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Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function

ABSTRACT: Methylation is a common post-translational modification that occurs primarily on lysine and arginine, but also on some other residues, such as histidine. METTL18 is the last uncharacterized member of a group of human methyltransferases (MTases) that mainly exert lysine methylation, and here we set out to elucidate its function. We found METTL18 to be a nuclear protein that contains a functional nuclear localization signal and accumulates in nucleoli. Recombinant METTL18 methylated a single protein in nuclear extracts and in isolated ribosomes from METTL18 knock-out (KO) cells. This protein was identified as 60S ribosomal protein L3 (RPL3), and we also performed an RPL3 interactomics screen and identified METTL18 as the most significantly enriched MTase. Protein mass spectrometry and amino acid analyses revealed that His-245 in RPL3 carries a 3-methylhistidine (3MH; also referred to as t-methylhistidine) modification, which was absent in METTL18 KO cells. In addition, both recombinant and endogenous METTL18 were found to be monomethylated at His-154, likely resulting from auto-methylation, and further corroborating METTL18 as a histidine-specific MTase. Finally, METTL18 KO cells displayed altered pre-rRNA processing, decreased polysomes formation and codon-specific changes in mRNA translation, indicating that METTL18-mediated methylation of RPL3 is important for optimal ribosome biogenesis and function. In conclusion, we have here established METTL18 as the second human histidine-specific protein MTase, and demonstrated its functional relevance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146364 | GEO | 2021/02/28

REPOSITORIES: GEO

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METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance

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