| First Author | Long L | Year | 2021 |
| Journal | Nature | Volume | 600 |
| Issue | 7888 | Pages | 308-313 |
| PubMed ID | 34795452 | Mgi Jnum | J:345359 |
| Mgi Id | MGI:7287971 | Doi | 10.1038/s41586-021-04109-7 |
| Citation | Long L, et al. (2021) CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity. Nature 600(7888):308-313 |
| abstractText | Nutrients are emerging regulators of adaptive immunity(1). Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism(2-4), 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. |
