| Author |
Gottlieb, S; Shang, WJ; Ye, DJ; Kubo, S; Jiang, PD; Shafer, S; Xu, LL; Zheng, LX; Park, AY; Song, J; Chan, WP; Zeng, ZQ; He, TY; Schwarz, B; Häupl, B; Oellerich, T; Lenardo, MJ; Yao, YK |
| Abstract |
T cell receptor (TCR) engagement causes a global cellular response that entrains signaling pathways, cell cycle regulation, and cell death. The molecular regulation of mRNA translation in these processes is poorly understood. Using a whole- genome CRISPR screen for regulators of CD95 (FAS/APO-1)- mediated T cell death, we identified AMBRA1, a protein previously studied for its roles in autophagy, E3 ubiquitin ligase activity, and cyclin regulation. T cells lacking AMBRA1 resisted FAS- mediated cell death by down- regulating FAS expression at the translational level. We show that AMBRA1 is a vital regulator of ribosome protein biosynthesis and ribosome loading on select mRNAs, whereby it plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translationally controlled by TCR stimulation via the CD28-PI3K-mTORC1-EIF4F pathway. Together, these findings shed light on the molecular control of translation after T cell activation and implicate AMBRA1 as a translational regulator governing TCR signaling, cell cycle progression, and T cell death. |
