title: Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy.
abstract: 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, Mariño 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.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Yang
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Bao
authors.initials: B
authors.lastname: Yong
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D000107:Acetylation; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D061986:MCF-7 Cells; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D058207:Sumoylation; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D058546:Class III Phosphatidylinositol 3-Kinases