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BAG6 promotes PINK1 signaling pathway and is essential for mitophagy.
Ragimbeau, Romain; El Kebriti, Leila; Sebti, Salwa; Fourgous, Elise; Boulahtouf, Abdelhay; Arena, Giuseppe; Espert, Lucile; Turtoi, Andrei; Gongora, Céline; Houédé, Nadine; Pattingre, Sophie.
Afiliação
  • Ragimbeau R; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
  • El Kebriti L; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
  • Sebti S; CHU de Nîmes, Nîmes, France.
  • Fourgous E; Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Boulahtouf A; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Arena G; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
  • Espert L; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
  • Turtoi A; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
  • Gongora C; IRIM, University of Montpellier, UMR 9004 CNRS, Montpellier, France.
  • Houédé N; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
  • Pattingre S; IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France.
FASEB J ; 35(2): e21361, 2021 02.
Article em En | MEDLINE | ID: mdl-33522017
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Transdução de Sinais / Chaperonas Moleculares / Mitofagia Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Quinases / Transdução de Sinais / Chaperonas Moleculares / Mitofagia Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article