1. Transfer RNA acetylation regulates in vivo mammalian stress signaling.
- Author
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Gamage ST, Khoogar R, Manage SH, Crawford MC, Georgeson J, Polevoda BV, Sanders C, Lee KA, Nance KD, Iyer V, Kustanovich A, Perez M, Thu CT, Nance SR, Amin R, Miller CN, Holewinski RJ, Meyer T, Koparde V, Yang A, Jailwala P, Nguyen JT, Andresson T, Hunter K, Gu S, Mock BA, Edmondson EF, Difilippantonio S, Chari R, Schwartz S, O'Connell MR, Chih-Chien Wu C, and Meier JL
- Abstract
Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac
4 C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu , increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, 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 translation control as well as therapeutic interventions., Competing Interests: DECLARATION OF INTERESTS The authors have no positions or financial interests to declare.- Published
- 2024
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