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ERR? negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.

ABSTRACT: Estrogen-related receptor ? (ERR?) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERR? deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERR? inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERR? stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERR? on IFN-I production was independent of its transcriptional activity and PCG-1?. Notably, ERR? chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERR? as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy.

SUBMITTER: He X

PROVIDER: S-EPMC5476288 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.

He Xiang X Ma Shengli S Tian Yinyin Y Wei Congwen C Zhu Yongjie Y Li Feng F Zhang Pingping P Wang Penghao P Zhang Yanhong Y Zhong Hui H

PLoS pathogens 20170607 6

Estrogen-related receptor α (ERRα) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERRα inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection indu ...[more]

PMID: 28591144

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Project description:The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-?) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-? stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-?. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-? reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-?. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity.IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-? transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-?. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

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ERR? negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.

Publications

ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.

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