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

Autor:	Małecki JM; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Odonohue MF; Molecular, Cellular and Developmental Biology Unit (MCD), Centre for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France., Kim Y; Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland., Jakobsson ME; Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation, Center for Protein Research (NNF-CPR), University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Gessa L; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Pinto R; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Wu J; Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland., Davydova E; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Moen A; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Olsen JV; Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation, Center for Protein Research (NNF-CPR), University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark., Thiede B; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway., Gleizes PE; Molecular, Cellular and Developmental Biology Unit (MCD), Centre for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France., Leidel SA; Department of Chemistry and Biochemistry, University of Bern, 3012 Bern, Switzerland., Falnes PØ; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316 Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2021 Apr 06; Vol. 49 (6), pp. 3185-3203.
DOI:	10.1093/nar/gkab088
Abstrakt:	Protein methylation 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 knockout (KO) cells, identified as 60S ribosomal protein L3 (RPL3). We also performed an RPL3 interactomics screen and identified METTL18 as the most significantly enriched MTase. We found that His-245 in RPL3 carries a 3-methylhistidine (3MH; τ-methylhistidine) modification, which was absent in METTL18 KO cells. In addition, both recombinant and endogenous METTL18 were found to be automethylated at His-154, thus further corroborating METTL18 as a histidine-specific MTase. Finally, METTL18 KO cells displayed altered pre-rRNA processing, decreased polysome 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. (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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