Studies on the Regulation of Autophagy Initiation by ULK1 O-GlcNAcylation

Abstract

Unc-51-Like-Kinase 1 (ULK1) is a target of both mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) whose role is to facilitate initiation of autophagy in response to starvation. Upon glucose starvation, dissociation of mTOR from ULK1 as well as phosphorylation by AMPK leads to activation of ULK1 activity. Here, I provide evidence that ULK1 is O-GlcNAcylated on threonine 754 site by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation. Surprisingly, ULK1 O-GlcNAcylation requires dephosphorylation of adjacent mTOR-dependent phosphorylation on Serine 757 site by protein phosphatase 1 (PP1) and phosphorylation by AMPK. O-GlcNAcylation of ULK1 is crucial for ATG14L phosphorylation and activation of lipid kinase VPS34, leading to production of phosphatidylinositol-(3)-phosphate (PI(3)P) required for phagophore formation and subsequent initiation of autophagy. Together, my findings provide new insights into the crosstalk between dephosphorylation and O-GlcNAcylation during autophagy process and specify a molecular framework for potential therapeutic intervention in autophagy-related diseases.