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Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins

  1. Verena Dederer
  2. Anton Khmelinskii
  3. Anna Gesine Huhn
  4. Voytek Okreglak
  5. Michael Knop
  6. Marius K Lemberg  Is a corresponding author
  1. University of Heidelberg, Germany
  2. Institute of Molecular Biology (IMB), Germany
  3. Calico Life Sciences LLC, United States
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Cite this article as: eLife 2019;8:e45506 doi: 10.7554/eLife.45506

Abstract

Tail-anchored (TA) proteins insert post-translationally into the endoplasmic reticulum (ER), the outer mitochondrial membrane (OMM) and peroxisomes. Whereas the GET pathway controls ER-targeting, no dedicated factors are known for OMM insertion, posing the question of how accuracy is achieved. The mitochondrial AAA-ATPase Msp1 removes mislocalized TA proteins from the OMM, but it is unclear, how Msp1 clients are targeted for degradation. Here we screened for factors involved in degradation of TA proteins mislocalized to mitochondria. We show that the ER-associated degradation (ERAD) E3 ubiquitin ligase Doa10 controls cytoplasmic level of Msp1 clients. Furthermore, we identified the uncharacterized OMM protein Fmp32 and the ectopically expressed subunit of the ER-mitochondria encounter structure (ERMES) complex Gem1 as native clients for Msp1 and Doa10. We propose that productive localization of TA proteins to the OMM is ensured by complex assembly, while orphan subunits are extracted by Msp1 and eventually degraded by Doa10.

Article and author information

Author details

  1. Verena Dederer

    Center for Molecular Biology of Heidelberg University (ZMBH), University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Anton Khmelinskii

    Institute of Molecular Biology (IMB), Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0256-5190
  3. Anna Gesine Huhn

    Center for Molecular Biology of Heidelberg University (ZMBH), University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4798-4951
  4. Voytek Okreglak

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael Knop

    Center for Molecular Biology of Heidelberg University (ZMBH), University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Marius K Lemberg

    Center for Molecular Biology of Heidelberg University (ZMBH), University of Heidelberg, Heidelberg, Germany
    For correspondence
    m.lemberg@zmbh.uni-heidelberg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0996-1268

Funding

Deutsche Forschungsgemeinschaft (SFB1036/2 TP10)

  • Anton Khmelinskii

Deutsche Forschungsgemeinschaft (SFB1036/2 TP10)

  • Michael Knop

Deutsche Forschungsgemeinschaft (SFB1036/2 TP12)

  • Marius K Lemberg

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

Reviewing Editor

  1. Ramanujan S Hegde, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: January 24, 2019
  2. Accepted: June 6, 2019
  3. Accepted Manuscript published: June 7, 2019 (version 1)

Copyright

© 2019, Dederer et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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