Acetylated hsp70 and KAP1-mediated Vps34 SUMOylation is required for autophagosome creation in autophagy Academic Article uri icon

Overview

MeSH Major

  • Autophagy
  • Class III Phosphatidylinositol 3-Kinases
  • HSP70 Heat-Shock Proteins
  • Multiprotein Complexes
  • Nuclear Proteins
  • Phagosomes
  • Repressor Proteins

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, MariƱo 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.

publication date

  • April 23, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3637746

Digital Object Identifier (DOI)

  • 10.1073/pnas.1217692110

PubMed ID

  • 23569248

Additional Document Info

start page

  • 6841

end page

  • 6

volume

  • 110

number

  • 17