2. Academic Validation
  3. C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy

C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy

  • Autophagy. 2022 Apr;18(4):829-840. doi: 10.1080/15548627.2021.1960116.
Bing-Ru Yan 1,  Taoyingnan Li 1 2,  Etienne Coyaud 3,  Estelle M N Laurent 3,  Jonathan St-Germain 3,  Yuhuan Zhou 1,  Peter K Kim 1 4,  Brian Raught 3 5,  John H Brumell 1 2 6 7
Affiliations

Affiliations

  • 1 Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • 2 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 4 Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • 5 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 6 Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
  • 7 SickKids IBD Centre, Hospital for Sick Children, Toronto, ON, Canada.
PMID: 34432599 DOI: 10.1080/15548627.2021.1960116
Abstract

Depolarized mitochondria can be degraded via Mitophagy, a selective form of Autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during Mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the Proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable Mitophagy.Abbreviations: ATG9A: Autophagy related 9A; Baf A1: bafilomycin A1; BioID: proximity-dependent biotin identification; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CCZ1: CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; DQ-BSA: dye quenched-bovine serum albumin; FYCO1: FYVE and coiled-coil domain Autophagy adaptor 1; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; KO: knockout; LRPPRC: leucine rich pentatricopeptide repeat containing; MG132: carbobenzoxy-Leu-Leu-leucinal; MON1: MON1 homolog, secretory trafficking associated; mtDNA: mitochondrial DNA; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RMC1: regulator of MON1-CCZ1; TBC1D15: TBC1 domain family member 15; TBC1D17: TBC1 domain family member 17; TOMM20: translocase of outer mitochondrial membrane 20; WDR91: WD repeat domain 91; WT: wild type.

Keywords

Autophagy; C5orf51; RAB7A; guanine nucleotide exchange factor; mitophagy.

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