AMBRA1 controls the translation of immune-specific genes in T lymphocytes

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. During 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 resist 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 loading on select mRNAs that plays a key role in balancing TCR signaling with cell cycle regulation pathways. We also found that AMBRA1 itself is translational 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 that governs TCR signaling, cell cycle progression and T cell death.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Michael J. Lenardo  

PROVIDER: MSV000096042 | MassIVE | Tue Oct 08 05:51:00 BST 2024

SECONDARY ACCESSION(S): PXD056612

REPOSITORIES: MassIVE