Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy

Mol Cell. 2011 Aug 19;43(4):572-85. doi: 10.1016/j.molcel.2011.06.018.

Abstract

Autophagy, the primary recycling pathway of cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the response to cellular stress. The Hsp90-Cdc37 chaperone complex coordinately regulates the activity of select kinases to orchestrate many facets of the stress response. Although both maintain mitochondrial integrity, the relationship between Hsp90-Cdc37 and autophagy has not been well characterized. Ulk1, one of the mammalian homologs of yeast Atg1, is a serine-threonine kinase required for mitophagy. Here we show that the interaction between Ulk1 and Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn is required for the phosphorylation and release of Atg13 from Ulk1, and for the recruitment of Atg13 to damaged mitochondria. Hsp90-Cdc37, Ulk1, and Atg13 phosphorylation are all required for efficient mitochondrial clearance. These findings establish a direct pathway that integrates Ulk1- and Atg13-directed mitophagy with the stress response coordinated by Hsp90 and Cdc37.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein-1 Homolog
  • Autophagy-Related Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / physiology*
  • Cell Differentiation
  • Cell Line
  • Chaperonins / metabolism
  • Chaperonins / physiology*
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / metabolism
  • HSP90 Heat-Shock Proteins / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • K562 Cells
  • Mice
  • Mitochondria / metabolism*
  • Phosphorylation
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / physiology

Substances

  • ATG13 protein, human
  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • CDC37 protein, human
  • Cell Cycle Proteins
  • HSP90 Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human
  • Chaperonins