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

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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