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

• 成果类型: Article
• 署名作者: Gottlieb, Simone; Shang, Wanjing; Ye, Deji; Kubo, Satoshi; Jiang, Ping Du; Shafer, Samantha; Xu, Leilei; Zheng, Lixin; Park, Ann Y.; Song, Jian; Chan, Waipan; Zeng, Zhiqin; He, Tingyan; Schwarz, Benjamin; Haeupl, Bjoern; Oellerich, Thomas; Lenardo, Michael J.; Yao, Yikun
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Chinese Academy of Sciences; Shanghai Institute of Nutrition & Health, CAS; University of Chinese Academy of Sciences, CAS; University of Occupational & Environmental Health - Japan; Shenzhen Children's Hospital; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Goethe University Frankfurt
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11325
• DOI: 10.1073/pnas.2416722121
• 发表日期: 2024-10-29
• 关键词: cell; identification; expression; apoptosis; proteins

摘要

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.