FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions.
FOSL1 Inhibits Type I Interferon Responses to Malaria and Viral Infections by Blocking TBK1 and TRAF3/TRIF Interactions.
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DOI：
10.1128/mbio.02161-16
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发表时间：
2017-01-03
期刊：
影响因子：
6.4
通讯作者：
Wang RF
中科院分区：
文献类型：
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作者：
Cai B;Wu J;Yu X;Su XZ;Wang RF
先天免疫反应在控制入侵病原体方面发挥着关键作用，但这种免疫反应必须受到严格调节。免疫反应不足或过度激活可能会导致有害甚至致命的后果。为了剖析复杂的宿主-寄生虫相互作用以及对感染的先天免疫反应的分子机制，我们研究了 FOS 样抗原 1 (FOSL1) 在调节宿主 I 型干扰素 (IFN-I) 对疟疾寄生虫和病毒感染的反应中的作用。 FOSL1 被认为是转录因子的一个组成部分，但最近被认为参与调节 IFN-I 对疟疾寄生虫感染的反应。在这里，我们证明 FOSL1 可以充当 IFN-I 信号传导的负调节因子。在用聚 (I:C)、疟疾寄生虫感染的红细胞 (iRBC) 或水疱性口炎病毒 (VSV) 刺激后，FOSL1 从细胞核“移位”到细胞质，通过削弱 TNF 受体相关因子 3 (TRAF3)、包含 TIR 结构域的接头诱导 IFN-β (TRIF) 和 Tank 结合激酶 1 (TBK1) 之间的相互作用TRAF3 和 TRIF 的 K63 连接多聚泛素化。重要的是，与野生型 (WT) 小鼠相比，FOSL1 敲除嵌合小鼠的外周血中疟原虫血症或 VSV 滴度水平较低，死亡率也较低。因此，我们的研究结果确定了 FOSL1 在负向调节宿主 IFN-I 对疟疾和病毒感染的反应中的新作用，并确定了控制疟疾和其他疾病的潜在药物靶点。病原体感染可引发强烈的宿主免疫反应，包括 I 型干扰素 (IFN-I) 的激活和产生。在这项研究中，我们研究了 FOSL1（一种以前被称为转录因子的分子）在负向调节 IFN-I 对疟疾和病毒感染的反应中的作用。我们发现，在刺激 IFN-I 产生后，FOSL1 上调并易位到细胞的细胞质中。 FOSL1 可以影响 TRAF3 和 TRIF 泛素化，从而损害 TRAF3、TRIF 和 TBK1 的关联，从而抑制 IFN-I 信号传导。 FOSL1 敲除嵌合小鼠的体内实验进一步验证了 FOSL1 在 IFN-I 产生和抗菌反应中的负面作用。该报告揭示了 FOSL1 在 IFN-I 信号传导中的新功能作用，并剖析了 FOSL1 调节 IFN-I 对疟疾和病毒感染的反应的机制，该机制可作为疾病控制和管理的潜在药物靶点进行探索。
Innate immune response plays a critical role in controlling invading pathogens, but such an immune response must be tightly regulated. Insufficient or overactivated immune responses may lead to harmful or even fatal consequences. To dissect the complex host-parasite interactions and the molecular mechanisms underlying innate immune responses to infections, here we investigate the role of FOS-like antigen 1 (FOSL1) in regulating the host type I interferon (IFN-I) response to malaria parasite and viral infections. FOSL1 is known as a component of a transcription factor but was recently implicated in regulating the IFN-I response to malaria parasite infection. Here we show that FOSL1 can act as a negative regulator of IFN-I signaling. Upon stimulation with poly(I:C), malaria parasite-infected red blood cells (iRBCs), or vesicular stomatitis virus (VSV), FOSL1 “translocated” from the nucleus to the cytoplasm, where it inhibited the interactions between TNF receptor-associated factor 3 (TRAF3), TIR domain-containing adapter inducing IFN-β (TRIF), and Tank-binding kinase 1 (TBK1) via impairing K63-linked polyubiquitination of TRAF3 and TRIF. Importantly, FOSL1 knockout chimeric mice had lower levels of malaria parasitemia or VSV titers in peripheral blood and decreased mortality compared with wild-type (WT) mice. Thus, our findings have identified a new role for FOSL1 in negatively regulating the host IFN-I response to malaria and viral infections and have identified a potential drug target for controlling malaria and other diseases. Infections of pathogens can trigger vigorous host immune responses, including activation and production of type I interferon (IFN-I). In this study, we investigated the role of FOSL1, a molecule previously known as a transcription factor, in negatively regulating IFN-I responses to malaria and viral infections. We showed that FOSL1 was upregulated and translocated into the cytoplasm of cells after stimulation for IFN-I production. FOSL1 could affect TRAF3 and TRIF ubiquitination and consequently impaired the association of TRAF3, TRIF, and TBK1, leading to inhibition of IFN-I signaling. In vivo experiments with FOSL1 knockout chimeric mice further validated the negative role of FOSL1 in IFN-I production and antimicrobial responses. This report reveals a new functional role for FOSL1 in IFN-I signaling and dissects the mechanism by which FOSL1 regulates IFN-I responses to malaria and viral infections, which can be explored as a potential drug target for disease control and management.