VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy

Hua Su; Fei Yang; Qiuting Wang; Qiuhong Shen; Jingtao Huang; Chao Peng; Yi Zhang; Wei Wan; Catherine C L Wong; Qiming Sun; Fudi Wang; Tianhua Zhou; Wei Liu

doi:10.1016/j.molcel.2017.07.024

VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy

Mol Cell. 2017 Sep 21;67(6):907-921.e7. doi: 10.1016/j.molcel.2017.07.024. Epub 2017 Aug 24.

Authors

Hua Su¹, Fei Yang¹, Qiuting Wang¹, Qiuhong Shen¹, Jingtao Huang¹, Chao Peng², Yi Zhang¹, Wei Wan¹, Catherine C L Wong², Qiming Sun¹, Fudi Wang¹, Tianhua Zhou¹, Wei Liu³

Affiliations

¹ Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Biochemistry and Molecular Biology, Program in Molecular and Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: [email protected].

PMID: 28844862
DOI: 10.1016/j.molcel.2017.07.024

Abstract

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.

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism
Acetylation
Animals
Autophagy*
Autophagy-Related Protein-1 Homolog / genetics
Autophagy-Related Protein-1 Homolog / metabolism
Beclin-1 / metabolism
Class III Phosphatidylinositol 3-Kinases / genetics
Class III Phosphatidylinositol 3-Kinases / metabolism*
Enzyme Activation
Female
HEK293 Cells
HeLa Cells
Hepatocytes / enzymology*
Hepatocytes / pathology
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Lipid Metabolism*
Liver / enzymology*
Liver / pathology
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism*
Phosphatidylinositol Phosphates / metabolism
Protein Binding
Protein Processing, Post-Translational*
RNA Interference
Signal Transduction
Stress, Physiological*
Transfection
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
p300-CBP Transcription Factors / genetics
p300-CBP Transcription Factors / metabolism*

Substances

BECN1 protein, human
Beclin-1
Intracellular Signaling Peptides and Proteins
Phosphatidylinositol Phosphates
TSC2 protein, human
Tsc2 protein, mouse
Tuberous Sclerosis Complex 2 Protein
Tumor Suppressor Proteins
phosphatidylinositol 3-phosphate
p300-CBP Transcription Factors
p300-CBP-associated factor
Phosphatidylinositol 3-Kinases
Class III Phosphatidylinositol 3-Kinases
PIK3C3 protein, mouse
Autophagy-Related Protein-1 Homolog
ULK1 protein, human
Ulk1 protein, mouse
AMP-Activated Protein Kinases