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

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• T cell receptor (TCR) engagement triggers complex cellular responses including signaling, cell cycle control, and cell death.
• The precise molecular mechanisms governing mRNA translation during these T cell responses remain largely unclear.

Purpose of the Study:

• To identify novel regulators of T cell death pathways, specifically focusing on CD95 (FAS/APO-1)-mediated apoptosis.
• To elucidate the role of the identified regulator, AMBRA1, in T cell activation, signaling, and cell fate.

Main Methods:

• A whole-genome CRISPR screen was employed to identify genes regulating CD95-mediated T cell death.
• Functional assays were conducted to assess the impact of AMBRA1 on T cell death, gene expression, and protein synthesis.

Main Results:

• AMBRA1 was identified as a key regulator of T cell death, with its absence conferring resistance to FAS-mediated apoptosis.
• AMBRA1 deficiency led to decreased FAS expression at the translational level.
• AMBRA1 was found to be essential for ribosome biogenesis and the loading of ribosomes onto specific mRNAs, impacting TCR signaling and cell cycle pathways.
• TCR stimulation was shown to translationally control AMBRA1 via the CD28-PI3K-mTORC1-EIF4F pathway.

Conclusions:

• AMBRA1 is a critical translational regulator that modulates T cell responses to TCR engagement.
• AMBRA1 plays a pivotal role in balancing TCR signaling, cell cycle progression, and T cell death.
• These findings reveal new insights into the translational control mechanisms governing T cell activation and survival.