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AMBRA1 controls the translation of immune-specific genes in T lymphocytes.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 29; Vol. 121 (44), pp. e2416722121. Date of Electronic Publication: 2024 Oct 22. - Publication Year :
- 2024
-
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.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.
- Subjects :
- Humans
Lymphocyte Activation
Mechanistic Target of Rapamycin Complex 1 metabolism
Mechanistic Target of Rapamycin Complex 1 genetics
fas Receptor metabolism
fas Receptor genetics
Animals
Gene Expression Regulation
Mice
CD28 Antigens metabolism
CD28 Antigens genetics
Phosphatidylinositol 3-Kinases metabolism
T-Lymphocytes immunology
T-Lymphocytes metabolism
Protein Biosynthesis
Receptors, Antigen, T-Cell metabolism
Receptors, Antigen, T-Cell genetics
Receptors, Antigen, T-Cell immunology
Adaptor Proteins, Signal Transducing metabolism
Adaptor Proteins, Signal Transducing genetics
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 44
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 39436665
- Full Text :
- https://doi.org/10.1073/pnas.2416722121