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. 2022 Apr;18(4):829-840.
doi: 10.1080/15548627.2021.1960116. Epub 2021 Aug 25.

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

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

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

Bing-Ru Yan et al. Autophagy. 2022 Apr.

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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Conflict of interest statement

The authors declare no competing interest.

Figures

Figure 1.
Figure 1.
miniTurbo, a proximity-based strategy to identify RAB7A interactors.
Figure 2.
Figure 2.
Identification of C5orf51 as a component of the MON1-CCZ1 GEF complex for RAB7A during mitophagy.
Figure 3.
Figure 3.
C5orf51 is required for clearance of depolarized mitochondria.
Figure 4.
Figure 4.
C5orf51 is required for RAB7A translocation to depolarized mitochondria.
Figure 5.
Figure 5.
C5orf51 promotes stability of RAB7A during mitophagy.
See this image and copyright information in PMC

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