The non-structural (NS1) protein of influenza A viruses is a non-essential virulence factor that has multiple accessory functions during viral infection. In recent years, the major role ascribed to NS1 has been its inhibition of host immune responses, especially the limitation of both interferon (IFN) production and the antiviral effects of IFN-induced proteins. The various roles NS1 has in regulating viral replication mechanisms, host innate/adaptive immune responses, and cellular signalling pathways.
Nonstructural protein 1 Proteins
Nonstructural protein 1 cDNAs
NS1 is notionally divided into two distinct functional domains: an N-terminal RNA-binding domain (residues 1–73), which in vitro binds with low affinity to several RNA species in a sequence independent manner, and a C-terminal 'effector' domain (residues 74–230), which predominantly mediates interactions with host-cell proteins, but also functionally stabilizes the RNA-binding domain. Full-length NS1 likely exists as a homodimer, with both the RNA binding and effector domains contributing to multimerization.
NS1 has a strain-specific length of 230–237 aa, and an approximate molecular mass of 26 kDa. The N-terminal 73 amino acids form a functional RNA-binding domain, whilst the effector domain predominantly mediates interactions with host-cell proteins. The final C-terminal ~20 amino acids may be natively unstructured. NS1 contains two nuclear localization sequences (NLS1 and NLS2), and a nuclear export sequence (NES). A nucleolar localization sequence (NoLS) has been reported for some strains, and is concomitant with NLS2.
NS1 is composed of N-terminal RNA-binding domain (RBD, amino acids 1–73) and C-terminal effector domain (ED, amino acids 74–207).
Schematic ribbon diagrams of the RNA-binding domain (PDB ID,2N74) and effector domain (PDB ID, 3EE8).
The influenza A virus NS1 protein interacts with a variety of proteins to inhibit host cell immune responses and promote viral replication. The NS1 protein is known to bind to double-stranded RNA via N-terminal RNA-binding domain and it specifically binds to the region of the RNA containing either 5'- or 3'-terminal common genomic sequence. The binding of influenza A virus NS1 protein to dsRNA protects the virus against the antiviral state induced by interferon-α/β.
NS1 is important for multiple viral functions, including:
• Temporal adjustment of viral RNA synthesis;
• Control of viral mRNA splicing;
• Adjustment of virus particle morphogenesis;
• Suppression of host apoptotic response through the activation of phosphoinositide 3-kinase (PI3K);
• Interact with replication intermediates of viral RNA to block molecules from recognition by cellular pattern recognition receptors (PRRs)
• Chang Woo Han.Structure and Function of the Influenza A Virus Non-Structural Protein 1.J. Microbiol. Biotechnol. 2019
• Benjamin G. Hale.The multifunctional NS1 protein of influenza A viruses.Journal of General Virology.2008
• Robert M. Krug.Functions of the Influenza A Virus NS1 Protein In Antiviral Defense.Curr Opin Virol. 2015
• Daniel Marc.Influenza virus non-structural protein NS1:interferon antagonism and beyond.Journal of General Virology.2014