Mitochondrial RNA m3C methyltransferase METTL8 relies on an isoform-specific N-terminal extension and modifies multiple heterogenous tRNAs

文献类型： 外文期刊

第一作者： Huang, Meng-Han

作者： Huang, Meng-Han;Wang, Jin-Tao;Zhang, Jian-Hui;Mao, Xue-Ling;Peng, Gui-Xin;Wang, En-Duo;Zhou, Xiao-Long;Zhang, Jian-Hui;Zhou, Xiao-Long;Peng, Gui-Xin;Wang, En-Duo;Lin, Xiuying;Lin, Huan;Lin, Xiuying;Lv, Daizhu;Yuan, Chen

作者机构：

关键词： tRNA; 3-methylcytidine; Methyltransferase; Aminoacylation

期刊名称：SCIENCE BULLETIN （ 影响因子：18.9； 五年影响因子：14.2 ）

ISSN： 2095-9273

年卷期： 2023 年 68 卷 18 期

页码：

收录情况： SCI

摘要： Methyltransferase-like 8 (METTL8) encodes a mitochondria-localized METTL8-Iso1 and a nucleolus -distributed METTL8-Iso4 isoform, which differ only in their N-terminal extension (N-extension), by mRNA alternative splicing. METTL8-Iso1 generates 3-methylcytidine at position 32 (m3C32) of mitochon-drial tRNAThr and tRNASer(UCN). Whether METTL8-Iso4 is an active m3C32 methyltransferase and the role of the N-extension in mitochondrial tRNA m3C32 formation remain unclear. Here, we revealed that METTL8-Iso4 was inactive in m3C32 generation due to the lack of N-extension, which contains several absolutely conserved modification-critical residues; the counterparts were likewise essential in cytoplas-mic m3C32 biogenesis by methyltransferase-like 2A (METTL2A) or budding yeasts tRNA N3-methylcytidine methyltransferase (Trm140), in vitro and in vivo. Cross-compartment/species tRNA modification assays unexpectedly found that METTL8-Iso1 efficiently introduced m3C32 to several cytoplasmic or even bacterial tRNAs in vitro. m3C32 did not influence tRNAThr N6-threonylcarbamoyladenosine (t6A) modification or aminoacylation. In addition to its interaction with mitochondrial seryl-tRNA synthetase (SARS2), we further discovered an interaction between mitochon-drial threonyl-tRNA synthetase (TARS2) and METTL8-Iso1. METTL8-Iso1 substantially stimulated the aminoacylation activities of SARS2 and TARS2 in vitro, suggesting a functional connection between mito-chondrial tRNA modification and charging. Altogether, our results deepen the mechanistic insights into mitochondrial m3C32 biogenesis and provide a valuable route to prepare cytoplasmic/bacterial tRNAs with only a m3C32 moiety, aiding in future efforts to investigate its effects on tRNA structure and function.(c) 2023 Science China Press. Published by Elsevier B.V. and Science China Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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