{"title":"LncRNA TubAR complexes with TUBB4A and TUBA1A to promote microtubule assembly and maintain myelination.","authors":"Xiaolin Liang, Meng Gong, Zhikai Wang, Jie Wang, Weiwei Guo, Aoling Cai, Zhenye Yang, Xing Liu, Fuqiang Xu, Wei Xiong, Chuanhai Fu, Xiangting Wang","doi":"10.1038/s41421-024-00667-y","DOIUrl":"10.1038/s41421-024-00667-y","url":null,"abstract":"<p><p>A long-standing hypothesis proposes that certain RNA(s) must exhibit structural roles in microtubule assembly. Here, we identify a long noncoding RNA (TubAR) that is highly expressed in cerebellum and forms RNA-protein complex with TUBB4A and TUBA1A, two tubulins clinically linked to cerebellar and myelination defects. TubAR knockdown in mouse cerebellum causes loss of oligodendrocytes and Purkinje cells, demyelination, and decreased locomotor activity. Biochemically, we establish the roles of TubAR in promoting TUBB4A-TUBA1A heterodimer formation and microtubule assembly. Intriguingly, different from the hypomyelination-causing mutations, the non-hypomyelination-causing mutation TUBB4A-R2G confers gain-of-function for an RNA-independent interaction with TUBA1A. Experimental use of R2G/A mutations restores TUBB4A-TUBA1A heterodimer formation, and rescues the neuronal cell death phenotype caused by TubAR knockdown. Together, we uncover TubAR as the long-elusive structural RNA for microtubule assembly and demonstrate how TubAR mediates microtubule assembly specifically from αβ-tubulin heterodimers, which is crucial for maintenance of cerebellar myelination and activity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"54"},"PeriodicalIF":33.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11106304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070585","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}
Cell DiscoveryPub Date : 2024-05-20DOI: 10.1038/s41421-024-00682-z
Song Li, Xinxing Ouyang, Hongxiang Sun, Jingsi Jin, Yao Chen, Liang Li, Qijun Wang, Yingzhong He, Jiwen Wang, Tongxin Chen, Qing Zhong, Yinming Liang, Philippe Pierre, Qiang Zou, Youqiong Ye, Bing Su
{"title":"DEPDC5 protects CD8<sup>+</sup> T cells from ferroptosis by limiting mTORC1-mediated purine catabolism.","authors":"Song Li, Xinxing Ouyang, Hongxiang Sun, Jingsi Jin, Yao Chen, Liang Li, Qijun Wang, Yingzhong He, Jiwen Wang, Tongxin Chen, Qing Zhong, Yinming Liang, Philippe Pierre, Qiang Zou, Youqiong Ye, Bing Su","doi":"10.1038/s41421-024-00682-z","DOIUrl":"10.1038/s41421-024-00682-z","url":null,"abstract":"<p><p>Peripheral CD8<sup>+</sup> T cell number is tightly controlled but the precise molecular mechanism regulating this process is still not fully understood. In this study, we found that epilepsy patients with loss of function mutation of DEPDC5 had reduced peripheral CD8<sup>+</sup> T cells, and DEPDC5 expression positively correlated with tumor-infiltrating CD8<sup>+</sup> T cells as well as overall cancer patient survival, indicating that DEPDC5 may control peripheral CD8<sup>+</sup> T cell homeostasis. Significantly, mice with T cell-specific Depdc5 deletion also had reduced peripheral CD8<sup>+</sup> T cells and impaired anti-tumor immunity. Mechanistically, Depdc5-deficient CD8<sup>+</sup> T cells produced high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced expression of ATF4, leading to spontaneous ferroptosis. Together, our study links DEPDC5-mediated mTORC1 signaling with CD8<sup>+</sup> T cell protection from ferroptosis, thereby revealing a novel strategy for enhancing anti-tumor immunity via suppression of ferroptosis.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"53"},"PeriodicalIF":33.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11102918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141065143","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":"Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study.","authors":"Yunyu Mao, Qibin Liao, Youwei Zhu, Mingyuan Bi, Jun Zou, Nairong Zheng, Lingyan Zhu, Chen Zhao, Qing Liu, Li Liu, Jun Chen, Ling Gu, Zhuoqun Liu, Xinghao Pan, Ying Xue, Meiqi Feng, Tianlei Ying, Pingyu Zhou, Zhanshuai Wu, Jian Xiao, Renfang Zhang, Jing Leng, Yongtao Sun, Xiaoyan Zhang, Jianqing Xu","doi":"10.1038/s41421-024-00658-z","DOIUrl":"10.1038/s41421-024-00658-z","url":null,"abstract":"<p><p>Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"49"},"PeriodicalIF":33.5,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916086","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}
Cell DiscoveryPub Date : 2024-05-07DOI: 10.1038/s41421-024-00679-8
Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao
{"title":"Mechanisms of ligand recognition and activation of melanin-concentrating hormone receptors.","authors":"Qian He, Qingning Yuan, Hong Shan, Canrong Wu, Yimin Gu, Kai Wu, Wen Hu, Yumu Zhang, Xinheng He, H Eric Xu, Li-Hua Zhao","doi":"10.1038/s41421-024-00679-8","DOIUrl":"10.1038/s41421-024-00679-8","url":null,"abstract":"<p><p>Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 and MCHR2 receptors, both of which are class A G protein-coupled receptors. MCHR1 predominately couples to inhibitory G protein, G<sub>i/o</sub>, and MCHR2 can only couple to G<sub>q/11</sub>. Here we present cryo-electron microscopy structures of MCH-activated MCHR1 with G<sub>i</sub> and MCH-activated MCHR2 with G<sub>q</sub> at the global resolutions of 3.01 Å and 2.40 Å, respectively. These structures reveal that MCH adopts a consistent cysteine-mediated hairpin loop configuration when bound to both receptors. A central arginine from the LGRVY core motif between the two cysteines of MCH penetrates deeply into the transmembrane pocket, triggering receptor activation. Integrated with mutational and functional insights, our findings elucidate the molecular underpinnings of ligand recognition and MCH receptor activation and offer a structural foundation for targeted drug design.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"10 1","pages":"48"},"PeriodicalIF":33.5,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851550","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}
Cell DiscoveryPub Date : 2024-05-04DOI: 10.1038/s41421-024-00671-2
Qingfeng Wang, Junfeng Ma, Yuxing Gong, Lifu Zhu, Huanyu Tang, Xingsheng Ye, Guannan Su, Fanfan Huang, Shiyao Tan, Xianbo Zuo, Yuan Gao, Peizeng Yang
{"title":"Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet’s uveitis","authors":"Qingfeng Wang, Junfeng Ma, Yuxing Gong, Lifu Zhu, Huanyu Tang, Xingsheng Ye, Guannan Su, Fanfan Huang, Shiyao Tan, Xianbo Zuo, Yuan Gao, Peizeng Yang","doi":"10.1038/s41421-024-00671-2","DOIUrl":"https://doi.org/10.1038/s41421-024-00671-2","url":null,"abstract":"<p>Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet’s uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"40 1","pages":""},"PeriodicalIF":33.5,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140834590","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}
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