Serine tRNAs Compete to Regulate the mRNA Translation Of Serine-sensitive Codons

Differential mRNA translation efficiency (mTE) of codons is important in regulating protein synthesis, cellular states, and can change in response to amino acid (AA) availability. While the mTE of codons is canonically associated with their corresponding transfer RNA (tRNA) isoacceptors, its regulation by AAs in mammalian cells remains unexplored. We found that ELAC2, a 3’ tRNA maturation endonuclease, decreases the mTE of UC[U/C] serine (Ser) codons in response to Ser-limitation. Ablation of ELAC2 restored UC[U/C] mTE but reduced the mTE of AG[U/C] Ser codons. Among the tRNASer isoacceptors, tRNASer(GCU) decreased the most in ELAC2-deficient cells. Surprisingly, tRNASer(GCU) delivery restored AG[U/C] mTE and reduced UC[C/U] mTE in ELAC2-deficient cells. Finally, we deciphered the effects of Ser-sensitive codons on mRNA translation and the human proteome. Our study revealed that in response to Ser-limitation, regulation of tRNASer(GCU) levels fine-tune the mTE of UC[C/U] or AG[U/C] Ser-sensitive codons and shapes the proteome.