| 2021 |
METTL9 is a broad-specificity methyltransferase that mediates formation of the majority of 1-methylhistidine (1MH) present in mouse and human proteomes, requiring a His-x-His (HxH) motif where 'x' is preferably a small amino acid. Substrates include S100A9 and NDUFB3 (subunit of mitochondrial respiratory Complex I). METTL9-mediated methylation enhances respiration via Complex I, and 1MH in an HxH-containing peptide reduces zinc binding affinity. |
In vitro methyltransferase assays, LC-MS/MS detection of 1MH, knockout mouse models, genetic deletion with Complex I activity assay, zinc-binding affinity measurements |
Nature communications |
High |
33563959
|
| 2021 |
METTL9 catalyzes Nπ-methylhistidine (N1-methylhistidine) formation on S100A9 at His-107 in vivo and in vitro. Methylation at His-107 overlaps with S100A9's zinc-binding site, attenuating its zinc affinity. METTL9 does not affect heterodimer formation of S100A9 with S100A8. |
siRNA screening coupled with methylhistidine analysis using LC-tandem MS; in vitro methyltransferase assay; zinc-binding affinity measurements |
The Journal of biological chemistry |
High |
34562450
|
| 2023 |
Crystal/cryo structure of METTL9 in complex with substrate revealed it specifically methylates the second histidine of the HxH motif while the first histidine serves as a recognition signature. The small 'x' residue is confined within the substrate pocket. An aspartate residue stabilizes the N3 atom of the histidine imidazole ring, presenting the N1 atom to SAM for methylation. METTL9 exhibits preferred consecutive 'C-to-N' directional methylation of tandem HxH repeats. |
X-ray crystallography of METTL9-substrate complex; biochemical methyltransferase assays; mutagenesis of active-site residues |
Cell insight |
High |
37398635
|
| 2022 |
In metastatic gastric cancer cells, METTL9 protein is predominantly localized in mitochondria, and METTL9 knockdown significantly reduces mitochondrial Complex I activity, inhibiting cell migration and invasion. |
shRNA knockdown; subcellular fractionation/localization; Complex I activity assay; migration and invasion assays in vitro |
Biochemistry and biophysics reports |
Medium |
35402738
|
| 2023 |
METTL9 knockdown in hepatocellular carcinoma cells reduces SLC7A11 expression (a key suppressor of ferroptosis), promoting ferroptosis and inhibiting HCC progression in vitro and in vivo. |
shRNA knockdown; overexpression; western blotting; cell viability/migration/invasion assays; PDX tumor growth experiments |
Cell death discovery |
Medium |
38017014
|
| 2025 |
METTL9 mediates N1-histidine methylation of the zinc transporter SLC39A7 at His45 and His49. This methylation suppresses ferroptosis through the PERK/ATF4 signaling pathway and downstream SLC7A11, which transports cystine for glutathione synthesis, thereby reducing intracellular ROS and inhibiting adipogenic differentiation of mesenchymal stem cells. |
In vitro and in vivo methyltransferase assays; site-specific mutagenesis (His45, His49); western blotting; ROS measurement; adipogenic differentiation assays; OVX mouse model |
Molecular medicine (Cambridge, Mass.) |
Medium |
40414869
|
| 2025 |
METTL9 sustains vertebrate neural development primarily via non-catalytic functions. METTL9 interacts with key regulators of cellular transport, endocytosis, and Golgi integrity; in Mettl9 KO cells, the Golgi becomes fragmented. This developmental role occurs through modulation of the secretory pathway and is largely independent of its histidine methyltransferase catalytic activity. |
Mouse embryonic stem cell KO, inducible degron, and catalytically inactive knock-in lines; neural differentiation assays; multi-omics; Xenopus laevis mettl9 knockdown; co-immunoprecipitation with transport/Golgi regulators; Golgi morphology imaging |
Nature communications |
High |
40745158
|
| 2024 |
METTL9 promotes histidine methylation of NF-κB RELA, resulting in inhibition of NLRP3 epigenetic transcription and suppression of neuronal pyroptosis in a Parkinson's disease mouse model. |
MPTP mouse model; electroacupuncture treatment; METTL9 deficiency; luciferase and ChIP assays for NF-κB binding to NLRP3 promoter; western blotting; TUNEL/flow cytometry |
Critical reviews in eukaryotic gene expression |
Low |
39072406
|
| 2025 |
Co-immunoprecipitation confirmed that METTL9 binds to SLC7A11, enhancing its stability and reducing its degradation, thus modulating ferroptosis in hepatocellular carcinoma independently of the classical GPX4 pathway. |
Co-immunoprecipitation (Co-IP); RNA sequencing; CUT&Tag; overexpression and knockdown experiments; in vivo mouse tumor models |
NPJ precision oncology |
Medium |
40523929
|
| 2025 |
METTL9 orthologues across eukaryotes retain in vitro methyltransferase activity on HxH-containing substrates (e.g., ARMC6 and DNAJB12), but show distinct substrate specificities. The X-ray structure of Ostreococcus tauri METTL9 revealed structural differences from human METTL9 that may explain its distinct substrate specificity. Tolerance for substitutions at the HxH flanking positions varies among orthologues (Hs > Dm > Ot). |
In vitro methyltransferase assays; peptide array substrate specificity profiling; X-ray crystallography of OtMETTL9 |
The Journal of biological chemistry |
High |
40451431
|
| 2026 |
A first-in-class inhibitor (METTL9i) binds within the SAM binding pocket of METTL9 with IC50 of 0.067 µM and inhibits METTL9 with selectivity over other methyltransferases. In cells, METTL9i engages METTL9 and reduces global 1-methylhistidine levels, confirming the SAM pocket as the catalytic site. |
Enzymatic inhibition assay (IC50 measurement); X-ray crystallography of METTL9i-METTL9 complex; cellular target engagement assay; global 1-MH quantification by MS |
Angewandte Chemie (International ed. in English) |
High |
41870122
|