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 beenfully elucidated. Ourfindings demonstrate that autoph-agy-inducing stress increases intracellular levels of acetylated induc-ible 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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Apr 23 2013|
- Breast cancer
- HDAC inhibitor
ASJC Scopus subject areas