Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy.
Autophagy is a stress-induced catabolic process in which cytoplasmic components, sequestered in double-membrane autophagic vesicles (AVs) or autophagosomes, are delivered to lysosomes for degradation and recycling [Kroemer G, Marino G, Levine B (2010) Mol Cell 40(2):280-293]. Activity of the class III phosphatidylinositol-3-OH-kinase (PI3K) vacuolar protein-sorting (Vps) 34, bound to coiled-coil ... moesin-like B-cell lymphoma 2 (Bcl-2)-interacting protein Beclin-1, is required for phosphoinositide generation, essential for AV formation in autophagy [Cuervo AM (2010) Nat Cell Biol 12(8):735-737]. However, how autophagy-inducing stress regulates Vps34 activity has not been fully elucidated. Our findings demonstrate that autophagy-inducing stress increases intracellular levels of acetylated inducible heat shock protein (hsp) 70, which binds to the Beclin-1-Vps34 complex. Acetylated hsp70 also recruits E3 ligase for SUMOylation, KRAB-ZFP-associated protein 1 (KAP1), inducing Lys840 SUMOylation and increasing Vps34 activity bound to Beclin 1. Knockdown of hsp70 abolished the Beclin-1-Vps34 complex formation, as well as inhibited KAP1 binding to Vps34 and AV formation. Notably, autophagy-inducing stress due to histone deacetylase inhibitor treatment induced AV formation in the wild-type but not hsp70.1/3 knockout mouse embryonic fibroblasts MEFs. These findings highlight a regulatory mechanism of Vps34 activity, which involves acetylated hsp70 and KAP1-dependent SUMOylation of Vps34 bound to Beclin 1.
Mesh Terms:
Acetylation, Animals, Apoptosis Regulatory Proteins, Autophagy, Class III Phosphatidylinositol 3-Kinases, Genetic Vectors, HEK293 Cells, HSP70 Heat-Shock Proteins, Humans, Immunoblotting, Immunoprecipitation, MCF-7 Cells, Mass Spectrometry, Mice, Mice, Knockout, Microscopy, Fluorescence, Multiprotein Complexes, Nuclear Proteins, Phagosomes, Repressor Proteins, Sumoylation
Acetylation, Animals, Apoptosis Regulatory Proteins, Autophagy, Class III Phosphatidylinositol 3-Kinases, Genetic Vectors, HEK293 Cells, HSP70 Heat-Shock Proteins, Humans, Immunoblotting, Immunoprecipitation, MCF-7 Cells, Mass Spectrometry, Mice, Mice, Knockout, Microscopy, Fluorescence, Multiprotein Complexes, Nuclear Proteins, Phagosomes, Repressor Proteins, Sumoylation
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 23, 2013
PubMed ID: 23569248
View in: Pubmed Google Scholar
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