Antagonising roles between PACT and influenza A virus polymerase subunits in viral replication and innate immune response

Abstract

Abstract Interplay between host innate immune responses and viral antagonism determines the effectiveness of viral replication and pathogenicity. Influenza A virus (IAV) confronts host antiviral responses including type I interferon production using multiple viral proteins such as NS1. We have previously shown that double stranded RNA-binding protein PACT is an essential coactivator of RIG-I in innate antiviral response. In this study, we have further shown that PACT has dual antiviral activity in both interferon-dependent and interferon-independent manners. We found that antiviral activity of PACT is mediated through not only the activation of RIG-I and interferon production but also the direct suppression of IAV polymerase activity. We found that PACT associates with IAV polymerase subunits, namely PB2, PB1 and PA, and inhibits viral replication. On the other hand, the three polymerase subunits also counteract PACT/RIG-I-mediated production of type-I interferon. Taken together, our findings reveal a new mechanism of virus-host interaction demonstrating the mutual antagonism between PACT and IAV polymerases during IAV infection and replication. Supported by RGC (HKU1/CRF/11G, N-HKU712/12, T11-707/15-R and C7011-15R), HMRF (12111312, 14130862, HKM-15-M01 and 15140662) and S. K. Yee MRF (2011).