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Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8019-24. doi: 10.1073/pnas.1405755111. Epub 2014 May 12.

The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins.

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1
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517.
2
Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517 peter@walterlab.ucsf.edu.

Abstract

The accuracy of tail-anchored (TA) protein targeting to the endoplasmic reticulum (ER) depends on the Guided Entry of Tail-Anchored (Get) protein targeting machinery. The fate of TA proteins that become inappropriately inserted into other organelles, such as mitochondria, is unknown. Here, we identify Msp1, a conserved, membrane-anchored AAA-ATPase (ATPase associated with a variety of cellular activities) that localizes to mitochondria and peroxisomes, as a critical factor in a quality control pathway that senses and degrades TA proteins mistargeted to the outer mitochondrial membrane (OMM). Pex15 is normally targeted by the Get pathway to the ER, from where it travels to peroxisomes. Loss of Msp1 or loss of the Get pathway results in the redistribution of Pex15 to mitochondria. Cells lacking both a functional Get pathway and Msp1 accumulate increased amounts of Pex15 on the OMM and display severely dysfunctional mitochondrial morphology. In addition, Msp1 binds and promotes the turnover of a Pex15 mutant that is misdirected to the OMM. Our data suggest that Msp1 functions in local organelle surveillance by extracting mistargeted proteins, ensuring the fidelity of organelle specific-localization of TA proteins.

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PMID:
24821790
PMCID:
PMC4050615
DOI:
10.1073/pnas.1405755111
[Indexed for MEDLINE]
Free PMC Article
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