Regulation Of Virus-induced Type Ⅰ Interferon Production By IRF3SUMOylation And Ubiquitination

The innate immune system constitutes the first line of host defense against viral infection. Recognition of pathogen-associated molecular patterns (PAMPs) derived from viruses by host pattern recognition receptors (PRRs) triggers a series of signaling cascades, leading to activation of key transcription factors, such as IRF3and NF-κB. These transcription factors initiate transcription of type Ⅰ interferons as well as proinflammatory cytokines, resulting in the cellular antiviral response. Among the earliest responses to viral infection is the production of type Ⅰ IFNs, which is critical for the antiviral innate immunity as well as the initiation of adaptive immunity. However, uncontrolled or excessive production of type Ⅰ IFNs leads to auto-immune diseases, such as systemic lupus erythematosus (SLE). To avoid such consequences, virus-induced production of type Ⅰ IFNs is tightly regulated at distinct levels to insure a functional antiviral status yet has no harm to the host.Recent studies indicate that post-translational modifications, such as phosphorylation, ubiquitination, SUMOylation and acetylation are extensively involved in the regulation of virus-induced production of type Ⅰ IFNs. Moreover, such modification processes could further be antagonized by different kinds of enzymes, such as phosphatase, de-ubiquitin enzymes and SUMO-specific proteases. To investigate the regulatory mechanisms of virus-induced signal transduction, we screened a cDNA library containing various enzymes for molecules that regulate virus-triggered type Ⅰ IFNs production. As a result, we indentified SUMO/Sentrin-specific protease2(SENP2) as a negative regulator of virus-induced production of type Ⅰ IFNs.Overexpression of SENP2inhibited virus-induced IFN-β production, whereas knockdown or knockout of SENP2had opposite effects. Consistently, the replication of NDV and SeV were markedly inhibited in Senp2-’-MEFs comparing to wild-type controls. The results of both reporter assay and co-IP experiment suggested that SENP2regulates virus-triggered signaling at the IRF3level. Overexpression of SENP2caused deSUMOylation, K48-linked ubiquitination and degradation of IRF3, whereas knockdown or knockout of SENP2had opposite effects. Further studies showed that SUMOylation and K48-linked ubiquitination of IRF3occurred at the same site, suggesting these two processes are competitive. Taken together, our results indicate that SENP2negatively regulates antiviral innate immunity by deSUMOylating IRF3and conditioning it for ubiquitination and degradation.In this study, we identified SENP2as a negative regulator of cellular antiviral response, which conditions IRF3for K48-linked ubiquitination and degradation As a transcription factor commonly used by different PRRs, IRF3is pivotal for virus-induced production of type Ⅰ IFNs. Our findings shed new light on the regulationf of IRF3stability. In addition, our findings provided an example of the cross-talk between ubiquitination and SUMOylation in innate immunity.