HemK2 functions for sufficient protein synthesis and RNA stability through eRF1 methylation during Drosophila oogenesis

Abstract

AbstractHemK2 is a well-conserved methyltransferase from yeast to human, but genuine substrates remain controversial, and its biological significance in the higher organism remains elusive. In this study, we report HemK2 functions for the methylation of eukaryotic Release Factor 1 (eRF1), which is required for female germline development inDrosophila melanogaster.Germline-knockdown ofhemk2(hemk2-GLKD) causes apoptosis of germline cells, and severe downregulation of eRF1 methylation and protein synthesis. Overexpression of methylation-deficient eRF1 phenocopies the defects observed inhemk2-GLKD, suggesting that eRF1 is the primary substrate for methylation by HemK2. We show thathemk2-GLKD also results in significant downregulation of mRNAs in germline cells, and the defects in egg formation and protein synthesis are partially rescued by blocking the no-go decay pathway. In addition,hemk2knockdown increases disome formation, suggesting that perturbation of eRF1 methylation results in ribosome stalling, which in turn triggers ribosome quality control to degrade actively translated mRNAs. We propose that eRF1 methylation by HemK2 is required for the efficient protein production and mRNA stability, to ensure the formation of the high-quality eggs.