| 2021 |
Human METTL18 is a histidine-specific methyltransferase that methylates His-245 of RPL3 (ribosomal protein L3), producing a 3-methylhistidine (τ-methylhistidine) modification. METTL18 localizes to the nucleus and accumulates in nucleoli, requires a functional nuclear localization signal, and was identified as the most significantly enriched MTase in an RPL3 interactomics screen. METTL18 is also automethylated at its own His-154. METTL18 knockout cells show altered pre-rRNA processing, decreased polysome formation, and codon-specific changes in mRNA translation. |
Recombinant protein in vitro methylation assay, RPL3 interactomics/Co-IP screen, mass spectrometry identification of 3-methylhistidine, METTL18 KO cell lines, polysome profiling, nuclear/nucleolar localization by imaging |
Nucleic acids research |
High |
33693809
|
| 2022 |
METTL18 methylates His-245 of RPL3 at the τ-N position in vitro and in cells. This modification specifically slows ribosome traversal on Tyr codons, allowing proper folding of newly synthesized proteins. Ribosome profiling showed that loss of METTL18 accelerates translation elongation at Tyr codons, and RPL3 methylation protects cells from aggregation of Tyr-rich proteins, linking histidine methylation to proteostasis maintenance. |
In vitro methylation assay with methyl-donor analog and quantitative MS, cryo-EM structural comparison of modified vs. unmodified ribosomes, genome-wide ribosome profiling, in vitro translation assay, protein aggregation assay in METTL18 KO cells |
eLife |
High |
35674491
|
| 2024 |
METTL18-mediated methylation of RPL3 indirectly regulates HSP90 integrity and protein levels, promoting actin polymerization via HSP90, which in turn leads to Src phosphorylation at Tyr-419 and Tyr-530 and downstream oncogenic signaling in HER2-negative breast cancer cells. Loss of METTL18 reduces metastatic responses in vitro and in vivo. |
METTL18 knockdown/overexpression in breast tumor cell lines, tumor xenograft model, confocal microscopy, F/G-actin assays, Western blot for Src phosphorylation and HSP90 |
International journal of biological sciences |
Medium |
39309445
|
| 2026 |
METTL18 is essential for pancreatic function in vivo: Mettl18 knockout mice show diabetic phenotypes, accumulation of pancreatitis-associated proteins, and activation of the unfolded protein response. Ribosome profiling in pancreatic acinar cells revealed that loss of METTL18 causes global translational alterations including accelerated elongation at proline codons, leading to improper protein folding and aggregation of pancreatitis-associated proteins (e.g., Reg1). |
Mettl18 knockout mouse model, ribosome profiling in pancreatic acinar cell line, mass spectrometry for N3-histidine methylation, protein aggregation assays, unfolded protein response markers |
Molecular metabolism |
High |
41713742
|
| 2010 |
Yeast Hpm1p (ortholog of human METTL18; encoded by YIL110W, also designated HPM1) is a seven-β-strand methyltransferase responsible for stoichiometric monomethylation at His-243 of ribosomal protein Rpl3, producing 3-methylhistidine. Deletion of HPM1 abolishes this modification; the modification is found in ribosomes and nucleus-containing fractions but not in ribosome-free cytosol. |
Top-down and bottom-up mass spectrometry, in vivo radiolabeling with SAM-[methyl-3H], high-resolution cation-exchange chromatography, TLC, deletion strain analysis of 37 methyltransferase candidates |
The Journal of biological chemistry |
High |
20864530
|
| 2014 |
Yeast Hpm1p (ortholog of human METTL18) has methyltransferase activity in vitro on ribosome-associated Rpl3p but NOT on free Rpl3p, indicating its activity depends on interactions with ribosomal components. hpm1-null cells show defective early rRNA processing, deficiency of 60S subunits, translation initiation defects, resistance to cycloheximide and verrucarin A, and decreased translational fidelity. |
In vitro methyltransferase assay with ribosome-associated vs. free Rpl3p, amino acid analysis, polysome profiling, rRNA processing assays, drug resistance plate assays, translational fidelity reporters |
Molecular and cellular biology |
High |
24865971
|
| 2016 |
Methylation of Rpl3p at His-243 by Hpm1p (yeast ortholog of METTL18) plays a significant role in translation elongation fidelity. The rpl3-H243A mutation (blocking methylation at this site) phenocopies Hpm1-deficient cells in pre-rRNA processing defects and translational accuracy defects, but NOT in perturbed ribosomal subunit levels. This indicates Hpm1p has multiple substrates, with Rpl3p methylation specifically contributing to translation elongation fidelity rather than subunit biogenesis. |
Rpl3-H243A mutagenesis, translational fidelity assays (stop codon readthrough, amino acid misincorporation, -1 frameshifting), pre-rRNA processing analysis, ribosomal subunit profiling |
RNA (New York, N.Y.) |
High |
26826131
|
| 2023 |
METTL18 is identified as one of the catalytic enzymes responsible for Nτ-methylhistidine modifications in mammals. A methodology using biochemical protein fractionation combined with LC-MS/MS quantification of methylhistidine was established; METTL18 is listed alongside SETD3 and METTL9 as known mammalian histidine methyltransferases. |
Biochemical fractionation, LC-MS/MS quantification of methylhistidine, in silico structural prediction |
Journal of biochemistry |
Low |
37279646
|
| 2022 |
Loss of yeast Hpm1p (ortholog of human METTL18) results in changes to protein structure and protein-protein interactions in the ribosome, membrane proteins, chromatin, and mitochondria as detected by quantitative crosslinking MS, independently of changes in protein abundance. Hpm1p deletion also results in increased sensitivity to nonribosomal stressors and differential abundance of proteins linked to sugar metabolism coordination. |
Quantitative proteomics, stable isotope labeling crosslinking MS (XL-MS), targeted MS for H243 methylation stoichiometry, growth assays |
Molecular & cellular proteomics : MCP |
Medium |
35609787
|