title: Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy.
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.
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Joung Hyuck
authors.initials: JH
authors.lastname: Joo
authors.forename: Frank C
authors.initials: FC
authors.lastname: Dorsey
authors.forename: Aashish
authors.initials: A
authors.lastname: Joshi
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hennessy-Walters
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Rose
authors.forename: Kelly
authors.initials: K
authors.lastname: McCastlain
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Rekha
authors.initials: R
authors.lastname: Iyengar
authors.forename: Chang Hwa
authors.initials: CH
authors.lastname: Jung
authors.forename: Der-Fen
authors.initials: DF
authors.lastname: Suen
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Steeves
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Yang
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Prater
authors.forename: Do-Hyung
authors.initials: DH
authors.lastname: Kim
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ney
authors.forename: John L
authors.initials: JL
authors.lastname: Cleveland
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D018833:Chaperonins / Q000378:metabolism / Q000502:physiology*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D020014:K562 Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology
chemical_list: C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D018833:Chaperonins