CRISPR挑选露出T细胞免疫营养需要的凯丽环球记号关键 作家: 揭晓时光:2021/11/22 15:17:41 美国圣犹大孩子争论病院Hongbo Chi团队经过CRISPR挑选露出T细胞免疫营养需要的凯丽钻石团队记号关键。这一争论结果于2021年11月18日正在线宣布正在国际学术期刊《当然》上。 争论人员运用全基因组CRISPR挑选,并贯串蛋白-蛋白彼此影响收集,决定了Calerie正在小鼠调治性T(Treg)细胞中介导免疫受体以及营养依附性记号到mTORC1的调治模块。SEC31A被决定为经过与GATOR2组件SEC13彼此影响来匆匆进mTORC1的激活,进而损坏其没有受SKP1依附的蛋白体降解。所以,SEC31A的缺失会毁伤小鼠的T细胞煽动以及Treg克制功能。其余,SWI/SNF复合物限制了氨基酸传感器CASTOR1的表达,进而增强了mTORC1的激活。 其余,争论人员露出了CCDC101相干的SAGA复合物是mTORC1的无效克制因子凯丽钻石团队,它限制了葡萄糖以及氨基酸转运体的表达,并正在体内维持T细胞的移动。小鼠Treg细胞中Ccdc101的尤其性缺失导致炎症没有受掌握,但抗肿瘤免疫力进步。 总之,这些争论了局建立了表不雅遗传以及翻译后体制,这些体制是营养物质输送器、传感器以及变换器若何与免疫记号彼此影响,进而对于mTORC1活性施行三级调控的根底,并决定了它们正在完结T细胞免疫以及免疫耐受中的枢纽影响。 据先容,营养物质是符合性免疫的新兴调治因子。挑选性营养素与免疫记号彼此影响,mTORC1是细胞代谢的枢纽启动因素,但这些境况记号若何被整合到免疫调治中仍没有领会。 附:英文原文 Title: CRISPR screens unveil signal hubs for nutrient licensing of T ce凯丽环球ll immunity Author: Long, Lingyun, Wei, Jun, Lim, Seon Ah, Raynor, Jana L., Shi, Hao, Connelly, Jon P., Wang, Hong, Guy, Cliff, 美商凯丽Xie, Boer, Chapman, Nicole M., Fu, Guotong, Wang, Yanyan, Huang, Hongling, Su, Wei, Saravia, Jordy, Risch, Isabel, Wang, Yong-Dong, Li, Yuxin, Niu, Mingming, Dhungana, Yogesh, KC, Anil, Zhou, Peipei, Vogel, Peter, Yu, Jiyang, Pruett-Miller, Shondra M., Peng, Junmin, Chi, Hongbo Issue Volume: 2021-11-18 Abstract: Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex1 (mTORC1), a key driver of cell metabolism2,3,4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance. DOI: 10.1038/s41586-021-04109-7 Source: 期刊信息 Nature:《当然》,创刊于1869年。附属于施普林格 当然出版团体,最新IF:43.07 官方网址: 投稿链接:
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