Mammalian tRNA acetylation determines translation efficiency and tRNA quality control.

Abstract

Acetylation is a conserved and pivotal RNA modification. Acetylation of tRNA occurs at C12 (ac⁴C12) in eukaryotic tRNAs. Yeast ac⁴C12 prevents tRNA^Ser from rapid tRNA decay (RTD) at higher temperatures. However, the biological function of ac⁴C12 in higher eukaryotes remains unexplored. Moreover, whether mammalian cells contain an RTD pathway is unclear. Here, we deleted Thumpd1, the indispensable factor for ac⁴C12 biogenesis, in NIH/3T3 cells. Loss of ac⁴C12 significantly reduced tRNA aminoacylation and translational efficiency physiologically, in particular, of those enriched with Ser/Leu codons with two U/A nucleotides. Remarkably, ac⁴C12 hypomodification selectively generated rapid tRNA^Leu(CAG) turnover under heat stress. We demonstrated that tRNA^Leu(CAG) was degraded by a mammalian RTD (mRTD) mechanism, consisting of Xrn1/Xrn2-mediated 5'-3' exonuclease digestion and intracellular pAp level control by Bpnt1/Bpnt2. Our results reveal both the pivotal roles of ac⁴C12 in translation and a mRTD pathway for tRNA quality control under heat stress in mammalian cells.