The class III phosphoinositide 3-kinase VPS34 plays a key role in the regulation of vesicular trafficking and macroautophagy. So far, we know little about the molecular mechanism of VPS34 activation besides its interaction with regulatory proteins to form complexes. Here, we report that VPS34 is specifically acetylated by the acetyltransferase p300, and p300-mediated acetylation represses VPS34 activity. Acetylation at K771 directly diminishes the affinity of VPS34 for its substrate PI, while acetylation at K29 hinders the VPS34-Beclin 1 core complex formation. Inactivation of p300 induces VPS34 deacetylation, PI3P production, and autophagy, even in AMPK^−/−, TSC2^−/−, or ULK1^−/− cells. In fasting mice, liver autophagy correlates well with p300 inactivation/VPS34 deacetylation, which facilitates the clearance of lipid droplets in hepatocytes. Thus, p300-dependent VPS34 acetylation/deacetylation is the physiological key to VPS34 activation, which controls the initiation of canonical autophagy and of non-canonical autophagy in which the upstream kinases of VPS34 can be bypassed.

III类磷酸肌醇3激酶VPS34在水泡运输和自噬的调控中起关键作用。到目前为止，除了VPS34与调节蛋白相互作用形成复合物以外，我们对VPS34激活的分子机制了解甚少。在这里，我们报道VPS34被乙酰转移酶p300特异性地乙酰化，而p300介导的乙酰化抑制了VPS34的活性。K771处的乙酰化直接降低了VPS34与其底物PI的亲和力，而K29处的乙酰化则阻碍了VPS34-Beclin 1核心复合物的形成。即使在AMPK ^-/-，TSC2 ^-/-或ULK1 ^-/-中，p300的失活也会引起VPS34脱乙酰基化，PI3P产生和自噬。细胞。在空腹小鼠中，肝脏自噬与p300失活/ VPS34脱乙酰作用密切相关，这有助于清除肝细胞中的脂滴。因此，p300依赖的VPS34乙酰化/去乙酰化是VPS34激活的生理关键，VPS34激活控制了规范性自噬和非规范性自噬的启动，在其中可以绕过VPS34的上游激酶。