METTL18 ensures pancreatic function by maintaining proper translation and proteostasis.

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.