Transfer RNA acetylation regulates in vivo mammalian stress signaling

作者：Supuni Thalalla Gamage, Roxane Khoogar, Shereen Howpay Manage, Judey T. DaRos, McKenna C. Crawford, Joe Georgeson, Bogdan Polevoda, Chelsea Sanders, Kendall A. Lee, Kellie D. Nance, Vinithra Iyer, Anatoly Kustanovich, Minervo Perez, Chu T. Thu, Sam R. Nance, Ruhul Amin, Christine N. Miller, Ronald J. Holewinski, Sudipto Das, Thomas J. Meyer, Vishal N. Kopardé, Acong Yang, Parthav Jailwala, Joe Nguyen, Þorkell Andrésson, Kent W. Hunter, Shuo Gu, Beverly A. Mock, Elijah F. Edmondson, Simone Difilippantonio, Raj Chari, Schraga Schwartz, Mitchell R. O’Connell, Colin Chih‐Chien Wu, Jordan L. Meier · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ads2923 · 被引用次数：13 · 研究领域：RNA modifications and cancer、RNA and protein synthesis mechanisms、RNA Research and Splicing

Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here, we investigate the impact of N 4 -acetylcytidine (ac 4 C), a highly conserved tRNA modification catalyzed by the essential acetyltransferase Nat10. By targeting Thumpd1, a nonessential adapter protein required for Nat10-catalyzed tRNA acetylation, we determine that loss of tRNA acetylation leads to reduced levels of tRNA Leu , increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality in mice, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translational control and therapeutic interventions.