The NS1 Protein of Influenza A Virus
Chen Zhao, Rei-Lin Kuo and Robert M. Krug
from: Influenza: Molecular Virology (Edited by: Qinghua Wang and Yizhi Jane Tao). Caister Academic Press, U.K. (2010)
The NS1 protein of influenza A viruses is a small (230-237-amino acid), multi-functional dimeric protein that participates in both protein-RNA and protein-protein interactions. It is comprised of two functional domains: N-terminal (amino acids 1-73) RNA-binding domain; and C-terminal (amino acids 74-230/237) effector domain. Here we focus on several of the best-characterized functional interactions of the NS1 protein. A major role of the NS1 protein is to counter host cell antiviral responses. Thus, the RNA-binding domain binds double-stranded (ds) RNA, thereby inhibiting the dsRNA activation of the antiviral oligo A synthetase/RNase L pathway that is induced by interferon-α/β (IFN-α/β). A region of the effector domain binds the protein kinase PKR, thereby preventing its activation that would otherwise lead to the shutdown of both viral and host protein synthesis. Another region of the effector domain binds the 30 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a cellular protein required for the 3' end processing of all cellular pre-mRNAs. As a consequence, the substantial amount of IFN-β pre-mRNA that is synthesized in virus-infected cells is not processed to form mature IFN-β mRNA, thereby suppressing the IFN response. The NS1 protein also has other functions that are not directly involved in countering host antiviral responses. The effector domain of the NS1 protein binds the P85β regulatory subunit of phosphoinositide 3-kinase (PI3K), resulting in the activation of PI3K and the Akt kinase, which in turn inhibits apoptosis. The C-termini of pathogenic influenza A viruses have a PDZ-binding motif that has been implicated in pathogenicity. The NS1 protein also interacts with the cellular nuclear export protein (TAP), and may have a role in the nuclear export of viral mRNAs. Finally, the NS1 protein functionally interacts with the viral polymerase complex in infected cells and likely has a role in the regulation of viral RNA synthesis read more ...