[en] Bcl-2-associated athanogen-6 (BAG6) is a nucleocytoplasmic shuttling protein involved in protein quality control. We previously demonstrated that BAG6 is essential for autophagy by regulating the intracellular localization of the acetyltransferase EP300, and thus, modifying accessibility to its substrates (TP53 in the nucleus and autophagy-related proteins in the cytoplasm). Here, we investigated BAG6 localization and function in the cytoplasm. First, we demonstrated that BAG6 is localized in the mitochondria. Specifically, BAG6 is expressed in the mitochondrial matrix under basal conditions, and translocates to the outer mitochondrial membrane after mitochondrial depolarization with carbonyl cyanide m-chlorophenyl hydrazine, a mitochondrial uncoupler that induces mitophagy. In SW480 cells, the deletion of BAG6 expression abrogates its ability to induce mitophagy and PINK1 accumulation. On the reverse, its ectopic expression in LoVo colon cancer cells, which do not express endogenous BAG6, reduces the size of the mitochondria, induces mitophagy, leads to the activation of the PINK1/PARKIN pathway and to the phospho-ubiquitination of mitochondrial proteins. Finally, BAG6 contains two LIR (LC3-interacting Region) domains specifically found in receptors for selective autophagy and responsible for the interaction with LC3 and for autophagosome selectivity. Site-directed mutagenesis showed that BAG6 requires wild-type LIRs domains for its ability to stimulate mitophagy. In conclusion, we propose that BAG6 is a novel mitophagy receptor or adaptor that induces PINK1/PARKIN signaling and mitophagy in a LIR-dependent manner.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Ragimbeau, Romain
El Kebriti, Leila
Sebti, Salwa
Fourgous, Elise F
Boulahtouf, Abdelhay
ARENA, Giuseppe ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Espert, Lucile
Turtoi, Andrei
Gongora, Céline
Houédé, Nadine
Pattingre, Sophie
External co-authors :
yes
Language :
English
Title :
BAG6 promotes PINK1 signaling pathway and is essential for mitophagy
Publication date :
February 2021
Journal title :
FASEB Journal
ISSN :
0892-6638
eISSN :
1530-6860
Publisher :
Federation of American Societies for Experimental Biology, Bethesda, United States - Maryland
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