The Role of NS1-BP in Influenza Virus Replication

Influenza A viruses are negative-sense, segmented RNA viruses which cause about 500,000 deaths worldwide per year. Genomic studies have shown that the non-structural protein (NS1) of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 is a multifunctional protein localized in the nucleus and in the cytoplasm. In the cytoplasm, NS1 inhibits host signaling pathways that result in down-regulation of interferon expression and innate immune response. In the nucleus, NS1 represses host gene expression. I have shown that NS1 binds an mRNA complex containing NXF1/TAP, NXT/p15, Rae1, and E1B-AP5, which are key components of the mRNA export machinery. By targeting this complex, NS1 blocks host mRNA export, and cells become highly permissive to viral replication. Another intranuclear pool of NS1 was found to interact with a host protein termed NS1-BP, which has been suggested to play a role in pre-mRNA splicing. However, the functions and mechanisms of NS1-BP involved in influenza life cycle remain to be elucidated. To investigate the function of NS1-BP, I first identified its binding partners by immunoprecipitation followed by mass spectrometry. I found interactions of NS1-BP with viral polymerase complex and host RNA polymerase II indicating that NS1-BP has a role in regulating viral RNA transcription and replication. I further showed that low levels of NS1-BP led to a decrease in viral polymerase activity resulting in inhibition of virus replication. Thus, I identified NS1-BP as a novel pro-viral factor required for proper replication of influenza virus. Since NS1 is a key contributor to the virulence of influenza viruses, discovering the function of NS1 interacting partners has major implications for antiviral therapy.