Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function
Open accessAbstract
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.
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Two complexes, Rpl12B-Rmt2 and Rpl7A-Fpr4, involving enzymes that introduce protein modifications such as arginine methylations or proline isomerizations, provide insight into mechanisms that expand the chemical diversity of ribosomal proteins at functional sites and possibly regulate translation.
“Two complexes, Rpl12B–Rmt2 and Rpl7A–Fpr4, involving enzymes that introduce protein modifications such as arginine methylations or proline isomerizations (47), provide insight into mechanisms that expand the chemical diversity of ribosomal proteins at functional sites (48) and possibly regulate translation (49).”
From Computed structures of core eukaryotic protein complexes (2021) · cites this paper as [49]
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References 73 · Cited by 59
- Authors
- Małecki, J. M., Odonohue, M.-F., Kim, Y., Jakobsson, M. E., Gessa, L., Pinto, R., Wu, J., Davydova, E., Moen, A., Olsen, J. V., Thiede, B., Gleizes, P.-E., Leidel, S. A., & Falnes, P. Ø.
- Affiliations
- University of Oslo (NO)
- Molecular, Cellular and Developmental Biology Unit (MCD), Centre for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France
- University of Bern (CH)
- University of Copenhagen (DK)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Małecki, Jędrzej M
- Falnes, Pål Ø
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-03-08
- Volume
- 49
- Issue
- 6
- Pages
- 3185-3203
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC8034639
- OpenAlex
- W3135663330
- Cited by
- 59
- References
- 73
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 5 · 2023: 15 · 2022: 8 · 2021: 8
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
- HAL (submittedVersion)
- BORIS (University Library Bern) (submittedVersion, cc-by-nc)
- NORA - Norwegian Open Research Archives (submittedVersion, cc-by-nc)
- Open Access CRIS of the University of Bern
- Funders
- Norwegian Cancer Society (107744-PR-2007-0132)
- Research Council of Norway (FRIMEDBIO-240009)
- Max Planck Society
- DFG Grant (LE 3260/3-1)
- Lundbeck Foundation (R231–2016-2682)
- Novo Nordisk Foundation (NNF16OC0022946, NNF14CC0001)
- Agence Nationale de la Recherche (ANR-16-CE11-0029-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- ribosomal protein L3, protein methylation, 3-methylhistidine, ribosome biogenesis, pre-rRNA processing, polysome formation, mRNA translation, nucleolus
- MeSH terms
- Ribosomal Protein L3, Cell Nucleolus, HeLa Cells, Histidine, Humans, Protein Methyltransferases, Ribosomal Proteins, Ribosomes, RNA Processing, Post-Transcriptional, RNA, Ribosomal, Protein Biosynthesis, Nuclear Localization Signals, Amino Acid Motifs, HEK293 Cells
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