Cellular and Molecular Life Sciences最新文献

{"title":"Melatonin antagonizes bone loss induced by mechanical unloading via IGF2BP1-dependent m⁶A regulation.","authors":"Liqun Xu, Lijun Zhang, Quan Sun, Xiaoyan Zhang, Junfei Zhang, Xiran Zhao, Zebing Hu, Shu Zhang, Fei Shi","doi":"10.1007/s00018-025-05588-x","DOIUrl":"10.1007/s00018-025-05588-x","url":null,"abstract":"<p><p>Disuse bone loss is prone to occur in individuals who lack mechanical stimulation due to prolonged spaceflight or extended bed rest, rendering them susceptible to fractures and placing an enormous burden on social care; nevertheless, the underlying molecular mechanisms of bone loss caused by mechanical unloading have not been fully elucidated. Numerous studies have focused on the epigenetic regulation of disuse bone loss; yet limited research has been conducted on the impact of RNA modification bone formation in response to mechanical unloading conditions. In this study, we discovered that m⁶A reader IGF2BP1 was downregulated in both osteoblasts treated with 2D clinostat and bone tissue in HLU mice. Supplementing IGF2BP1 could promote osteoblast proliferation and partially alleviate the adverse effects of mechanical unloading on bone formation. Mechanistically, IGF2BP1 inhibited the degradation of Lef1 mRNA by directly binding to its mRNA and recognizing the m⁶A modification. Furthermore, LEF1 promoted osteoblast proliferation by upregulating c-Myc and Cyclin D1 expression, as well as participated in mediating IGF2BP1-induced osteoblast activity under mechanical unloading. Notably, Melatonin (MT) might participate in the regulation of the IGF2BP1/LEF1 axis, thereby regulating the proliferation of osteoblasts and bone formation. Collectively, this study revealed a new insight into the regulation of the MT/IGF2BP1/LEF1 pathway in the process of unloading-induced bone loss, which could potentially contribute to establishing therapeutic strategies for disuse osteoporosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"60"},"PeriodicalIF":6.2,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028064","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747058/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747067/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746987/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11753444/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747030/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial-derived TNF/Eiger signaling promotes somatosensory neurite sculpting.","authors":"Ting Zheng, Keyao Long, Su Wang, Menglong Rui","doi":"10.1007/s00018-024-05560-1","DOIUrl":"https://doi.org/10.1007/s00018-024-05560-1","url":null,"abstract":"<p><p>The selective elimination of inappropriate projections is essential for sculpting neural circuits during development. The class IV dendritic arborization (C4da) sensory neurons of Drosophila remodel the dendritic branches during metamorphosis. Glial cells in the central nervous system (CNS), are required for programmed axonal pruning of mushroom body (MB) γ neurons during metamorphosis in Drosophila. However, it is entirely unknown whether the glial cells are involved in controlling the neurite pruning of C4da sensory neurons. Here, we show that glial deletion of Eiger (Egr), orthologous to mammalian tumor necrosis factor TNF superfamily ligand, results in dendrite remodeling deficiency of Drosophila C4da sensory neurons. Moreover, the attenuation of neuronal Wengen (Wgn) and Grindelwald (Grnd), the receptors for TNF ligands, is also examined for defects in dendrite remodeling. We further discover that Wgn and Grnd facilitate dendrite elimination through the JNK Signaling. Overall, our findings demonstrate that glial-derived Egr signal links to the neuronal receptor Wgn/Grnd, activating the JNK signaling pathway and promoting developmental neuronal remodeling. Remarkably, our findings reveal a crucial role of peripheral glia in dendritic pruning of C4da neurons.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"47"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058301","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":"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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751250/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11751279/pdf/","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":"OA","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747065/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}