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METTL18 Ensures Pancreatic Function by Maintaining Proper Translation and Proteostasis

ABSTRACT: Methyltransferases fine-tune various biomolecules by site-specific methylation. METTL18, an N3-position-specific histidine methyltransferase, modifies H245 of the ribosomal protein RPL3 (uL3), thereby regulating translation dynamics and proteostasis. However, the physiological role of this enzyme in vivo remains to be elucidated. Here, we show that METTL18 is essential for pancreatic function by regulating translation and suppressing protein aggregation. Mettl18 knockout (KO) mice exhibited partial preweaning lethality, and the surviving mice showed a marked reduction in N3-histidine methylation in the pancreas, diabetic phenotypes, and accumulation of pancreatitis-associated proteins. Ribosome profiling in a pancreatic acinar cell line revealed that loss of METTL18 caused global translational alterations, including accelerated elongation at proline codons. The improper ribosome traverse compromises protein folding, resulting in the aggregation of pancreatitis-associated proteins, including Reg1, and activation of the unfolded protein response. Our findings establish histidine methylation as a physiologically important post-translational modification and highlight METTL18 as a key regulator of pancreatic function through the maintenance of proteostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE303714 | GEO | 2026/02/17

REPOSITORIES: GEO

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Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)

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METTL18 Ensures Pancreatic Function by Maintaining Proper Translation and Proteostasis

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