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Transfer RNA acetylation regulates in vivo mammalian stress signaling

ABSTRACT: Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac4C), 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 eIF2-alpha phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, revealing a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated signaling in mammalian organisms. Insights into how tRNA modifications shape phenotype and signaling in response to stress provide a foundation for novel strategies for therapeutic intervention and translational control.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Jordan Meier

PROVIDER: MSV000095557 | MassIVE | Thu Aug 08 08:58:00 BST 2024

REPOSITORIES: MassIVE

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