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O-GlcNAcylation of eIF2α regulates the phospho-eIF2α-mediated ER stress response.

Authors
 Insook Jang ; Han Byeol Kim ; Jin Won Cho ; Jae-woo Kim ; Jong Shin Yoo ; Hyeonjin Choi ; Jin Young Kim ; Hojoong Seo 
Citation
 BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, Vol.1853(8) : 1860~1869, 2015 
Journal Title
 BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 
ISSN
 0167-4889 
Issue Date
2015
Abstract
O-GlcNAcylation is highly involved in cellular stress responses including the endoplasmic reticulum (ER) stress response. For example, glucosamine-induced flux through the hexosamine biosynthetic pathway can promote ER stress and ER stress inducers can change the total cellular level of O-GlcNAcylation. However, it is largely unknown which component(s) of the unfolded protein response (UPR) is directly regulated by O-GlcNAcylation. In this study, eukaryotic translation initiation factor 2α (eIF2α), a major branch of the UPR, was O-GlcNAcylated at Ser 219, Thr 239, and Thr 241. Upon ER stress, eIF2α is phosphorylated at Ser 51 by phosphorylated PKR-like ER kinase and this inhibits global translation initiation, except for that of specific mRNAs, including activating transcription factor 4, that induce stress-responsive genes such as C/EBP homologous protein (CHOP). Hyper-O-GlcNAcylation induced by O-GlcNAcase inhibitor (thiamet-G) treatment or O-GlcNAc transferase (OGT) overexpression hindered phosphorylation of eIF2α at Ser 51. The level of O-GlcNAcylation of eIF2α was changed by dithiothreitol treatment dependent on its phosphorylation at Ser 51. Point mutation of the O-GlcNAcylation sites of eIF2α increased its phosphorylation at Ser 51 and CHOP expression and resulted in increased apoptosis upon ER stress. These results suggest that O-GlcNAcylation of eIF2α affects its phosphorylation at Ser 51 and influences CHOP-mediated cell death. This O-GlcNAcylation of eIF2α was reproduced in thiamet-G-injected mouse liver. In conclusion, proper regulation of O-GlcNAcylation and phosphorylation of eIF2α is important to maintain cellular homeostasis upon ER stress.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/140657
DOI
10.1016/j.bbamcr.2015.04.017
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Biochemistry & Molecular Biology
Yonsei Authors
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Link
 http://www.sciencedirect.com/science/article/pii/S0167488915001366
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