VPS34 Acetylation By P300 Regulates Its Lipid Kinase Activity And The Initiation Of Autophagy

Autophagy is an intracellular lysosome-mediated degradation system conserved among eukaryotes.During this process,a portion of the cytoplasm including protein aggregates or damaged organelles are transported to lysosome and degraded,which maintains cell homeostasis.The landmark event in autophagy is the generation of a double-membrane structure called the autophagosome.More than 30 kinds of autophagy related genes(ATG)are identified and most of them are involved in the formation of autophagosome.Phosphatidylinositol 3-phosphate(PI3P)generated by the activation of the class ? PI3 kinase VPS34 is required for autophagosome formation.So far,we know little about the molecular mechanism of VPS34 activation besides its interaction with the regulatory proteins to form protein complexes.Here we report that acetylation controls the activity of VPS34 as a PI3 kinase,VPS34 is specifically acetylated by the acetyltranferase p300,and p300-mediated acetylation represses VPS34 activity.Acetylation by p300 at K771 directly diminishes VPS34 affinity to its substrate PI,while acetylation at K29 hinders VPS34 to bind Beclin 1 for the core complex formation.Inactivation of p300 leads to VPS34 deacetylation,PI3P production and autophagy,even in AMPK-/-,TSC2-/-and ULK1-/-cells.In fasting mice,induction of liver autophagy is tightly associated with p300 inactivation and VPS34 deacetylation in the tissue.Thus,p300-mediated VPS34 acetylation is the physiological key to VPS34 activity regulation in the initiation of canonical autophagy,and non-canonical autophagy in which the kinases up stream of VPS34 can be bypassed.