The proposed project aims at deciphering the molecular mechanism of the inhibition of the TRIM25/RIG-I-mediated interferon response by the influenza A virus NS1 protein with the main focus on the characterization of the TRIM25-NS1 interaction and NS1 muta

在病毒识别时诱导I型干扰素(IFN)对于建立抗病毒状态是至关重要的。TRIM25通过泛素化和激活胞质病毒RNA传感器RIG-I，在应对甲型流感病毒感染的干扰素诱导中发挥关键作用。反过来，甲型流感病毒已经进化出机制来中和TRIM25的作用，从而逃避RIG-I的识别。最初的研究表明，各种甲型流感病毒株的非结构蛋白1(NS1)直接与TRIM25相互作用，并抑制其泛素化RIG-I的酶活性。然而，NS1如何抑制TRIM25的确切分子机制以及TRIM25-NS1复合体的详细结构仍有待确定。本研究旨在阐明NS1抑制TRIM25的分子机制。此外，拟议的研究旨在剖析TRIM25-NS1相互作用的确切性质。最后，由于对新宿主物种的适应是甲型流感病毒的一个重要特征，将确定不同物种的TRIM25序列差异如何影响NS1-TRIM25相互作用和NS1对抗TRIM25/rig-I介导的干扰素反应的能力

Induction of type I interferons (IFNs) upon virus recognition is essential for the establishment of an antiviral state. TRIM25 plays a critical role in IFN induction in response to influenza A virus infection by ubiquitinating and activating the cytosolic viral RNA sensor RIG-I. In turn, influenza A viruses have evolved mechanisms to counteract the action of TRIM25, thereby evading recognition by RIG-I. First studies showed that the non-structural protein 1 (NS1) of various influenza A virus strains directly interacts with TRIM25 and inhibits its enzymatic activity to ubiquitinate RIG-I. However, the precise molecular mechanisms of how NS1 inhibits TRIM25 as well as the detailed architecture of the TRIM25-NS1 complex remain to be determined. This study aims at deciphering the molecular mechanism of the TRIM25 inhibition by NS1. Furthermore, the proposed study is directed toward dissecting the precise nature of the TRIM25-NS1 interaction. Finally, since adaptation to new host species is an important feature of influenza A viruses, it will be determined how sequence variations in TRIM25 from different species influence the NS1-TRIM25 interaction and NS1 ability to antagonize the TRIM25/RIG-I-mediated IFN response