小柯机器人

美国圣犹大儿童研究医院Hongbo Chi团队通过CRISPR筛选揭示T细胞免疫营养供给的信号枢纽。这一研究成果于2021年11月18日在线发表在国际学术期刊《自然》上。

研究人员利用全基因组CRISPR筛选，并结合蛋白-蛋白相互作用网络，确定了在小鼠调节性T（T_reg）细胞中介导免疫受体和营养依赖性信号到mTORC1的调节模块。SEC31A被确定为通过与GATOR2组件SEC13相互作用来促进mTORC1的激活，从而保护其不受SKP1依赖的蛋白体降解。因此，SEC31A的缺失会损害小鼠的T细胞启动和T_reg抑制功能。此外，SWI/SNF复合物限制了氨基酸传感器CASTOR1的表达，从而增强了mTORC1的激活。

此外，研究人员揭示了CCDC101相关的SAGA复合物是mTORC1的有效抑制因子，它限制了葡萄糖和氨基酸转运体的表达，并在体内维持T细胞的静止。小鼠T_reg细胞中Ccdc101的特异性缺失导致炎症不受控制，但抗肿瘤免疫力提高。

总之，这些研究结果建立了表观遗传和翻译后机制，这些机制是营养物质运输器、传感器和转换器如何与免疫信号相互作用，进而对mTORC1活性进行三级调控的基础，并确定了它们在实现T细胞免疫和免疫耐受中的关键作用。

据介绍，营养物质是适应性免疫的新兴调节因子。选择性营养素与免疫信号相互作用，mTORC1是细胞代谢的关键驱动因素，但这些环境信号如何被整合到免疫调节中仍不清楚。

附：英文原文

Title: CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity

Author: Long, Lingyun, Wei, Jun, Lim, Seon Ah, Raynor, Jana L., Shi, Hao, Connelly, Jon P., Wang, Hong, Guy, Cliff, 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: https://www.nature.com/articles/s41586-021-04109-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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