Cellular and Molecular Life Sciences最新文献

{"title":"Poly(ADP-ribose)polymerase 2 is zinc-dependent enzyme and nucleosome reorganizer.","authors":"Natalya Maluchenko, Alexandra Saulina, Olga Geraskina, Elena Kotova, Anna Korovina, Grigoriy Armeev, Mikhail Kirpichnikov, Alexey Feofanov, Vasily Studitsky","doi":"10.1007/s00018-025-05785-8","DOIUrl":"10.1007/s00018-025-05785-8","url":null,"abstract":"<p><p>Poly(ADP-ribose)polymerase 2 (PARP2) is a nuclear protein, DNA damage sensor and an emerging target for development of anti-cancer drugs. Previously it was discovered that PARP2 binds to nucleosomes; however, critical factors involved in this process remain unknown. We demonstrated that in the presence of Mg²⁺ or Ca²⁺ ions PARP2 forms complexes with a nucleosome containing different number of PARP2 molecules without altering conformation of nucleosomal DNA. In contrast, Zn²⁺ ions directly interact with PARP2 inducing a local alteration of the secondary structure of the protein and PARP2-mediated, reversible structural reorganization of nucleosomes. WGR domain of PARP2 is the target for Zn²⁺ ions since this domain contains two putative Zn^2+-binding sites, binds Zn²⁺ ions and alone drives Zn²⁺-mediated reorganization of nucleosomes. Auto(poly-ADP-ribosylation) activity of PARP2 is enhanced by Mg²⁺ ions and modulated by Zn²⁺ ions: suppressed or enhanced depending on the occupancy of two functionally different zinc binding sites. The data suggest that transient changes in concentration of cations can differentially modulate PARP2 activity, local chromatin structure and the DNA damage response.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"267"},"PeriodicalIF":6.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 antimicrobial peptide Angie 5 inhibits TcdA and TcdB from Clostridioides difficile.","authors":"Stefanie Lietz, Lena-Marie Sokolowski, Katrin Lindner, Armando A Rodríguez, Ludger Ständker, Verena Vogel, Barbara Spellerberg, Steffen Stenger, Daniel Alpízar-Pedraza, Katharina Ernst, Panagiotis Papatheodorou, Holger Barth","doi":"10.1007/s00018-025-05799-2","DOIUrl":"10.1007/s00018-025-05799-2","url":null,"abstract":"<p><p>Clostridioides (C.) difficile is a spore-forming, toxin-producing nosocomial human gut pathogen and a causative agent of gastrointestinal infections, leading to mild to severe diarrhea. Severe C. difficile infections (CDI) can cause life-threatening conditions, such as pseudomembranous colitis, colonic perforation, or toxic megacolon. The main virulence factors of C. difficile and responsible for CDI symptoms are two AB-type protein toxins, toxin A (TcdA) and toxin B (TcdB). TcdA and TcdB are large, single-chain proteins with multiple domains and glucosyltransferase activity. After receptor-mediated endocytosis, acidification of endosomes triggers insertion and pore formation of the toxins into the endosomal membrane for the delivery of their toxic glucosyltransferase domain (GTD) into the cytosol. There, the GTD glucosylates its target proteins, small GTPases of the Rho and/or Ras family, which leads amongst others to the collapse of the actin cytoskeleton and eventually to cell death. Here, we describe in silico predicted antimicrobial peptides, denoted as Angies, since they derive from the human endogenous protein angiogenin, as inhibitors for TcdA and TcdB. The strongest inhibitory capacity provided the derivative Angie 5, consistently in HeLa and Vero cells, as well as in the physiologically more relevant colon carcinoma cell line CaCo-2. Angie 5 delayed TcdA/TcdB-mediated glucosylation of its substrate proteins and, consequently, toxin-induced cell rounding as a consequence of actin-depolymerization. Moreover, the same Angie peptides that neutralized TcdA/TcdB also prevented the growth of C. difficile in vitro. In conclusion, our study paves the way for the development of antimicrobial peptide-based anti-toxin strategies to address C. difficile-associated diseases (CDADs).</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"265"},"PeriodicalIF":6.2,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian ontogenetic metabolomics atlas: an interactive resource with insights from rat plasma, tissues, and feces.","authors":"Lucie Rudl Kulhava, Pavel Houdek, Michaela Novakova, Jiri Hricko, Michaela Paucova, Ondrej Kuda, Martin Sladek, Oliver Fiehn, Alena Sumova, Tomas Cajka","doi":"10.1007/s00018-025-05783-w","DOIUrl":"10.1007/s00018-025-05783-w","url":null,"abstract":"<p><p>Circadian rhythms regulate key physiological processes through clock genes in central and peripheral tissues. While circadian gene expression during development has been well studied, the temporal dynamics of metabolism across tissues remain less understood. Here, we present the Circadian Ontogenetic Metabolomics Atlas (COMA), which maps circadian metabolic rhythms across 16 rat anatomical structures. The brain (suprachiasmatic nuclei, medial prefrontal cortex) and periphery (liver, plasma) span developmental stages from embryonic E19 to postnatal P2, P10, P20, and P28. Fecal samples include all four postnatal stages, while additional peripheral tissues were analyzed at P20 and P28. Using a multiplatform liquid chromatography-mass spectrometry approach, we annotated 851 metabolites from 1610 samples. We identified distinct circadian shifts, particularly during the transition from nursing to solid food intake (P10-P20), with an average of 24% of metabolites exhibiting circadian oscillations across sample types, as determined by JTK_CYCLE. Our study also underscores the importance of standardized sampling, as metabolite intensities fluctuate with both circadian rhythms and development. COMA serves as an open-access resource ( https://coma.metabolomics.fgu.cas.cz ) for exploring circadian metabolic regulation and its role in developmental biology.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"264"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1 disrupts blood-brain barrier via CaMKII/Nrf2 in ischemic stroke.","authors":"Huimin Fu, Yang Yu, Shangyuan Wang, Peixian Xu, Yuting Sun, Jiaqi Li, Xiaoli Ge, Shuming Pan","doi":"10.1007/s00018-025-05804-8","DOIUrl":"10.1007/s00018-025-05804-8","url":null,"abstract":"<p><p>Ischemic stroke (IS) leads to the disruption of blood-brain barrier (BBB) integrity, resulting in brain edema. In this process, endothelial cells, as a crucial component of the BBB, are subjected to external pressure and tensile stress. Piezo1, a mechanically-sensitive ion channel, may be activated by sensing these stresses, further exacerbating the destruction of the BBB. Our findings indicated that after cerebral ischemia/reperfusion (I/R) injury, the expression of Piezo1 in endothelial cells increased. In endothelial-specific Piezo1 knockout (Piezo1^ECKO) mice, brain damage, neurological deficits, and BBB disruption caused by I/R injury were significantly alleviated. Moreover, oxidative stress and the inflammatory response in the cerebral cortex induced by I/R were also reduced. In vitro, by activating or knocking out Piezo1 in bEnd.3 cells under oxygen-glucose deprivation/reperfusion (OGD/R), we observed similar effects, further corroborating the in vivo findings. To elucidate the molecular mechanism, we found that the protective effect of Piezo1 deficiency on BBB integrity is mediated by the alleviation of p-CaMKII and the enhancement of Nrf2 nuclear translocation. This, in turn, leads to the upregulation of NQO-1 and HO-1 expression. In summary, our research indicates that Piezo1 exacerbates BBB disruption after cerebral I/R injury by promoting oxidative stress, inflammation, and mitochondrial dysfunction. This process is closely linked to the activation of the Ca²⁺/CaMKII and Nrf2 pathways, suggesting that Piezo1 may be a potential therapeutic target for IS.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"259"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 impact of ¹²C⁶ heavy ion irradiation-induced cellular mutations on the replication of the foot-and-mouth disease virus and the role of Cbr3.","authors":"Xiangdong Song, Shiyu Tao, Fanglan An, Xiaoming Li, Yanyan Chang, Xuerong Liu, Yan Cui","doi":"10.1007/s00018-025-05628-6","DOIUrl":"10.1007/s00018-025-05628-6","url":null,"abstract":"<p><p>Foot-and-mouth disease (FMD) is an infectious disease in animals caused by the foot-and-mouth disease virus (FMDV). However, the mechanism of FMDV infection in host cells remains unclear. In this study, we utilized ¹²C⁶ heavy ion irradiation technology to process BHK-21 cells and systematically screened and evaluated cell lines with distinct virus replication characteristics. We subsequently employed proteomics to detect the differences between these cell lines and the control BHK-21 cell line following ¹²C⁶ heavy ion irradiation. Both cell lines exhibited common downregulation of cell adhesion molecules but also exhibited distinct upregulation pathways. In terms of immune and metabolic responses, BHK-5 infection triggered an immune response, including the upregulation of cytokine-cytokine receptor signaling pathways and lysosome-related pathways, while the upregulation of drug metabolism pathways enhanced the ability to metabolize exogenous substances. Conversely, BHK-7 infection tended to promote metabolic pathway changes that favor virus replication, such as the upregulation of folate biosynthesis, polysaccharide degradation, and linolenic acid metabolism pathways. Additionally, we observed significant downregulation of Cbr3 in cell lines that promoted virus replication and significant upregulation in those that inhibited virus replication. Upon validating the results in Cbr3 knockout cells, we found that knocking out Cbr3 could increase FMDV replication by increasing the cellular content of prostaglandin E2 (PGE2), suggesting a close relationship between FMDV replication and PGE2 levels. This method can increase the production efficiency of FMDV vaccines while reducing manufacturing costs. This study innovatively employed ¹²C⁶ heavy ion irradiation technology to induce cell transformation and explored its impact on FMDV, offering a new perspective for understanding virus replication mechanisms and potentially providing a target and idea for developing novel antiviral strategies.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"261"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NR4A2 attenuates early brain injury after intracerebral hemorrhage by promoting M2 microglial polarization via TLR4/TRAF6/NF-κB pathway inhibition.","authors":"Di Hu, Cheng Huang, Ling Tang, Jiawen Lei, Jiaqi Wang, Wenzheng Hu, Minshan Chen, Siyuan Song, Lin Lu, Pingyi Xu","doi":"10.1007/s00018-025-05755-0","DOIUrl":"10.1007/s00018-025-05755-0","url":null,"abstract":"<p><p>In the early stage of intracerebral hemorrhage (ICH), rebleeding occurs when blood from the initial hematoma permeates the surrounding brain parenchyma through the disrupted blood-brain barrier (BBB), exacerbating brain injury. Neuroinflammation is a critical driver of the pathological processes underlying this phenomenon. Research on microglia near early hematomas revealed that promoting the transition of microglia to the M2 phenotype could mitigate perihematomal inflammatory damage. Recent studies have shown that the nuclear receptor-related 1 protein (NR4A2) can regulate microglial function and inhibit inflammation. However, the functions of NR4A2 in the development of ICH are still unclear. In this study, we explored the potential protective effect and mechanism of NR4A2 in ICH models. Our results demonstrated that the expression of NR4A2 was significantly decreased in both ICH rats and cell models. Increasing NR4A2 activity could effectively decrease the hematoma volume, improve the neurological prognosis and alleviate perihematomal BBB damage. In vivo and in vitro experiments revealed that NR4A2 inhibited perihematomal inflammatory damage by driving microglial polarization toward the anti-inflammatory M2 phenotype. Mechanistically, NR4A2 targeted TLR4 and inhibited the TRAF6/NF-κB pathway, thereby promoting M2 microglial polarization, reducing inflammatory cell extravasation and maintaining the integrity of the BBB. Conversely, the protective effects of NR4A2 were negated when CRX-527 (a TLR4 agonist) was introduced. These findings suggest that NR4A2 represents a promising therapeutic target for ICH.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"262"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PAK1 regulates oligodendroglial proliferation and repopulation in homeostatic and demyelinating brain.","authors":"Yan Wang, Bokyung Kim, Xiangyi Shi, Huimin Chen, Joohyun Park, Meina Zhu, Evelyn M Wong, Audrey Y Park, Jonathan Chernoff, Fuzheng Guo","doi":"10.1007/s00018-025-05728-3","DOIUrl":"10.1007/s00018-025-05728-3","url":null,"abstract":"<p><p>Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, macrocephaly, and white matter anomaly in children. Oligodendroglial lineage cells undergo extensive proliferation and population expansion in human and rodent brain during early postnatal development. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, using a series of genetic mouse models, we show that PAK1 controls oligodendroglial progenitor cell (OPC) proliferation and regeneration during normal brain development and in brain white matter injury. Unlike differentiating oligodendrocytes, OPCs display high levels of PAK1 kinase activity which maintains them in a proliferative progenitor state through modulating PDGFRa-mediated mitogenic signaling and acts as a molecular brake limiting OPC differentiation. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion in a cell-autonomous manner. Transgenic mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic brain. Furthermore, OPC proliferation and intra-lesional repopulation are significantly impaired in mice of OPC-specific PAK1 deletion or kinase inhibition after white matter injury. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a proliferative progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"260"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"African swine fever virus A151R downregulates cGAS-STING-mediated IFN-β production by promoting lipid peroxidation through ferritinophagy-induced ferroptosis.","authors":"Yiqin Chen, Junjie Wang, Ying Zhou, Mingze Liu, Wenjie Li, Yian Deng, Yonggen Yang, Chunyue Fang, Sai Niu, Jinxia Dai, Hanchuan Dai","doi":"10.1007/s00018-025-05732-7","DOIUrl":"10.1007/s00018-025-05732-7","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"263"},"PeriodicalIF":6.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycosphingolipid synthesis is impaired in SLC35A2-CDG and improves with galactose supplementation.","authors":"Andrea Jáñez Pedrayes, Sam De Craemer, Jakub Idkowiak, Dries Verdegem, Christian Thiel, Rita Barone, Mercedes Serrano, Tomáš Honzík, Eva Morava, Pieter Vermeersch, François Foulquier, Willy Morelle, Johannes V Swinnen, Daisy Rymen, David Cassiman, Bart Ghesquière, Peter Witters","doi":"10.1007/s00018-025-05759-w","DOIUrl":"10.1007/s00018-025-05759-w","url":null,"abstract":"<p><p>SLC35A2-CDG is an X-linked congenital disorder of glycosylation (CDG), characterized by defective UDP-galactose transport into the Golgi and endoplasmic reticulum and consequent insufficient galactosylation of glycans. Clinically, this translates into a range of predominantly neurological symptoms. Although the pathomechanism of this disorder is not fully understood, oral galactose supplementation has led to clinical and biochemical improvement in some patients. Here, we show that protein glycosylation (N- and O-linked) was only minimally disturbed in SLC35A2-CDG patient-derived fibroblasts. However, lipid glycosylation was significantly impaired, with accumulation of glucosylceramide and deficiency of digalactosylated glycosphingolipids (GSLs) and complex gangliosides. Galactose supplementation increased UDP-galactose, its transport into the Golgi, and improved deficient GSL synthesis through direct incorporation of the provided galactose. This improved GSL homeostasis in all patient-derived fibroblasts and in another SLC35A2 deficient cell model (CHO-Lec8). Additionally, SLC35A2-CDG serum analysis identified hydroxylated GSLs, particularly GM3, as potential disease biomarkers. Given the essential role of gangliosides in central nervous system function, their deficiency is likely a key factor in the neurological involvement of this disorder. These findings pave the way for new nutritional therapies with GSL supplements and highlight the importance of studying lipid glycosylation to better understand the complex pathophysiology of CDG.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"257"},"PeriodicalIF":6.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3'-end modifications.","authors":"Gunjan Dadhwal, Hebatallah Samy, Jonathan Bouvette, Fatima El-Azzouzi, Pierre Dagenais, Pascale Legault","doi":"10.1007/s00018-025-05795-6","DOIUrl":"10.1007/s00018-025-05795-6","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"258"},"PeriodicalIF":6.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}