Abstract

Adaptation of the functional proteome is essential to counter pathogens during infection, yet precisely timed degradation of these response proteins after pathogen clearance is likewise key to preventing autoimmunity. Interferon Regulatory Factor 1 (IRF1) plays an essential role as a transcription factor in driving the expression of immune response genes during infection. The striking difference in functional output with other IRFs, is that IRF1 also drives the expression of various cell cycle inhibiting factors, making it an important tumor suppressor. Thus, it is critical to regulate the abundance of IRF1 to achieve a 'Goldilocks' zone in which there is sufficient IRF1 to prevent tumorigenesis, yet not too much which could drive excessive immune activation. Using genetic screening, we identified the E3 ligase receptor Speckle Type BTB/POZ Protein (SPOP) to mediate IRF1 proteasomal turnover in human and mouse cells. We identified S/T-rich degrons in IRF1 required for its SPOP MATH domain-dependent turnover. In the absence of SPOP, elevated IRF1 protein levels functionally increased IRF1-dependent cellular responses, underpinning the biological significance of SPOP in curtailing IRF1 protein abundance.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Irene Schwartz

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  2. Milica Vunjak

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  3. Valentina Budroni

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6606-2031
  4. Adriana Cantoran García

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  5. Marialaura Mastrovito

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  6. Adrian Soderholm

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  7. Matthias Hinterndorfer

    Vienna BioCenter PhD Program, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2435-4690
  8. Melanie de Almeida

    Vienna BioCenter PhD Program, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  9. Kathrin Hacker

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  10. Jingkui Wang

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  11. Kimon Froussios

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2812-0525
  12. Julian Jude

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9091-9867
  13. Thomas Decker

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9683-0620
  14. Johannes Zuber

    Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8810-6835
  15. Gijs A Versteeg

    Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria
    For correspondence
    gijs.versteeg@univie.ac.at
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6150-2165

Funding

Stand-Alone grant (P30231-B)

  • Gijs A Versteeg

Stand-Alone grant (P30415-B)

  • Gijs A Versteeg

Special Research grant (SFB grant F79)

  • Gijs A Versteeg

Doctoral School grant from the Austrian Science Fund (DK grant W1261)

  • Thomas Decker
  • Gijs A Versteeg

European Research Council (ERC-StG-336860)

  • Johannes Zuber

Austrian Science Fund (SFB grant F4710)

  • Johannes Zuber

Stand-Alone grant (P25186-B22)

  • Thomas Decker

Special Research Grant (SFB grant F6103)

  • Thomas Decker

DOC fellowship of the Austrian Academy of Sciences

  • Milica Vunjak
  • Valentina Budroni
  • Melanie de Almeida
  • Thomas Decker

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

Copyright

© 2023, Schwartz 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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  1. Irene Schwartz
  2. Milica Vunjak
  3. Valentina Budroni
  4. Adriana Cantoran García
  5. Marialaura Mastrovito
  6. Adrian Soderholm
  7. Matthias Hinterndorfer
  8. Melanie de Almeida
  9. Kathrin Hacker
  10. Jingkui Wang
  11. Kimon Froussios
  12. Julian Jude
  13. Thomas Decker
  14. Johannes Zuber
  15. Gijs A Versteeg
(2023)
SPOP targets the immune transcription factor IRF1 for proteasomal degradation
eLife 12:e89951.
https://doi.org/10.7554/eLife.89951

Share this article

https://doi.org/10.7554/eLife.89951

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