Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection
Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection
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RIG-I 的强 Lys63 连接泛素化促进早期乙型流感病毒感染中细胞因子的爆发
DOI：
10.1128/jvi.00549-16
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发表时间：
2016-07-01
影响因子：
5.4
通讯作者：
Liu, Wenjun
中科院分区：
文献类型：
--
作者：
Jiang, Jingwen;Li, Jing;Liu, Wenjun
甲型流感和B型流感病毒感染均引起宿主先天免疫应答。在这里，我们报告说，强大的生产I型和III型干扰素（IFN），IFN-刺激的基因，和促炎因子可以诱导流感病毒B，而不是流感病毒感染早期感染肺泡上皮细胞（A549）。这种反应主要依赖于视黄酸诱导基因I（RIG-I）介导的信号通路。B型流感病毒感染促进RIG-1的强烈Lys 63连接的泛素化，导致细胞因子爆发。已知甲型流感病毒NS 1蛋白（NS 1-A）与RIG-I和TRIM 25相互作用以抑制RIG-I介导的信号传导的活化。然而，本结果表明流感B病毒NS 1蛋白（NS 1-B）不能与RIG-I相互作用，但参与RIG-I/TRIM 25/NS 1-B三元复合物的形成。此外，我们证明了NS 1-B的N-末端RNA结合结构域（RBD）负责与TRIM 25的相互作用，并且这种相互作用阻断了NS 1-B C-末端效应结构域（TED）对RIG-I泛素化的抑制作用。我们的研究结果揭示了宿主细胞因子对流感B病毒感染的反应通过宿主和病毒蛋白之间的调节相互作用的新机制。
Influenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N-terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C-terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins.