4.6 Article

Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 298, 期 4, 页码 -

出版社

ELSEVIER
DOI: 10.1016/j.jbc.2022.101788

关键词

m3C; 3-methylcytosine; METTL8; methyltransferase-like 8; mt; mitochondrial; MTS; mitochondrial targeting sequence; ORF; open reading frame; PHA; Positive Hybridization in the Absence of Modification; RFP; red fluorescent protein; RT; reverse transcriptase; sgRNAs; sequence guide RNAs

资金

  1. National Science Foundation CAREER Award [1552126]
  2. Div Of Molecular and Cellular Bioscience
  3. Direct For Biological Sciences [1552126] Funding Source: National Science Foundation

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The study reveals that METTL8 is necessary for m3C formation in mt-tRNAs in humans and suggests a potential role for m3C modification in mitochondrial tRNA structure.
A subset of eukaryotic tRNAs is methylated in the anticodon loop, forming 3-methylcytosine (m3C) modifications. In mammals, the number of tRNAs containing m3C modifications has been expanded to include mitochondrial (mt) tRNA-SerUGA and mt-tRNA-Thr-UGU. However, whereas the enzymes catalyzing m3C formation in nuclear-encoded tRNAs have been identified, the proteins responsible for m3C modification in mt-tRNAs are unknown. Here, we show that m3C formation in human mt-tRNAs is dependent upon the methyltransferase-Like 8 (METTL8) enzyme. We find that METTL8 is a mitochondria-associated protein that interacts with mitochondrial seryl-tRNA synthetase, as well as with mttRNAs containing m3C. We demonstrate that human cells deficient in METTL8 exhibit loss of m3C modification in mttRNAs, but not nuclear-encoded tRNAs. Consistent with the mitochondrial import of METTL8, the formation of m3C in METTL8-deficient cells could be rescued by re-expression of WT METTL8, but not by a METTL8 variant lacking the N-terminal mitochondrial localization signal. Notably, we found METTL8-deficiency in human cells causes alterations in the native migration pattern of mt-tRNA-Ser-UGA, suggesting a role for m3C in tRNA folding. Altogether, these findings demonstrate that METTL8 is required for m3C formation in mt-tRNAs and uncover a potential function for m3C modification in mitochondrial tRNA structure.

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