The E3 Ubiquitin Ligase Ro52 Negatively Regulates IFN- Production Post-Pathogen Recognition by Polyubiquitin-Mediated Degradation of IRF3

Molecular and Cellular Therapeutics, Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(3):1780-6. DOI: 10.4049/jimmunol.181.3.1780
Source: PubMed


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-beta 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-beta 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-beta 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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    • "One subset of Trim proteins that include Trim5, Trim14, Trim15, and Trim44 has been shown to positively regulate the antiviral response by ubiquitinating multiple targets in the pathway (Ottosson et al., 2006; Reymond et al., 2001; Uchil et al., 2013; Yang et al., 2013). On the other hand, Trim21, Trim27, Trim30 and Trim38 were recently shown to function as negative regulators of the antiviral response by mediating proteasomal degradation of various signaling factors (Higgs et al., 2008; Shi et al., 2008; Zhao et al., 2012; Zurek et al., 2012). Interestingly, some Trims like Trim21 are functionally flexible and can regulate the innate immune pathway in a positive or negative manner. "
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    • "The effect of TRIM21 on IRF stability relies on its E3 ubiquitin ligase activity: by adding poly-ubiquitin chains on specific lysine residue(s) on the IRFs, TRIM21, like other E3 ubiquitin ligases, creates a signal that targets the activated transcription factor for proteasomal- or lysosomal-mediated degradation, thus achieving termination of signaling [16], [21], [30]. Having shown that all the isoforms interact with TRIM21 uniformly, we next assessed the ability of TRIM21 to ubiquitinate the single IRF5 isoforms. "
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