Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Małecki, Jȩdrzej M. ; Odonohue, Marie Francoise ; Kim, Yeji ; Jakobsson, Magnus E. LU ; Gessa, Luca ; Pinto, Rita ; Wu, Jie ; Davydova, Erna ; Moen, Anders and Olsen, Jesper V. , et al. (2021) In Nucleic Acids Research 49(6). p.3185-3203
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
volume
49
issue
6
pages
19 pages
publisher
Oxford University Press
external identifiers
  • pmid:33693809
  • scopus:85104047800
ISSN
0305-1048
DOI
10.1093/nar/gkab088
language
English
LU publication?
no
additional info
Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
id
6d16c98f-62b0-4ab4-9f40-178c46b525a1
date added to LUP
2021-08-16 11:59:14
date last changed
2025-01-27 15:06:53
@article{6d16c98f-62b0-4ab4-9f40-178c46b525a1,
  abstract     = {{<p>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. </p>}},
  author       = {{Małecki, Jȩdrzej M. and Odonohue, Marie Francoise and Kim, Yeji and Jakobsson, Magnus E. and Gessa, Luca and Pinto, Rita and Wu, Jie and Davydova, Erna and Moen, Anders and Olsen, Jesper V. and Thiede, Bernd and Gleizes, Pierre Emmanuel and Leidel, Sebastian A. and Falnes, Pål}},
  issn         = {{0305-1048}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{6}},
  pages        = {{3185--3203}},
  publisher    = {{Oxford University Press}},
  series       = {{Nucleic Acids Research}},
  title        = {{Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function}},
  url          = {{http://dx.doi.org/10.1093/nar/gkab088}},
  doi          = {{10.1093/nar/gkab088}},
  volume       = {{49}},
  year         = {{2021}},
}