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O-GlcNAcylation of core components of the translation initiation machinery regulates protein synthesis

Li, Xuexia and Zhu, Qiang and Shi, Xiaoliu and Cheng, Yaxian and Li, Xueliu and Xu, Huan and Duan, Xiaotao and Hsieh-Wilson, Linda C. and Chu, Jennifer and Pelletier, Jerry and Ni, Maowei and Zheng, Zhiguo and Li, Sihui and Yi, Wen (2019) O-GlcNAcylation of core components of the translation initiation machinery regulates protein synthesis. Proceedings of the National Academy of Sciences of the United States of America, 116 (16). pp. 7857-7866. ISSN 0027-8424. PMCID PMC6475381. https://resolver.caltech.edu/CaltechAUTHORS:20190402-110054908

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1813026116DOIArticle
https://www.pnas.org/content/suppl/2019/04/01/1813026116.DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475381/PubMed CentralArticle
ORCID:
AuthorORCID
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Yi, Wen0000-0002-4257-3355
Additional Information:© 2019 National Academy of Sciences. Published under the PNAS license. Edited by Barry S. Cooperman, University of Pennsylvania, Philadelphia, PA, and accepted by Editorial Board Member Yale E. Goldman March 6, 2019 (received for review July 30, 2018). PNAS published ahead of print April 2, 2019. This work was supported by the National Science Foundation of China (Grants 91753125, 31270865, c, and 31570804), the National Key Research and Development Program of China (2016YFA0100303), the National Science Foundation of Zhejiang Province (LR15C050001), and the National Institutes of Health [R01 AG060540-13 (to L.C.H.-W.)]. The tissue samples were supplied by Zhejiang Cancer Hospital Biospecimen Repository and the National Human Genetic Resources Sharing Service Platform (Grant 2005DKA21300). Author contributions: W.Y. designed research; Xuexia Li, Q.Z., X.S., Y.C., Xueliu Li, H.X., and X.D. performed research; X.D., L.C.H.-W., J.C., J.P., M.N., and Z.Z. contributed reagents/analytic tools; Xuexia Li, Q.Z., X.S., Y.C., Xueliu Li, X.D., J.C., J.P., S.L., and W.Y. analyzed data; and S.L. and W.Y. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. B.S.C. is a guest editor invited by the Editorial Board. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1813026116/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
National Natural Science Foundation of China91753125
National Natural Science Foundation of China31270865
National Natural Science Foundation of China31270865
National Key Research and Development Program of China2016YFA0100303
National Science Foundation of Zhejiang ProvinceLR15C050001
NIHR01 AG060540-13
Zhejiang Cancer HospitalUNSPECIFIED
NIH2005DKA21300
Subject Keywords:protein synthesis; translation initiation; glycosylation
Issue or Number:16
PubMed Central ID:PMC6475381
Record Number:CaltechAUTHORS:20190402-110054908
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190402-110054908
Official Citation: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, Wen Yi. Proceedings of the National Academy of Sciences Apr 2019, 116 (16) 7857-7866; DOI: 10.1073/pnas.1813026116
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94365
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:02 Apr 2019 18:13
Last Modified:01 Apr 2020 16:35

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