Cellular and Molecular Life Sciences最新文献

{"title":"BRAT1 - a new therapeutic target for glioblastoma.","authors":"Alicia Haydo, Jennifer Schmidt, Alisha Crider, Tim Kögler, Johanna Ertl, Stephanie Hehlgans, Marina E Hoffmann, Rajeshwari Rathore, Ömer Güllülü, Yecheng Wang, Xiangke Zhang, Christel Herold-Mende, Francesco Pampaloni, Irmgard Tegeder, Ivan Dikic, Mingji Dai, Franz Rödel, Donat Kögel, Benedikt Linder","doi":"10.1007/s00018-024-05553-0","DOIUrl":"https://doi.org/10.1007/s00018-024-05553-0","url":null,"abstract":"<p><p>Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"52"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001061","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":"Serotonin receptor 5-HT7 modulates inflammatory-associated functions of macrophages.","authors":"Frauke S Bahr, Franziska E Müller, Martina Kasten, Nils Benen, Irina Sieve, Michaela Scherr, Christine S Falk, Denise Hilfiker-Kleiner, Melanie Ricke-Hoch, Evgeni Ponimaskin","doi":"10.1007/s00018-024-05570-z","DOIUrl":"https://doi.org/10.1007/s00018-024-05570-z","url":null,"abstract":"<p><p>The hormone and neurotransmitter serotonin regulates numerous physiological functions within the central nervous system and in the periphery upon binding to specific receptors. In the periphery, the serotonin receptor 7 (5-HT7R) is expressed on different immune cells including monocytes and macrophages. To investigate the impact of 5-HT7R-mediated signaling on macrophage properties, we used human THP-1 cells and differentiated them into pro-inflammatory M1- and anti-inflammatory M2-like macrophages. Pharmacological 5-HT7R activation with the specific agonist LP-211 especially modulates morphology of M1-like macrophages by increasing the number of rounded cells. Furthermore, 5-HT7R stimulation results in significantly reduced phagocytic and migratory ability of M1-like macrophages. Noteworthy, LP-211 treatment leads to changes in secretory properties of all macrophage types with the highest effects obtained for M0- and M2c-like macrophages. Finally, the importance of 5-HT7R for regulation of phagocytosis was confirmed in human primary CD14⁺ cells. These results indicate that 5-HT7R activation selectively impairs basic functions of macrophages and might thus be a new access point for the modulation of macrophage responses in the future treatment of inflammatory diseases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"51"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001132","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":"Activation and evasion of inflammasomes during viral and microbial infection.","authors":"Dan Ren, Xiaoou Ye, Ruiming Chen, Xiuzhi Jia, Xianhong He, Jinhui Tao, Tengchuan Jin, Songquan Wu, Hongliang Zhang","doi":"10.1007/s00018-025-05575-2","DOIUrl":"https://doi.org/10.1007/s00018-025-05575-2","url":null,"abstract":"<p><p>The inflammasome is a cytoplasmic multiprotein complex that induces the maturation of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) or pyroptosis by activating caspases, which play critical roles in regulating inflammation, cell death, and various cellular processes. Multiple studies have shown that the inflammasome is a key regulator of the host defence response against pathogen infections. During the process of pathogenic microbe invasion into host cells, the host's innate immune system recognizes these microbes by activating inflammasomes, triggering inflammatory responses to clear the microbes and initiate immune responses. Moreover, microbial pathogens have evolved various mechanisms to inhibit or evade the activation of inflammasomes. Therefore, we review the interactions between viruses and microbes with inflammasomes during the invasion process, highlight the molecular mechanisms of inflammasome activation induced by microbial pathogen infection, and highlight the corresponding strategies that pathogens employ to evade inflammasome activity. Finally, we also discuss potential therapeutic strategies for the treatment of pathogenic microbial infections via the targeting of inflammasomes and their products.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"56"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001057","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":"TMAO accelerates cellular aging by disrupting endoplasmic reticulum integrity and mitochondrial unfolded protein response.","authors":"Fahimeh Varzideh, Emanuele Farroni, Urna Kaunsakar, Mahaba Eiwaz, Stanislovas S Jankauskas, Gaetano Santulli","doi":"10.1007/s00018-024-05546-z","DOIUrl":"https://doi.org/10.1007/s00018-024-05546-z","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"53"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001142","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":"Sirtuin 2 exacerbates renal tubule injury and inflammation in diabetic mice via deacetylation of c-Jun/c-Fos.","authors":"Li Chen, Dan Li, Zishun Zhan, Jingjing Quan, Juan Peng, Zhijun Huang, Bin Yi","doi":"10.1007/s00018-024-05567-8","DOIUrl":"https://doi.org/10.1007/s00018-024-05567-8","url":null,"abstract":"<p><p>Diabetic nephropathy (DN) is a serious complication of diabetes, and inflammation plays a crucial role. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, which is involved in the regulation of cell metabolism, proliferation and longevity through deacetylation. Our previous research showed a positive correlation between urinary SIRT2 levels and renal injury markers in DN patients. Therefore, this study explored the specific role of SIRT2 in DN and its regulatory relationship with inflammatory response. Increased expression of SIRT2 was observed in kidney tissues of DN mice and in HK2 cells induced by HG/PA. SIRT2 knockout mice alleviated microalbuminuria, inflammatory responses, and kidney damage induced by HFD/STZ. In HK2 cells, reducing SIRT2 expression or inhibiting its acetylase activity alleviated the inflammatory response induced by HG/PA, whereas overexpression of SIRT2 exacerbated this response. Further investigation revealed that SIRT2 directly interacts with c-Jun/c-Fos, promoting their deacetylation. And inhibitors of c-Jun/c-Fos partially reversed the upregulation of inflammatory factors caused by SIRT2 overexpression. Meanwhile, disrupting SIRT2 reduced the binding activity between AP-1 and the MCP-1 promoter, while overexpressing SIRT2 further increased their binding activity in HK2 cells. Interestingly, SIRT2 increased its phosphorylation while deacetylating c-Jun, leading to nuclear accumulation of p-c-Jun. In conclusion, SIRT2 knockout can alleviate kidney injury and inflammatory response in HFD/STZ mice. The mechanism is related to the increased acetylation of c-Jun/c-Fos in renal tubular epithelial cells, accompanied by crosstalk between c-Jun phosphorylation and acetylation. Blocking SIRT2 could therefore be a potential therapeutic target for DN.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"45"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001141","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":"Double-stranded RNA orbivirus disrupts the DNA-sensing cGAS-sting axis to prevent type I IFN induction.","authors":"Andrés Louloudes-Lázaro, Pablo Nogales-Altozano, José M Rojas, Jeury Veloz, Ana B Carlón, Piet A Van Rijn, Verónica Martín, Ana Fernández-Sesma, Noemí Sevilla","doi":"10.1007/s00018-025-05580-5","DOIUrl":"https://doi.org/10.1007/s00018-025-05580-5","url":null,"abstract":"<p><p>Cyclic GMP-AMP synthase (cGAS) is a DNA sensing cellular receptor that induces IFN-I transcription in response to pathogen and host derived cytosolic DNA and can limit the replication of some RNA viruses. Some viruses have nonetheless evolved mechanisms to antagonize cGAS sensing. In this study, we evaluated the interaction between Bluetongue virus (BTV), the prototypical dsRNA virus of the Orbivirus genus and the Sedoreoviridae family, and cGAS. We found mitochondrial damage and DNA accumulation in the cytoplasm of infected cells. In addition, we show that BTV infection blocks DNA-induced IFN-I transcription and that virus infection prevents DNA sensing by inducing cGAS and STING degradation. We identify BTV-NS3 as the viral protein responsible for cGAS degradation, showing that NS3 physically interacts with cGAS and induces its degradation through an autophagy-dependent mechanism. Taken together, these findings identify for the first time a mechanism by which a dsRNA virus interferes with a DNA sensing pathway to evade the innate immune response.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"55"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001105","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":"Cytoophidium complexes resonate with cell fates.","authors":"Yi-Lan Li, Ji-Long Liu","doi":"10.1007/s00018-025-05578-z","DOIUrl":"https://doi.org/10.1007/s00018-025-05578-z","url":null,"abstract":"<p><p>Metabolism is a fundamental characteristic of life. In 2010, we discovered that the metabolic enzyme CTP synthase (CTPS) can assemble a snake like structure inside cells, which we call the cytoophidium. Including CTPS, an increasing number of metabolic enzymes have been found to form cytoophidia in cells. However, the distribution and relationship among cytoophidia formed by different metabolic enzymes remain elusive. Here we investigate five metabolic enzymes that can form cytoophidia, namely Asn1, Bna5, CTPS (i.e. Ura7), Glt1, and Prs5 in Saccharomyces cerevisiae. We find that multiple cytoophidia can be assembled into cytoophidium complexes by docking one after another. Glt1 cytoophidia tend to assemble in non-quiescent cells, while CTPS cytoophidia are more abundant in quiescent cells and form complexes with Prs5 and Asn1 cytoophidia. Blocking CTPS cytoophidium assembly can lead to a non-quiescent phenotype and increase the assembly of Glt1 cytoophidia, Bna5 cytoophidia, and a cytoophidium complex of them. Blocking CTPS cytoophidium assembly also inhibits the NAD biosynthesis pathway, which includes Bna5 and Sir2. Consistent with this result, the non-quiescent phenotype caused by blocking CTPS cytoophidium assembly can be rescued by blocking Glt1 cytoophidium assembly, supplementing nicotinic acid, or overexpressing Sir2. Our results indicate that the assembly of cytoophidium complexes with different compositions resonates with distinct cell fates.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"54"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001097","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":"Integration of CRISPR/dCas9-Based methylation editing with guide positioning sequencing identifies dynamic changes of mrDEGs in breast cancer progression.","authors":"Baolong Zhang, Jin Li, Wenqiang Yu","doi":"10.1007/s00018-024-05562-z","DOIUrl":"https://doi.org/10.1007/s00018-024-05562-z","url":null,"abstract":"<p><p>Dynamic changes in DNA methylation are prevalent during the progression of breast cancer. However, critical alterations in aberrant methylation and gene expression patterns have not been thoroughly characterized. Here, we utilized guide positioning sequencing (GPS) to conduct whole-genome DNA methylation analysis in a unique human breast cancer progression model: MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and metastatic carcinoma). By integrating with mRNA-seq and matched clinical expression data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), six representative methylation-related differentially expressed genes (mrDEGs) were identified, including CAVIN2, ARL4D, DUSP1, TENT5B, P3H2, and MMP28. To validate our findings, we independently developed and optimized the dCas9-DNMT3L-DNMT3A system, achieving a high efficiency with a 98% increase in methylation at specific sites. DNA methylation levels significantly increased for the six genes, with CAVIN2 at 67.75 ± 1.05%, ARL4D at 53.29 ± 6.32%, DUSP1 at 57.63 ± 8.46%, TENT5B at 44.00 ± 5.09%, P3H2 at 58.50 ± 3.90%, and MMP28 at 49.60 ± 5.84%. RT-qPCR confirmed an inverse correlation between increased DNA methylation and gene expression. Most importantly, we mimicked tumor progression in vitro, demonstrating that transcriptional silencing of the TENT5B promotes cell proliferation in MCF10A cells owing to the crosstalk between hypermethylation and histone deacetylation. This study unveils the practical implications of DNA methylation dynamics of mrDEGs in reshaping epigenomic features during breast cancer malignant progression through integrated data analysis of the methylome and transcriptome. The application of the CRISPR/dCas9-based methylation editing technique elucidates the regulatory mechanisms and functional roles of individual genes within the DNA methylation signature, providing valuable insights for understanding breast cancer pathogenesis and facilitating potential therapeutic approaches in epigenome editing for patients with breast cancer.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"46"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001125","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":"N⁶-Methylandenosine-related lncRNAs as potential biomarkers for predicting prognosis and the immunotherapy response in pancreatic cancer.","authors":"Zhihui Bai, Qianlin Xia, Wanli Xu, Zhirong Wu, Xiaomeng He, Xin Zhang, Zhefeng Wang, Mengting Luo, Huaqin Sun, Songmei Liu, Jin Wang","doi":"10.1007/s00018-024-05573-w","DOIUrl":"https://doi.org/10.1007/s00018-024-05573-w","url":null,"abstract":"<p><p>Emerging evidence has shown that the N⁶-methyladenosine (m⁶A) modification of RNA plays key roles in tumorigenesis and the progression of various cancers. However, the potential roles of the m⁶A modification of long noncoding RNAs (lncRNAs) in pancreatic cancer (PaCa) are still unknown. To analyze the prognostic value of m⁶A-related lncRNAs in PaCa, an m6A-related lncRNA signature was constructed as a risk model via Pearson's correlation and univariate Cox regression analyses in The Cancer Genome Atlas (TCGA) database. The tumor microenvironment (TME), tumor mutation burden, and drug sensitivity of PaCa were investigated by m⁶A-related lncRNA risk score analyses. We established an m⁶A-related risk prognostic model consisting of five lncRNAs, namely, LINC01091, AC096733.2, AC092171.5, AC015660.1, and AC005332.6, which not only revealed significant differences in immune cell infiltration associated with the TME between the high-risk and low-risk groups but also predicted the potential benefit of immunotherapy for patients with PaCa. Drugs such as WZ8040, selumetinib, and bortezomib were also identified as more effective for high-risk patients. Our results indicate that the m⁶A-related lncRNA risk model could be an independent prognostic indicator, which may provide valuable insights for identifying therapeutic approaches for PaCa.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"48"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001129","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":"Single-cell RNA sequencing of the carotid artery and femoral artery of rats exposed to hindlimb unloading.","authors":"Chengfei Li, Yikai Pan, Yuan Wang, Xi Li, Yateng Tie, Shuhan Li, Ruonan Wang, Xingcheng Zhao, Jieyi Fan, Xianchun Yan, Yongchun Wang, Xiqing Sun","doi":"10.1007/s00018-024-05572-x","DOIUrl":"https://doi.org/10.1007/s00018-024-05572-x","url":null,"abstract":"<p><strong>Background: </strong>Prolonged spaceflight is known to cause vascular deconditioning and remodeling. Tail suspension, a widely used spaceflight analog, is reported to result in vascular remodeling of rats. However, little is known about the cellular atlas of the heterogeneous cells of CA and FA from hindlimb-unloaded rats.</p><p><strong>Methods: </strong>Firstly, we leveraged scRNA-seq to perform clustering analysis to identify diverse cell populations and sub-clusters within CA and FA from rats subjected to 3 months of hindlimb unloading. The dysregulated genes specific for artery types and cell types in HU group compared to Con were unraveled. Then R package \"Cellchat\" was used to reveal ligand-receptor cellular communication. At last, the TF network analysis was performed using the SCENIC R package to predict the pivotal TFs in rat artery remodeling induced by hindlimb unloading.</p><p><strong>Results: </strong>Clustering analysis identified ECs, SMCs, fibroblasts, and a spectrum of immune cells, as well as neuronal and stem cells. Notably, an increased percentage of ECs in the CA and a diminished proportion of SMCs in both CA and FA were observed following tail suspension. Intersection of dysregulated genes specific for artery type and cell type after tail suspension revealed several gene sets involved in ECM remodeling, inflammation, vasoconstriction, etc. Fibroblasts, in particular, exhibited the most significant gene expression variability, highlighting their plasticity. Subclustering within ECs, SMCs and fibroblasts revealed specialized subsets engaged in processes such as EndoMT and cell cycle checkpoint regulation. Additionally, enhanced intercellular interactions among major cell types, especially between SMC and fibroblast, underscored the importance of cell communication in vascular remodeling. Several TFs were identified as potentially influential in the vascular remodeling process under simulated microgravity conditions.</p><p><strong>Conclusions: </strong>This study presents the first cellular atlas of the conductive arteries in hindlimb-unloaded rats, revealing a spectrum of dysregulated gene profiles. The identification of the subclusters of ECs, SMCs and fibroblasts, cellular communication analysis and transcription factors prediction are also included in this work. The findings provide a reference for future research on vascular deconditioning following long-duration spaceflight.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"50"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001134","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}