| O-GlcNAcylation is an abundant and dynamic post-translational modification on serine and threonine residues of nuclear and cytoplasmic proteins. O-GlcNAc Transferase (OGT) and Nuclear Cytoplasmic O-GlcNAcase and Acetyltransferase (NCOAT) are the only two enzymes and major regulators in this process. In the past two decades, many studies have demonstrated its important modulation roles in nutrient sensing, protein turnover, cell cycle progression, transcription, translation as well as stress resistance. Among these biological functions, the understanding of O-GlcNAcylation dependent oxidative stress is relatively unknown. This study aims to examine the effects of O-GlcNAcylation on JNK1 and FOXO4 transcription factors under acute oxidative stress treatment.;Oxidative stress is an imbalance between production and clearance of reactive oxygen species (ROS) in cells. Overload oxidative stress may cause many aging-related diseases including Type II diabetes, neurodegenerative disorders and muscle atrophy. MAPK death signal and PI3 kinase survival signal are two of the major evolutionary conserved phosphorylation cascade pathways involved in oxidative stress mediated cellular response. In this study, we show that OGT overexpression in cells have a high survival rate and a low cell death under acute hydrogen peroxide. Further studies found that OGT specifically associates with, and O-GlcNAcylates, JNK1 but not ERK1 and p38-MAPK. Oxidative stress induced JNK1 O-GlcNAcylation also prevented phosphorylation-dependent death signal transduction. On the other hand, hydrogen peroxide induced OGT interaction with FOXO4 and enhanced its transcriptional activity on survival target gene regulation.;Overall, the current work demonstrates OGT and O-GlcNAcylation can positively regulate the FOXO4 survival signal, and can negatively modulate the JNK1 death signal to protect cells from acute oxidative stress. These data provide one molecular mechanism to explain O-GlcNAcylation-dependent stress resistance and cell survival upon acute oxidative stress as well as other stress stimuli.;Keywords: O-GlcNAc Transferase, Oxidative stress, JNK1, FOXO4. |
