A protein quality control pathway at the mitochondrial outer membrane

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Abstract

Maintaining the essential functions of mitochondria requires mechanisms to recognize and remove misfolded proteins. However, quality control (QC) pathways for misfolded mitochondrial proteins remain poorly-defined. Here, we establish temperature-sensitive (ts-) peripheral mitochondrial outer membrane (MOM) proteins as novel model QC substrates in Saccharomyces cerevisiae. The ts- proteins sen2-1HA^ts and sam35-2HA^ts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HA^ts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HA^ts is ubiquitinated primarily by San1. Mitochondria-associated degradation (MAD) of both substrates requires SSA family HSP70s and the HSP40 Sis1, providing the first evidence for chaperone involvement in MAD. In addition to a role for the Cdc48-Npl4-Ufd1 AAA-ATPase complex, Doa1 and a mitochondrial pool of the transmembrane Cdc48 adaptor, Ubx2, are implicated in their degradation. This study reveals a unique QC pathway comprised of a combination of cytosolic and mitochondrial factors that distinguish it from other cellular QC pathways.

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All data generated of analyzed during this study are included in the manuscript and supporting files. Source data for all figure quantifications have been provided.

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Meredith B Metzger

Center for Cancer Research, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, United States

For correspondence
metzgermb@mail.nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6248-0009
Jessica L Scales

Center for Cancer Research, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, United States

Competing interests
The authors declare that no competing interests exist.
Mitchell F Dunklebarger

Center for Cancer Research, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, United States

Competing interests
The authors declare that no competing interests exist.
Jadranka Loncarek

Center for Cancer Research, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, United States

Competing interests
The authors declare that no competing interests exist.
Allan M Weissman

Center for Cancer Research, Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, United States

For correspondence
weissmaa@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7865-7702

Funding

National Institutes of Health, National Cancer Institute, Center for Cancer Research (Intramural Research Program)

Allan M Weissman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.