Endosomal Rab cycles regulate Parkin-mediated mitophagy.
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson's disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how ... other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Mesh Terms:
Autophagy-Related Proteins, Endosomes, Guanine Nucleotide Exchange Factors, HeLa Cells, Humans, Membrane Proteins, Mitochondrial Degradation, Protein Interaction Maps, Ubiquitin-Protein Ligases, Vesicular Transport Proteins, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins
Autophagy-Related Proteins, Endosomes, Guanine Nucleotide Exchange Factors, HeLa Cells, Humans, Membrane Proteins, Mitochondrial Degradation, Protein Interaction Maps, Ubiquitin-Protein Ligases, Vesicular Transport Proteins, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins
Elife
Date: Dec. 23, 2017
PubMed ID: 29360040
View in: Pubmed Google Scholar
Download Curated Data For This Publication
213986
Switch View:
- Interactions 29