AMBRA1 controls the translation of immune-specific genes in T lymphocytes
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.
Authors
- Thomas Oellerich (ORCID: https://orcid.org/0000-0001-6570-6125)
- Simone Gottlieb (ORCID: https://orcid.org/0000-0003-0550-4761)
- Ann Y. Park (ORCID: https://orcid.org/0000-0002-0130-1521)
- Waipan Chan (ORCID: https://orcid.org/0000-0002-9109-6583)
- Benjamin Schwarz (ORCID: https://orcid.org/0000-0002-5894-953X)
- Yikun Yao
- Deji Ye (ORCID: https://orcid.org/0000-0002-5161-8359)
- Satoshi Kubo (ORCID: https://orcid.org/0000-0001-9693-9263)
- Michael J. Lenardo (ORCID: https://orcid.org/0000-0003-1584-468X)
- Björn Häupl (ORCID: https://orcid.org/0009-0000-9445-9565)
- Lixin Zheng (ORCID: https://orcid.org/0000-0003-0760-4176)
- Wanjing Shang (ORCID: https://orcid.org/0009-0007-0646-7946)
- Jian Song (ORCID: https://orcid.org/0000-0002-0289-3063)
- Tingyan He (ORCID: https://orcid.org/0000-0002-0222-2091)
- Ping Jiang
- Leilei Xu (ORCID: https://orcid.org/0000-0002-2467-8612)
- Samantha Shafer (ORCID: https://orcid.org/0000-0001-9429-414X)
- Zhiqin Zeng
Institutions
- Goethe University Frankfurt (DE)
- University of Occupational and Environmental Health Japan (JP)
- Shanghai Institute of Nutrition and Health (CN)
- National Institute of Allergy and Infectious Diseases (US)
- Shenzhen Children's Hospital (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1073/pnas.2416722121
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 1.20
Funders
- University of Occupational and Environmental Health
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- University of Chinese Academy of Sciences
- National Science and Technology Major Project
- National Institutes of Health
- National Key Research and Development Program of China
- National Institute of Allergy and Infectious Diseases
- NHLBI Division of Intramural Research