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

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

Molecular cell, 2017-09, Vol.67 (6), p.907-921.e7 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
VPS34 Acetylation Controls Its Lipid Kinase Activity and the Initiation of Canonical and Non-canonical Autophagy
Autor: Su, Hua ; Yang, Fei ; Wang, Qiuting ; Shen, Qiuhong ; Huang, Jingtao ; Peng, Chao ; Zhang, Yi ; Wan, Wei ; Wong, Catherine C.L. ; Sun, Qiming ; Wang, Fudi ; Zhou, Tianhua ; Liu, Wei
Assuntos: Acetylation ; AMP-Activated Protein Kinases - genetics ; AMP-Activated Protein Kinases - metabolism ; 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 ; p300-CBP Transcription Factors - genetics ; p300-CBP Transcription Factors - metabolism ; 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
É parte de: Molecular cell, 2017-09, Vol.67 (6), p.907-921.e7
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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. [Display omitted] •VPS34 is a direct target of acetyltransferase p300•Deacetylation of VPS34 is required for canonical and non-canonical autophagy•Acetylation of VPS34 hinders VPS34-PI and VPS34-Beclin 1 interactions•Acetyltransferase p300 is an alternative homeostatic sensor Su et al. report a novel mechanism for the activity regulation of lipid kinase VPS34. The acetyltransferase p300-mediated acetylation inhibits VPS34 activity. Deacetylation of VPS34 enhances VPS34-PI interaction and VPS34-Beclin 1 core complex formation. This p300-VPS34 pathway is critical to the initiation of canonical and non-canonical autophagy.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

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

United States: Elsevier Inc

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