METTL18 ensures pancreatic function by maintaining proper translation and proteostasis

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Methyltransferases are enzymes that modify biomolecules through methylation.
• METTL18 is a specific histidine methyltransferase targeting ribosomal protein RPL3 (uL3).
• The in vivo function of METTL18 in physiological processes is not well understood.

Purpose of the Study:

• To investigate the physiological role of METTL18 in vivo.
• To determine the impact of METTL18 on pancreatic function, translation, and proteostasis.

Main Methods:

• Generation and analysis of Mettl18 knockout (KO) mice.
• Assessment of pancreatic function, methylation levels, and protein aggregation.
• Ribosome profiling in a pancreatic acinar cell line to study translational alterations.

Main Results:

• Mettl18 KO mice displayed preweaning lethality, reduced pancreatic N3-histidine methylation, diabetic phenotypes, and protein aggregation.
• Loss of METTL18 induced global translational changes, including accelerated elongation at proline codons.
• Impaired protein folding led to aggregation of pancreatitis-associated proteins and unfolded protein response activation.

Conclusions:

• METTL18 is essential for pancreatic function and maintaining proteostasis.
• Histidine methylation is a physiologically significant post-translational modification.
• METTL18 regulates translation dynamics to prevent protein aggregation and disease phenotypes.