O-GlcNAc-regulated arginine methylation

a new paradigm in survival signaling

Albert Lee, Devin Miller, Roger Henry, Natasha Zachara

Research output: Contribution to journalMeeting abstract

Abstract

The modification of nuclear, mitochondrial and cytoplasmic proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a novel regulator of cell survival and cardioprotection. Notably, the elevation of O-GlcNAc levels is protective in both in vivo and in vitro models of heat stress, oxidative stress, hypoxia, ischemia reperfusion injury and trauma hemorrhage. However, the mechanisms by which O-GlcNAc regulates protein function leading to enhanced cell survival have not been defined. In this study, we have used Stable Isotope Labeling of Amino Acids in Cell Culture (SILAC), in combination with an O-GlcNAc immunoprecipitation, to screen for proteins whose O-GlcNAcylation status changes in response to hydrogen peroxide treatment (a mimic of ischemia reperfusion injury). We identified >90 proteins that were putatively O-GlcNAc modified, including the protein arginine methyltransferases PRMT1 and PRMT 4 (also known as Carm1). Notably, when O-GlcNAc levels were lowered by overexpression of O-GlcNAcase or deletion of OGT, arginine methylation was increased on a subset of cellular proteins. These data suggest that O-GlcNAc may regulate cell survival by altering the activity of PRMT1 and PRMT4 and subsequent methylation of non-histone proteins. Interestingly, PRMT1 is thought to promote cell death by methylating proteins such as BAD and Foxo, preventing their phosphorylation by Akt. Consistent with a hypothesis in which O-GlcNAc promotes AKT phosphorylation and survival, the pro-apoptotic protein BAD is hypophosphorylated in the OGT null and this can be reversed by the inhibition of methyltransferases. The studies described highlight a potential molecular mechanism by which O-GlcNAc protects cells from oxidative damage via the tripartite interplay between O-GlcNAc, methylation and phosphorylation.
Original languageEnglish
Article number10
Pages (from-to)1521-1521
Number of pages1
JournalGlycobiology
Volume22
Issue number11
Publication statusPublished - Nov 2012
Externally publishedYes
EventJoint Meeting of the Society for Glycobiology and American Society for Matrix Biology - San Diego, United States
Duration: 11 Nov 201214 Nov 2012

Cite this

Lee, A., Miller, D., Henry, R., & Zachara, N. (2012). O-GlcNAc-regulated arginine methylation: a new paradigm in survival signaling. Glycobiology, 22(11), 1521-1521. [10].