SPOP targets the immune transcription factor IRF1 for proteasomal degradation
- University of Vienna, Austria
- Vienna Biocenter, Austria
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Matthias Hinterndorfer
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.
Reviewing Editor
- John W Schoggins, The University of Texas Southwestern Medical Center, United States
Version history
- Preprint posted: October 11, 2022 (view preprint)
- Received: June 5, 2023
- Accepted: August 16, 2023
- Accepted Manuscript published: August 25, 2023 (version 1)
- Version of Record published: September 8, 2023 (version 2)
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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SPOP targets the immune transcription factor IRF1 for proteasomal degradation
eLife 12:e89951.
https://doi.org/10.7554/eLife.89951
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