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The E3 Ubiquitin Ligase Ro52 Negatively Regulates IFN-β Production Post-Pathogen Recognition by Polyubiquitin-Mediated Degradation of IRF3¹

Rowan Higgs^*, Joan Ní Gabhann^*, Nadia Ben Larbi^*, Eamon P. Breen^*, Katherine A. Fitzgerald and Caroline A. Jefferies^2,*

^* Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland; and Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by Science Foundation Ireland, the Health Research Board, and by National Institute of Allergy and Infectious Diseases, National Institutes of Health (AI067497 to K.A.F.).

² Address correspondence and reprint requests to Dr. Caroline Jefferies, Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland. E-mail address: cjefferies{at}rcsi.ie

³ Abbreviations used in this paper: PRR, pathogen recognition receptor; IRF, interferon regulatory factor; SLE, systemic lupus erythematosus; TRIF, TIR domain containing adaptor inducing IFN-β; HEK, human embryonic kidney; HA, hemagglutinin; PRD, positive regulatory domain; polyI:C, polyinosinic:polycytidylic acid; shRNA, short hairpin RNA.

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