A protein quality control pathway at the mitochondrial outer membrane

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 sen2-1HAts and sam35-2HAts are degraded from the MOM by the ubiquitin-proteasome system. Ubiquitination of sen2-1HAts is mediated by the ubiquitin ligase (E3) Ubr1, while sam35-2HAts 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.

Data availability

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.

Article and author information

Author details

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6248-0009
  2. 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.
  3. 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.
  4. 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.
  5. 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.
    ORCID icon "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.

Reviewing Editor

  1. Agnieszka Chacinska, University of Warsaw, Poland

Publication history

  1. Received: August 14, 2019
  2. Accepted: March 1, 2020
  3. Accepted Manuscript published: March 2, 2020 (version 1)
  4. Version of Record published: April 6, 2020 (version 2)

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.

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  1. Meredith B Metzger
  2. Jessica L Scales
  3. Mitchell F Dunklebarger
  4. Jadranka Loncarek
  5. Allan M Weissman
(2020)
A protein quality control pathway at the mitochondrial outer membrane
eLife 9:e51065.
https://doi.org/10.7554/eLife.51065

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