In response to injury, cells and tissues remodel their cellular environment to repair damaged structures and if necessary to initiate apoptosis. This process, known as the cellular stress response, includes robust and dynamic changes in the modification of intracellular proteins by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Acute enhancment of O-GlcNAcylation reduces apoptosis and necrosis in both in vivo and in vitro models of injury that include cardiac ischemia reperfusion injury. To provide insight into mechanisms underpinning this phenomena, we have engineered forms of the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA), the enzymes that catalyze the addition and removal of O-GlcNAc, that enable regulation of protein O-GlcNAcylation with biologically inert small molecules. Using these and other tools, we have demonstrated that AMP-dependent protein kinase (AMPK) is one target of the O-GlcNAc transferase during oxidaitve stress. Augmenting O-GlcNAcylation in cells and tissues leads to activation of AMPK, as well as ULK1 and autophagy. Deletion or inhibition of AMPK blocks the impact of O-GlcNAcylation on autophagic flux. Moreover, inhibition of autophagy compromizes the cytoprotection associated with enhanced O-GlcNAcylation. Together, these data suggest that activation of AMPK and autophagy by O-GlcNAc plays a critical role in cytoprotection.

Chemogenetics reveals a role for dynamic O-GlcNAcylation in regulating AMPK-signaling and cytoprotection

2019 Fall National Meeting

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