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.
“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]
The Abstract (page unavailable) reports that Ro52/TRIM21 limits IFN-β production by promoting IRF3 degradation. The Introduction (page unavailable) also identifies TRIM5α and TRIM25 as important in antiviral defense, but does not establish that several TRIM proteins regulate IFN-β production or its action specifically. (LLM, conf=0.84)
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Update on Pathogenesis of Sjogren's Syndrome
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TRIM56 Is an Essential Component of the TLR3 Antiviral Signaling Pathway
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TRIM27 Negatively Regulates NOD2 by Ubiquitination and Proteasomal Degradation
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TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease
Jones, E. L., Laidlaw, S. M., & Dustin, L. B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.738473 · Cited by 112 · see citing works
Cytoplasmic Mechanisms of Recognition and Defense of Microbial Nucleic Acids
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TRIM21 – A potential novel therapeutic target in cancer
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Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing
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Precision autophagy directed by receptor regulators – emerging examples within the TRIM family
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Emerging Role of Ubiquitination in Antiviral RIG-I Signaling
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Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?
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TRIM59 interacts with ECSIT and negatively regulates NF-κB and IRF-3/7-mediated signal pathways
Kondo, T., Watanabe, M., & Hatakeyama, S. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.05.028 · Cited by 93 · see citing works
Immunologic and genetic considerations of cutaneous lupus erythematosus: A comprehensive review
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OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity
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DDX24 Negatively Regulates Cytosolic RNA-Mediated Innate Immune Signaling
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Zhao, W., Wang, L., Zhang, M., Wang, P., Yuan, C., Qi, J., Hong, M., & Gao, C. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103506 · Cited by 84 · see citing works
Siednienko, J., Gajanayake, T., Fitzgerald, K. A., Moynagh, P. N., & Miggin, S. M. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003093 · Cited by 84 · see citing works
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A review of the role and clinical utility of anti-Ro52/TRIM21 in systemic autoimmunity
Lee, A. Y. S. (2017) · Rheumatology International · doi:10.1007/s00296-017-3718-1 · Cited by 83 · see citing works
Liu, H., Li, M., Song, Y., & Xu, W. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02479 · Cited by 82 · see citing works
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Self-citationTo TRIM the Immunity: From Innate to Adaptive Immunity
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KAP1/TRIM28: an inhibitor of IRF5 function in inflammatory macrophages.
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High Ro52 Expression in Spontaneous and UV-Induced Cutaneous Inflammation
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TRIM38 Negatively Regulates TLR3-Mediated IFN-β Signaling by Targeting TRIF for Degradation
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TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells
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TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation
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Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors
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Fish antiviral tripartite motif (TRIM) proteins
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Interferons in Sjögren’s Syndrome: Genes, Mechanisms, and Effects
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Autoantigen TRIM21/Ro52 as a Possible Target for Treatment of Systemic Lupus Erythematosus
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Intracellular antibody‐mediated immunity and the role of TRIM21
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Proteasome protease mediated regulation of cytokine induction and inflammation
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- 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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