TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1
TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1
复制标题
TRIM9 短亚型通过将 GSK3 beta 招募到 TBK1 来优先促进 DNA 和 RNA 病毒诱导的 I 型干扰素产生
DOI：
10.1038/cr.2016.27
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发表时间：
2016-05-01
期刊：
影响因子：
44.1
通讯作者：
Wang, Rong-Fu
中科院分区：
文献类型：
--
作者：
Qin, Yunfei;Liu, Qingxiang;Wang, Rong-Fu
I型干扰素（IFN）是由DNA传感器cGAS和RNA传感器RIG-I和MDA 5的病毒DNA和RNA识别介导的抗病毒先天免疫信号传导的重要组分。这些DNA和RNA传感器的激活分别导致STING和MAVS的募集，并聚集在TANK结合激酶1（TBK 1）信号传导上，用于随后的IFN调节因子3（IRF 3）的磷酸化。然而，控制TBK 1激活的机制仍然不清楚。在这里，我们确定三方基序9短亚型（TRIM 9 s）作为一个积极的调节因子在I型IFN信号。在病毒感染后，TRIM 9经历Lys-63连接的自身多聚泛素化，并作为将GSK 3 β桥连到TBK 1的平台，导致IRF 3信号转导的激活。有趣的是，我们发现TRIM 9 s选择性地抑制促炎细胞因子的产生，但增强I型IFN以及IFN刺激基因的表达，以响应病毒感染。我们的研究结果揭示了TRIM 9在抗病毒免疫中的新的双重功能，其用于平衡促炎反应和I型IFN的产生。
Type I interferon (IFN) is an important component of antiviral innate immune signaling mediated by viral DNA and RNA recognition by the DNA sensor cGAS and RNA sensors RIG-I and MDA5. Activation of these DNA and RNA sensors leads to the recruitment of STING and MAVS, respectively, and converges on TANK-binding kinase 1 (TBK1) signaling for subsequent phosphorylation of IFN regulatory factor 3 (IRF3). However, the mechanisms that control TBK1 activation are still poorly defined. Here, we identify tripartite motif 9 short isoform (TRIM9s) as a positive regulator in type I IFN signaling. Upon viral infection, TRIM9s undergoes Lys-63-linked auto-polyubiquitination and serves as a platform to bridge GSK3 beta to TBK1, leading to the activation of IRF3 signaling. Interestingly, we found that TRIM9s selectively inhibits the production of pro-inflammatory cytokines, but enhances the expression of type I IFNs as well as IFN-stimulated genes, in response to viral infection. Our findings reveal novel dual functions of TRIM9s in antiviral immunity, which serve to balance pro-inflammatory response and production of type I IFNs.