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YOD1/TRAF6 association balances p62-dependent IL-1 signaling to NF-κB

  1. Gisela Schimmack
  2. Kenji Schorpp
  3. Kerstin Kutzner
  4. Torben Gehring
  5. Jara Kerstin Brenke
  6. Kamyar Hadian
  7. Daniel Krappmann  Is a corresponding author
  1. Helmholtz Zentrum München - German Research Center for Environmental Health, Germany
Research Article
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Cite this article as: eLife 2017;6:e22416 doi: 10.7554/eLife.22416

Abstract

The ubiquitin ligase TRAF6 is a key regulator of canonical IκB kinase (IKK)/NF-κB signaling in response to interleukin-1 (IL-1) stimulation. Here, we identified the deubiquitinating enzyme YOD1 (OTUD2) as a novel interactor of TRAF6 in human cells. YOD1 binds to the C-terminal TRAF homology domain of TRAF6 that also serves as the interaction surface for the adaptor p62/Sequestosome-1, which is required for IL-1 signaling to NF-κB. We show that YOD1 competes with p62 for TRAF6 association and abolishes the sequestration of TRAF6 to cytosolic p62 aggregates by a non-catalytic mechanism. YOD1 associates with TRAF6 in unstimulated cells but is released upon IL-1κ stimulation, thereby facilitating TRAF6 auto-ubiquitination as well as NEMO/IKKκ substrate ubiquitination. Further, IL-1 triggered IKK/NF-κB signaling and induction of target genes is decreased by YOD1 overexpression and augmented after YOD1 depletion. Hence, our data define that YOD1 antagonizes TRAF6/p62-dependent IL-1 signaling to NF-κB.

Article and author information

Author details

  1. Gisela Schimmack

    Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Kenji Schorpp

    Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Kerstin Kutzner

    Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Torben Gehring

    Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Jara Kerstin Brenke

    Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Kamyar Hadian

    Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Krappmann

    Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
    For correspondence
    daniel.krappmann@helmholtz-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7640-3234

Funding

Deutsche Forschungsgemeinschaft (SPP1365)

  • Daniel Krappmann

Wilhelm Sander-Stiftung (2012.075.2)

  • Daniel Krappmann

Deutsche Forschungsgemeinschaft (SFB1054 A4)

  • Daniel Krappmann

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

Reviewing Editor

  1. David Wallach, The Weizmann Institute of Science, Israel

Publication history

  1. Received: October 15, 2016
  2. Accepted: February 26, 2017
  3. Accepted Manuscript published: February 28, 2017 (version 1)
  4. Version of Record published: March 7, 2017 (version 2)

Copyright

© 2017, Schimmack 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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