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, Doa

SUBMITTER: Wu X 

PROVIDER: S-EPMC4828692 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature