METTL10 trimethylation of eEF1A at K318 enhances protein synthesis and tumorigenesis.

Abstract

eEF1A is an essential non-ribosomal translation elongation factor that mediates the high-fidelity delivery of aminoacyl-tRNAs to elongating ribosomes. Like histone H3, eEF1A undergoes extensive lysine methylation, with five distinct residues targeted by dedicated lysine methyltransferases (KMTs). However, compared with histone methylation, relatively little is known about the molecular and physiological functions of eEF1A lysine methylation. Here, we focus on METTL10, the KMT that catalyzes trimethylation of eEF1A at lysine 318 (eEF1AK318me3). We show that the METTL10-eEF1AK318me3 axis modestly enhances global protein synthesis and supports pancreatic ductal adenocarcinoma (PDAC) tumorigenesis in vivo. We identify the 236 amino-acid isoform as the catalytically active endogenous form of METTL10 and demonstrate that it is required for eEF1AK318me3 generation in multiple human cell lines. Further, we provide evidence that eEF1AK318 is the principal physiologic target of METT10. Loss of eEF1AK318 modestly reduces global protein synthesis across multiple cancer cell lines without substantially impacting polysome formation. METTL10 depletion attenuates proliferation of multiple cancer cell lines, an effect that depends on its catalytic activity. Moreover, elevated eEF1AK318me3 levels in PDAC tumors are associated with poor patient outcomes. Finally, METTL10 ablation attenuates tumor growth and extends survival in a KRAS^G12D-driven PDAC mouse model. Together, our work identifies the METTL10-eEF1AK318me3 axis as a regulator of protein synthesis and implicates it in PDAC pathogenesis.