Dynamic Regulation of Mitochondrial Import by the Ubiquitin System.

Autor:	Phu L; Department of Microchemistry, Proteomics and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Rose CM; Department of Microchemistry, Proteomics and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Tea JS; Department of Clinical Operations, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Wall CE; Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Verschueren E; Department of Microchemistry, Proteomics and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Cheung TK; Department of Microchemistry, Proteomics and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA., Kirkpatrick DS; Department of Microchemistry, Proteomics and Lipidomics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: donaldk@gene.com., Bingol B; Department of Neuroscience, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: barisb@gene.com.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2020 Mar 05; Vol. 77 (5), pp. 1107-1123.e10.
DOI:	10.1016/j.molcel.2020.02.012
Abstrakt:	Mitochondria import nearly their entire proteome from the cytoplasm by translocating precursor proteins through the translocase of the outer membrane (TOM) complex. Here, we show dynamic regulation of mitochondrial import by the ubiquitin system. Acute pharmacological inhibition or genetic ablation of the mitochondrial deubiquitinase (DUB) USP30 triggers accumulation of Ub-substrates that are normally localized inside the mitochondria. Mitochondrial import of USP30 substrates is impaired in USP30 knockout (KO) cells, suggesting that deubiquitination promotes efficient import. Upstream of USP30, the E3 ligase March5 ubiquitinates mitochondrial proteins whose eventual import depends on USP30. In USP30 KOs, exogenous March5 expression induces accumulation of unimported translocation intermediates that are degraded by the proteasomes. In USP30 KO mice, TOM subunits have reduced abundance across multiple tissues. Together these data highlight how protein import into a subcellular compartment can be regulated by ubiquitination and deubiquitination by E3 ligase and DUB machinery positioned at the gate. Competing Interests: Declaration of Interests All authors are employees of Genentech, Inc. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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