title: RNF185, a novel mitochondrial ubiquitin E3 ligase, regulates autophagy through interaction with BNIP1.
abstract: Autophagy is an evolutionarily conserved catabolic process that allows recycling of cytoplasmic organelles, such as mitochondria, to offer a bioenergetically efficient pathway for cell survival. Considerable progress has been made in characterizing mitochondrial autophagy. However, the dedicated ubiquitin E3 ligases targeting mitochondria for autophagy have not been revealed. Here we show that human RNF185 is a mitochondrial ubiquitin E3 ligase that regulates selective mitochondrial autophagy in cultured cells. The two C-terminal transmembrane domains of human RNF185 mediate its localization to mitochondrial outer membrane. RNF185 stimulates LC3II accumulation and the formation of autophagolysosomes in human cell lines. We further identified the Bcl-2 family protein BNIP1 as one of the substrates for RNF185. Human BNIP1 colocalizes with RNF185 at mitochondria and is polyubiquitinated by RNF185 through K63-based ubiquitin linkage in vivo. The polyubiquitinated BNIP1 is capable of recruiting autophagy receptor p62, which simultaneously binds both ubiquitin and LC3 to link ubiquitination and autophagy. Our study might reveal a novel RNF185-mediated mechanism for modulating mitochondrial homeostasis through autophagy.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tang
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Wu
authors.forename: Junying
authors.initials: J
authors.lastname: Jia
authors.forename: Talin
authors.initials: T
authors.lastname: Suo
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D003600:Cytosol / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D051336:Mitochondrial Membranes / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D054829:RING Finger Domains; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C502778:ATG5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071187:Autophagy-Related Protein 5; C119020:BNIP1 protein, human; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025821:Polyubiquitin; C569560:RNF185 protein, human; D044767:Ubiquitin-Protein Ligases