title: Doa1 targets ubiquitinated substrates for mitochondria-associated degradation.
abstract: Mitochondria-associated degradation (MAD) mediated by the Cdc48 complex and proteasome degrades ubiquitinated mitochondrial outer-membrane proteins. MAD is critical for mitochondrial proteostasis, but it remains poorly characterized. We identified several mitochondrial Cdc48 substrates and developed a genetic screen assay to uncover regulators of the Cdc48-dependent MAD pathway. Surprisingly, we identified Doa1, a substrate-processing factor of Cdc48 that inhibits the degradation of some Cdc48 substrates, as a critical mediator of the turnover of mitochondrial Cdc48 substrates. Deletion ofDOA1causes the accumulation and mislocalization of substrates on mitochondria. Profiling of Cdc48 cofactors shows that Doa1 and Cdc48(-Ufd1-Npl4)form a functional complex mediating MAD. Biochemically, Doa1 interacts with ubiquitinated substrates and facilitates substrate recruitment to the Cdc48(-Ufd1-Npl4)complex. Functionally, Doa1 is critical for cell survival under mitochondrial oxidative stress, but not ER stress, conditions. Collectively, our results demonstrate the essential role of the Doa1-Cdc48(-Ufd1-Npl4)complex in mitochondrial proteostasis and suggest that Doa1 plays dual roles on the Cdc48 complex.
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China jianghui@nibs.ac.cn wuxi@nibs.ac.cn.
authors.forename: Xi
authors.initials: X
authors.lastname: Wu
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China jianghui@nibs.ac.cn wuxi@nibs.ac.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D063306:Mitophagy / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D000074405:Valosin Containing Protein; D015003:Yeasts / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D008565:Membrane Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein