Journal
JOURNAL OF CELL BIOLOGY
Volume 213, Issue 1, Pages 49-63Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201510098
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Funding
- National Basic Research Program of China 973 [2012CB837503]
- municipal government of Beijing
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Mitochondria-associated degradation (MAD) mediated by the Cdc48 complex and proteasome degrades ubiquitinated mitochondrial outer-membrane proteins. MAD is critical for mitochondria! proteostasis, but it remains poorly characterized. We identified several mitochondria! 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 mitochondria! Cdc48 substrates. Deletion of DOA1 causes 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 mitochondria! proteostasis and suggest that Doa1 plays dual roles on the Cdc48 complex.
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