Title: O-GlcNAcylation of Core Components of the Translation Initiation Machinery Regulates Protein Synthesis

Xuexia Li, Qiang Zhu, Xiaoliu Shi, Yaxian Cheng, Xueliu Li, Huan Xu, Xiaotao Duan, Linda C. Hsieh-Wilson, Jennifer Chu, Jerry Pelletier, Maowei Ni, Zhiguo Zheng, Sihui Li, and Wen Yi

PNAS April 16, 2019 116 (16) 7857-7866; first published April 2, 2019 https://doi.org/10.1073/pnas.1813026116

Abstract

Protein synthesis is essential for cell growth, proliferation, and survival. Protein synthesis is a tightly regulated process that involves multiple mechanisms. Deregulation of protein synthesis is considered as a key factor in the development and progression of a number of diseases, such as cancer. Here we show that the dynamic modification of proteins by O-linked β-N-acetyl-glucosamine (O-GlcNAcylation) regulates translation initiation by modifying core initiation factors eIF4A and eIF4G, respectively. Mechanistically, site-specific O-GlcNAcylation of eIF4A on Ser322/323 disrupts the formation of the translation initiation complex by perturbing its interaction with eIF4G. In addition, O-GlcNAcylation inhibits the duplex unwinding activity of eIF4A, leading to impaired protein synthesis, and decreased cell proliferation. In contrast, site-specific O-GlcNAcylation of eIF4G on Ser61 promotes its interaction with poly(A)-binding protein (PABP) and poly(A) mRNA. Depletion of eIF4G O-GlcNAcylation results in inhibition of protein synthesis, cell proliferation, and soft agar colony formation. The differential glycosylation of eIF4A and eIF4G appears to be regulated in the initiation complex to fine-tune protein synthesis. Our study thus expands the current understanding of protein synthesis, and adds another dimension of complexity to translational control of cellular proteins.

Link: https://www.pnas.org/content/early/2019/04/01/1813026116