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O‐GlcNAcylation Regulates Ischemia‐Induced Neuronal Apoptosis Through AKT Signaling
Author(s) -
GONG ChengXin,
Shi Jianhua,
Gu Jinhua,
Dai Chunling,
Gu Jianlan,
Jin Xiaoxia,
Sun Jianming,
Iqbal Khalid,
Liu Fei
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.570.3
Subject(s) - protein kinase b , apoptosis , phosphorylation , ischemia , microbiology and biotechnology , signal transduction , immunoprecipitation , chemistry , pi3k/akt/mtor pathway , biology , medicine , biochemistry , gene
Apoptosis plays an important role in ischemia‐induced neuronal death and the loss of neural function of the affected area. The molecular mechanism by which cerebral ischemia causes apoptosis remains elusive. In this study, we found that O‐GlcNAcylation, a unique protein posttranslational modification with O‐linked β‐N‐acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co‐immunoprecipitation and mutagenesis techniques, we identified O‐GlcNAc modification likely at both Thr308 and Ser473 of AKT. O‐GlcNAcylation‐induced apoptosis was attenuated by over‐expression of AKT in cultured cells. We further found a dynamic elevation of protein O‐GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O‐GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O‐GlcNAcylation in ischemic mouse brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O‐GlcNAcylation that promotes apoptosis through down‐regulation of AKT activity. These findings provide a novel mechanism through which O‐GlcNAcylation regulates ischemia‐induced neuronal apoptosis through AKT signaling.