– 講演タイトル

Transfer RNA modification is a major determinant to coordinate mRNA stability, proteostasis, and longevity

– 抄録

Transfer RNAs (tRNAs) harbor diverse post-transcriptional modifications that are essential for maintaining the accuracy and efficiency of protein synthesis. Here, we identify MTL-A and MTL-B as previously uncharacterized human tRNA methyltransferases responsible for 2ʹ-O-methylation at position 39 (Nm39) in cytoplasmic tRNAs, and show that each enzyme selectively modifies distinct tRNA substrates. Analysis of MTL-A/B double-knockout cells revealed that Nm39 regulates ribosome elongation dynamics at specific codons and is required to maintain the stability of mRNAs enriched with optimal codons. Consistent with this, codon stability coefficients (CSCs) determined from transcriptome-wide mRNA half-lives were extensively reorganized in the double knockout cells, resulting in a global reversal of the codon optimality landscape across virtually all sense codons in human cells. These findings demonstrate that Nm39 not only modulates translation elongation at individual codons but also serves as a key molecular determinant of codon optimality. Furthermore, Nm39 promotes co-translational protein folding, thereby contributing to proteostasis. The double-knockout cells exhibited increased sensitivity to iron deficiency but enhanced resistance to oxidative stress. In Drosophila melanogaster, loss of Mtl-A significantly shortened lifespan, whereas its overexpression extended lifespan, indicating that Nm39 also contributes to organismal longevity. Collectively, our findings not only elucidate Nm39 biogenesis but also demonstrate that codon optimality is not a static property encoded in the genome, but a dynamic feature established by tRNA modification. More broadly, we identify Nm39 as an epitranscriptomic regulator that coordinates mRNA stability, translational control, proteostasis, and aging through the establishment of codon optimality.

– 参考文献

・Suzuki, T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol 22, 375–392 (2021).

・Presnyak, V. et al. Codon optimality is a major determinant of mRNA stability. Cell 160, 1111–1124 (2015).

・Nedialkova, D. D. & Leidel, S. A. Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161, 1606–1618 (2015).