Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 16, Pages 7857-7866Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1813026116
Keywords
protein synthesis; translation initiation; glycosylation
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Funding
- National Science Foundation of China [91753125, 31270865, 31322019, 31570804]
- National Key Research and Development Program of China [2016YFA0100303]
- National Science Foundation of Zhejiang Province [LR15C050001]
- National Institutes of Health [R01 AG060540-13]
- National Human Genetic Resources Sharing Service Platform [2005DKA21300]
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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 beta-N-acetyl-glucosamine (O-GIcNAcylation) regulates translation initiation by modifying core initiation factors eIF4A and eIF4G, respectively. Mechanistically, site-specific O-GIcNAcylation of eIF4A on Ser322/323 disrupts the formation of the translation initiation complex by perturbing its interaction with eIF4G. In addition, O-GIcNAcylation inhibits the duplex unwinding activity of eIF4A, leading to impaired protein synthesis, and decreased cell proliferation. In contrast, site-specific O-GIcNAcylation of eIF4G on Ser61 promotes its interaction with poly(A)-binding protein (PABP) and poly(A) mRNA. Depletion of eIF4G O-GIcNAcylation 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.
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