Mol. Cell 67, 907–921 (2017)

The class III phosphoinositide 3-kinase VPS34 generates phosphatidylinositol 3-phosphate (PI3P) to regulate vesicular trafficking and autophagy. VPS34 interacts with regulatory proteins in complexes during autophagy induction, yet VPS34 activation is not fully understood. Liu and colleagues report that VPS34 is regulated by p300 and p300-mediated activation of VPS34 can be used, not only during starvation-induced autophagy, but also during non-canonical autophagy induction, independent of upstream kinases.

Using bioinformatics followed by acetylation assays and experiments using histone deacetylase family inhibitors, the authors showed that VPS34 is regulated by p300-mediated acetylation. Mutant analyses indicated that acetylation suppresses VPS34 lipid kinase activity by decreasing its affinity for its substrate PI. Testing VPS34 interaction with its regulator Beclin1 showed that acetylation hindered VPS34–Beclin1 complex formation. The authors showed that p300-mediated VPS34 acetylation functions in response to starvation as well as in non-canonical autophagy.

These data uncover a previously unknown pathway for of VPS34 activation and indicate that p300 acetylation controls VPS34 kinase activity and complex formation with its regulatory proteins. Whether acetylation regulates other VPS34-dependent membrane processes remains to be determined.