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The E3 Ubiquitin Ligase Ro52 Negatively Regulates IFN-β Production Post-Pathogen Recognition by Polyubiquitin-Mediated Degradation of IRF3
Open accessAbstract
Induction of type I IFNs is a fundamental cellular response to both viral and bacterial infection. The role of the transcription factor IRF3 is well established in driving this process. However, equally as important are cellular mechanisms for turning off type I IFN production to limit this response. In this respect, IRF3 has previously been shown to be targeted for ubiquitin-mediated degradation postviral detection to turn off the IFN-β response. In this study, we provide evidence that the E3 ligase Ro52 (TRIM21) targets IRF3 for degradation post-pathogen recognition receptor activation. We demonstrate that Ro52 interacts with IRF3 via its C-terminal SPRY domain, resulting in the polyubiquitination and proteasomal degradation of the transcription factor. Ro52-mediated IRF3 degradation significantly inhibits IFN-β promoter activity, an effect that is reversed in the presence of the proteasomal inhibitor MG132. Specific targeting of Ro52 using short hairpin RNA rescues IRF3 degradation following polyI:C-stimulation of HEK293T cells, with a subsequent increase in IFN-β production. Additionally, shRNA targeting of murine Ro52 enhances the production of the IRF3-dependent chemokine RANTES following Sendai virus infection of murine fibroblasts. Collectively, this demonstrates a novel role for Ro52 in turning off and thus limiting IRF3-dependent type I IFN production by targeting the transcription factor for polyubiquitination and subsequent proteasomal degradation.
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“Several TRIM proteins regulate production and action of IFN-β during innate immune response.”
From TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation (2015) · cites this paper as [36]
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Self-citationInnate immune recognition of viral infection
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TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity
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Metadata
- Authors
- Higgs, R., Gabhann, J. N., Larbi, N. B., Breen, E. P., Fitzgerald, K. A., & Jefferies, C. A.
- Affiliations
- Royal College of Surgeons in Ireland (IE)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Higgs, Rowan
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-08-01
- Volume
- 181
- Issue
- 3
- Pages
- 1780-1786
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2824853
- OpenAlex
- W2129691636
- Cited by
- 310
- References
- 47
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 10 · 2023: 21 · 2022: 17 · 2021: 25 · 2020: 14 · 2019: 17 · 2018: 20 · 2017: 14 · 2016: 13 · 2015: 17 · 2014: 18 · 2013: 24 · 2012: 19
- FWCI
- 7.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- Health Research Board
- Science Foundation Ireland
- National Institutes of Health (AI067497, AI067497 to K.A.F)
- National Institute of Allergy and Infectious Diseases (R01AI067497, R37AI067497, AI-067497, R56AI067497)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Ro52, TRIM21, IRF3, type I interferon, interferon-beta, E3 ubiquitin ligase, polyubiquitination, proteasomal degradation, SPRY domain, interferon regulation, RANTES, Sendai virus, viral infection, chemokine production
- MeSH terms
- DEAD Box Protein 58, SS-A Antigen, Cell Line, Humans, Promoter Regions, Genetic, Protein Binding, Receptors, Immunologic, Ribonucleoproteins, Signal Transduction, Interferon-beta, Polyubiquitin, Ubiquitin-Protein Ligases, Interferon Regulatory Factor-3, Toll-Like Receptor 3, Toll-Like Receptor 4, DEAD-box RNA Helicases
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