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

Lingyun Long, Jun Wei, Seon Ah Lim, Jana L. Raynor, Hao Shi, Jon P. Connelly, Hong Wang, Cliff Guy, Boer Xie, Nicole M. Chapman, Guotong Fu, Yanyan Wang, Hongling Huang, Wei Su, Jordy Saravia, Isabel Risch, Yong Dong Wang, Yuxin Li, Mingming Niu, Yogesh DhunganaAnil Kc, Peipei Zhou, Peter Vogel, Jiyang Yu, Shondra M. Pruett-Miller, Junmin Peng, Hongbo Chi

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2–4, 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.

Original languageEnglish
Pages (from-to)308-313
Number of pages6
JournalNature
Volume600
Issue number7888
DOIs
StatePublished - 9 Dec 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

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