The non-structural protein 1 (NS1) of
influenza virus is a potent antagonist of the cellular antiviral interferon (IFN) response. It is a multifunctional protein with two domains, a dsRNA binding domain (RBD) and an effector domain (ED) which interacts with various cellular proteins. Although, initially sequestration of dsRNA was considered the primary mechanism for countering IFN, subsequent studies have shown that the interactions of ED with various cellular proteins are likely involved. NS1 is shown to be a virulence determinant, especially in the highly pathogenic H5N1 viruses that are currently a threat for another
influenza pandemic.
Among various
influenza virus strains, NS1 is relatively well conserved with major differences occurring in the linker region and the C-terminus, where several NS1 proteins contain truncations. How these differences contribute to virulence remains unknown but these differences seem to have an effect on NS1 function that may be strain specific. In recent years, substantial progress has been made toward understanding of the structural aspects of this two-domain protein.
Further reading:
Labels: H5N1 viruses, Influenza virus, Influenza virus strains, Interferon, NS1 protein
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.
Further reading:
Labels: Influenza A, NS1 protein, Pathogenic influenza A viruses, PDZ-binding motif