Cell Discovery最新文献

{"title":"RBBP6 maintains glioblastoma stem cells through CPSF3-dependent alternative polyadenylation.","authors":"Peng Lin, Wenyan Chen, Zhilin Long, Jichuan Yu, Jiayao Yang, Zhen Xia, Qiulian Wu, Xinyu Min, Jing Tang, Ya Cui, Fuyi Liu, Chun Wang, Jian Zheng, Wei Li, Jeremy N Rich, Lei Li, Qi Xie","doi":"10.1038/s41421-024-00654-3","DOIUrl":"10.1038/s41421-024-00654-3","url":null,"abstract":"<p><p>Glioblastoma is one of the most lethal malignant cancers, displaying striking intratumor heterogeneity, with glioblastoma stem cells (GSCs) contributing to tumorigenesis and therapeutic resistance. Pharmacologic modulators of ubiquitin ligases and deubiquitinases are under development for cancer and other diseases. Here, we performed parallel in vitro and in vivo CRISPR/Cas9 knockout screens targeting human ubiquitin E3 ligases and deubiquitinases, revealing the E3 ligase RBBP6 as an essential factor for GSC maintenance. Targeting RBBP6 inhibited GSC proliferation and tumor initiation. Mechanistically, RBBP6 mediated K63-linked ubiquitination of Cleavage and Polyadenylation Specific Factor 3 (CPSF3), which stabilized CPSF3 to regulate alternative polyadenylation events. RBBP6 depletion induced shortening of the 3'UTRs of MYC competing-endogenous RNAs to release miR-590-3p from shortened UTRs, thereby decreasing MYC expression. Targeting CPSF3 with a small molecular inhibitor (JTE-607) reduces GSC viability and inhibits in vivo tumor growth. Collectively, RBBP6 maintains high MYC expression in GSCs through regulation of CPSF3-dependent alternative polyadenylation, providing a potential therapeutic paradigm for glioblastoma.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10951364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypercompact TnpB and truncated TnpB systems enable efficient genome editing in vitro and in vivo","authors":"Ming Wang, Zhaolin Sun, Yue Liu, Pengbin Yin, Chuanyu Liang, Lin Tan, Lei Wei, Yuzhan Wang, Haikuan Yu, Yunfei Zhu, Xiaoxiang Hu, Ning Li, Ran Zhang","doi":"10.1038/s41421-023-00645-w","DOIUrl":"https://doi.org/10.1038/s41421-023-00645-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140172696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into human organic cation transporter 1 transport and inhibition.","authors":"Shuhao Zhang, Angqi Zhu, Fang Kong, Jianan Chen, Baoliang Lan, Guodong He, Kaixuan Gao, Lili Cheng, Xiaoou Sun, Chuangye Yan, Ligong Chen, Xiangyu Liu","doi":"10.1038/s41421-024-00664-1","DOIUrl":"10.1038/s41421-024-00664-1","url":null,"abstract":"<p><p>The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities.","authors":"Claudio Pulito, Federica Mori, Andrea Sacconi, Frauke Goeman, Maria Ferraiuolo, Patrizia Pasanisi, Carlo Campagnoli, Franco Berrino, Maurizio Fanciulli, Rebecca J Ford, Massimo Levrero, Natalia Pediconi, Ludovica Ciuffreda, Michele Milella, Gregory R Steinberg, Mario Cioce, Paola Muti, Sabrina Strano, Giovanni Blandino","doi":"10.1038/s41421-024-00655-2","DOIUrl":"10.1038/s41421-024-00655-2","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10937647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-modal molecular determinants of clinically relevant osteoporosis subtypes.","authors":"Chunchun Yuan, Xiang-Tian Yu, Jing Wang, Bing Shu, Xiao-Yun Wang, Chen Huang, Xia Lv, Qian-Qian Peng, Wen-Hao Qi, Jing Zhang, Yan Zheng, Si-Jia Wang, Qian-Qian Liang, Qi Shi, Ting Li, He Huang, Zhen-Dong Mei, Hai-Tao Zhang, Hong-Bin Xu, Jiarui Cui, Hongyu Wang, Hong Zhang, Bin-Hao Shi, Pan Sun, Hui Zhang, Zhao-Long Ma, Yuan Feng, Luonan Chen, Tao Zeng, De-Zhi Tang, Yong-Jun Wang","doi":"10.1038/s41421-024-00652-5","DOIUrl":"10.1038/s41421-024-00652-5","url":null,"abstract":"<p><p>Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10933295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures reveal variant Tau amyloid fibrils between the rTg4510 mouse model and sporadic human tauopathies.","authors":"Wanbing Zhao, Kaien Liu, Yun Fan, Qinyue Zhao, Youqi Tao, Mengwei Zhang, Linhua Gan, Wenbo Yu, Bo Sun, Dan Li, Cong Liu, Jian Wang","doi":"10.1038/s41421-023-00637-w","DOIUrl":"10.1038/s41421-023-00637-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140048821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping crossover events of mouse meiotic recombination by restriction fragment ligation-based Refresh-seq","authors":"Yan Wang, Yijun Chen, Junpeng Gao, Haoling Xie, Yuqing Guo, Jingwei Yang, Jun’e Liu, Zonggui Chen, Qingqing Li, Mengyao Li, Jie Ren, Lu Wen, Fuchou Tang","doi":"10.1038/s41421-023-00638-9","DOIUrl":"https://doi.org/10.1038/s41421-023-00638-9","url":null,"abstract":"<p>Single-cell whole-genome sequencing methods have undergone great improvements over the past decade. However, allele dropout, which means the inability to detect both alleles simultaneously in an individual diploid cell, largely restricts the application of these methods particularly for medical applications. Here, we develop a new single-cell whole-genome sequencing method based on third-generation sequencing (TGS) platform named Refresh-seq (restriction fragment ligation-based genome amplification and TGS). It is based on restriction endonuclease cutting and ligation strategy in which two alleles in an individual cell can be cut into equal fragments and tend to be amplified simultaneously. As a new single-cell long-read genome sequencing method, Refresh-seq features much lower allele dropout rate compared with SMOOTH-seq. Furthermore, we apply Refresh-seq to 688 sperm cells and 272 female haploid cells (secondary polar bodies and parthenogenetic oocytes) from F1 hybrid mice. We acquire high-resolution genetic map of mouse meiosis recombination at low sequencing depth and reveal the sexual dimorphism in meiotic crossovers. We also phase the structure variations (deletions and insertions) in sperm cells and female haploid cells with high precision. Refresh-seq shows great performance in screening aneuploid sperm cells and oocytes due to the low allele dropout rate and has great potential for medical applications such as preimplantation genetic diagnosis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140037107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The E3 ubiquitin ligase MARCH2 protects against myocardial ischemia-reperfusion injury through inhibiting pyroptosis via negative regulation of PGAM5/MAVS/NLRP3 axis.","authors":"Shuolin Liu, Yaguang Bi, Tianting Han, Yiran E Li, Qihang Wang, Ne Natalie Wu, Chenguo Xu, Junbo Ge, Ronggui Hu, Yingmei Zhang","doi":"10.1038/s41421-023-00622-3","DOIUrl":"10.1038/s41421-023-00622-3","url":null,"abstract":"<p><p>Inflammasome activation and pyroptotic cell death are known to contribute to the pathogenesis of cardiovascular diseases, such as myocardial ischemia-reperfusion (I/R) injury, although the underlying regulatory mechanisms remain poorly understood. Here we report that expression levels of the E3 ubiquitin ligase membrane-associated RING finger protein 2 (MARCH2) were elevated in ischemic human hearts or mouse hearts upon I/R injury. Genetic ablation of MARCH2 aggravated myocardial infarction and cardiac dysfunction upon myocardial I/R injury. Single-cell RNA-seq analysis suggested that loss of MARCH2 prompted activation of NLRP3 inflammasome in cardiomyocytes. Mechanistically, phosphoglycerate mutase 5 (PGAM5) was found to act as a novel regulator of MAVS-NLRP3 signaling by forming liquid-liquid phase separation condensates with MAVS and fostering the recruitment of NLRP3. MARCH2 directly interacts with PGAM5 to promote its K48-linked polyubiquitination and proteasomal degradation, resulting in reduced PGAM5-MAVS co-condensation, and consequently inhibition of NLRP3 inflammasome activation and cardiomyocyte pyroptosis. AAV-based re-introduction of MARCH2 significantly ameliorated I/R-induced mouse heart dysfunction. Altogether, our findings reveal a novel mechanism where MARCH2-mediated ubiquitination negatively regulates the PGAM5/MAVS/NLRP3 axis to protect against cardiomyocyte pyroptosis and myocardial I/R injury.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COASY variant as a new genetic cause of riboflavin-responsive lipid storage myopathy","authors":"Yilei Zheng, Tongling Liufu, Bing Wen, Chao Zhou, Lingchun Liu, Yusen Qiu, Wenquan Zou, Wei Zhang, Yu Li, Jianfeng Pei, Yiheng Zeng, Wanjin Chen, Chunhua Zhang, Yun Yuan, Guochun Wang, Chuanzhu Yan, Xin Lu, Jianwen Deng, Zhaoxia Wang, Daojun Hong","doi":"10.1038/s41421-023-00641-0","DOIUrl":"https://doi.org/10.1038/s41421-023-00641-0","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139978326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.","authors":"Hanwen Zhu, Patricia Hixson, Wen Ma, Ji Sun","doi":"10.1038/s41421-024-00660-5","DOIUrl":"10.1038/s41421-024-00660-5","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":null,"pages":null},"PeriodicalIF":33.5,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}