmacological inhibition of AMPK with dorsomorphin (compound C) abolished cytokine production in VPS34-IN1-treated cells. Together, these results indicate that differential cytokine responses to autophagy inhibition are driven primarily by metabolic rewiring rather than autophagic flux per se, highlighting the interplay between metabolism, mitochondrial ROS, and signaling pathways in pDC activation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120090"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145628447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “A fluorescent protein C-terminal fusion knock-in is functional with TRPA1 but not TRPC5” [Biochim. Biophys. Acta Mol. Cell Res. 1872(2) (2025) 119887]","authors":"Aaron Tragl ,&nbsp;Alexandra Ptakova ,&nbsp;Viktor Sinica ,&nbsp;Rathej Meerupally ,&nbsp;Christine König ,&nbsp;Carolina Roza ,&nbsp;Ivan Barvík ,&nbsp;Viktorie Vlachova ,&nbsp;Katharina Zimmermann","doi":"10.1016/j.bbamcr.2025.120042","DOIUrl":"10.1016/j.bbamcr.2025.120042","url":null,"abstract":"","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120042"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina” [Biochim. Biophys. Acta (BBA) Mol. Cell Res. 1867 (2020) 118732 10.1016/j.bbamcr.2020.118732]","authors":"Marcelo Cossenza ,&nbsp;Renato Socodato ,&nbsp;Telmo A. Mejía-García ,&nbsp;Ivan Domith ,&nbsp;Camila C. Portugal ,&nbsp;Luis F.H. Gladulich ,&nbsp;Aline T. Duarte-Silva ,&nbsp;Latika Khatri ,&nbsp;Shannon Antoine ,&nbsp;Franz Hofmann ,&nbsp;Edward B. Ziff ,&nbsp;Roberto Paes-de-Carvalho","doi":"10.1016/j.bbamcr.2025.120050","DOIUrl":"10.1016/j.bbamcr.2025.120050","url":null,"abstract":"","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120050"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Inhibition of autophagy sensitises cells to hydrogen peroxide-induced apoptosis: Protective effect of mild thermotolerance acquired at 40 °C” [Biochim. Biophys. Acta Mol. Cell Res. (2016) volume 1863(12) 3050-3064 / PMID: 27666506]","authors":"M. Redza-Dutordoir,&nbsp;S. Kassis,&nbsp;H. Ve,&nbsp;M. Grondin,&nbsp;D.A. Averill-Bates","doi":"10.1016/j.bbamcr.2025.120061","DOIUrl":"10.1016/j.bbamcr.2025.120061","url":null,"abstract":"","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120061"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Activation of ER stress and apoptosis by hydrogen peroxide in HeLa cells: Protective role of mild heat preconditioning at 40 °C” [Biochim. Biophys. Acta Mol. Cell Res., 1813 (2011) 1987–1999. / PMID: 21875624]","authors":"Pragathi Pallepati,&nbsp;Diana A. Averill-Bates","doi":"10.1016/j.bbamcr.2025.120084","DOIUrl":"10.1016/j.bbamcr.2025.120084","url":null,"abstract":"","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1873 2","pages":"Article 120084"},"PeriodicalIF":3.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}