Hsp90-Cdc37 Chaperone Complex Regulates Ulk1- and Atg13-Mediated Mitophagy

SummaryAutophagy, 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.

Graphical AbstractFigure optionsDownload high-quality image (175 K)Download as PowerPoint slideHighlights
► Hsp90-Cdc37 interacts with Ulk1, regulating its stability and activation
► Ulk1 phosphorylates Atg13 on S318 and promotes its release to damaged mitochondria
► Ulk1-directed Atg13 S318 phosphorylation is regulated by Hsp90-Cdc37 interactions
► Atg13 S318 phosphorylation is selectively required for mitophagy