ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.
ERRα negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction.
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ERR α 通过抑制 TBK1-IRF3 相互作用负调节 I 型干扰素诱导
DOI：
10.1371/journal.ppat.1006347
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发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Zhong H
中科院分区：
文献类型：
--
作者：
He X;Ma S;Tian Y;Wei C;Zhu Y;Li F;Zhang P;Wang P;Zhang Y;Zhong H
雌激素相关受体α（ERRα）是控制能量稳态的核受体超家族成员;然而，其在调节抗病毒天然免疫中的确切作用仍有待阐明。在这里，我们发现ERRα缺陷在体内和体外都赋予了对病毒感染的抵抗力。在机制上，ERRα抑制I型干扰素（IFN-I）的产生和多种干扰素刺激基因（ISG）的表达。此外，我们发现病毒感染诱导TBK 1依赖性ERRα稳定化，这反过来又与TBK 1和IRF 3相关，从而阻碍TBK 1-IRF 3的形成、IRF 3磷酸化、IRF 3二聚化和IRF 3的DNA结合亲和力。ERRα对IFN-I产生的影响与其转录活性和PCG-1α无关。值得注意的是，ERRα化学抑制剂XCT 790具有广泛的抗病毒效力。这项工作不仅确定了ERRα作为抗病毒信号传导的关键负调节因子，而且为未来的抗病毒治疗提供了潜在的靶点。ERRα作为参与代谢信号传导的核受体超家族成员，其在抗病毒天然免疫中的确切作用尚不清楚。在这里，我们发现ERRα缺陷导致干扰素产生增加，导致体内和体外对病毒感染的抵抗力增强。从机制上讲，病毒感染诱导TBK 1依赖性ERRα稳定化，进而增加其与TBK 1和IRF 3的结合，以防止功能性TBK 1-IRF 3复合物的形成。ERRα对IFN-I产生的影响与其转录活性和PCG-1α无关。值得注意的是，ERRα化学抑制剂XCT 790具有广泛的抗病毒效力。综上所述，我们的研究结果确定ERRα是RLRs-TLR信号通路中TBK 1的重要负下游调节因子，并提出了病毒感染的潜在治疗靶点。
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 induced TBK1-dependent ERRα 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 ERRα on IFN-I production was independent of its transcriptional activity and PCG-1α. Notably, ERRα chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERRα as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy. As a member of the nuclear receptor superfamily involved in metabolism signaling, the precise role of ERRα in antiviral innate immunity remains to be clarified. Here, we showed that ERRα deficiency led to increased interferon production, resulting in enhanced resistance to viral infection both in vivo and in vitro. Mechanistically, viral infection induced TBK1-dependent ERRα stabilization, which in turn increased its binding to TBK1 and IRF3 to prevent the formation of a functional TBK1-IRF3 complex. The effect of ERRα on IFN-I production was independent of its transcriptional activity and PCG-1α. Notably, ERRα chemical inhibitor XCT790 has broad antiviral potency. Taken together, our results identified ERRα as an important negative downstream regulator of TBK1 in RLRs-TLRs signaling pathways and suggested a potential therapeutic target for viral infection.