The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

Abstract

Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae family and have a negative sense eight-segment single-stranded RNA genome that encodes 11 different proteins. The only control over influenza seasonal epidemic outbreaks around the world are vaccines, annually updated according to viral strains in circulation, but, because of high rates of mutation and recurrent genetic assortment, new viral strains of influenza are constantly emerging, increasing the likelihood of pandemics. Vaccination effectiveness is limited, calling for new preventive and therapeutic approaches and a better understanding of the virus-host interactions. In particular, grasping the role of influenza non-structural protein 1 (NS1) and related known interactions in the host cell is pivotal to better understand the mechanisms of virus infection and replication, and thus propose more effective antiviral approaches. In this review, we assess the structure of NS1, its dynamics, and multiple functions and interactions, to highlight the central role of this protein in viral biology and its potential use as an effective therapeutic target to tackle seasonal and pandemic influenza.

Keywords: NS1; PPIs; influenza virus; molecular modeling; protein structure; protein–protein interactions; structural bioinformatics.

Figure 1

Schematic representation of the influenza virion. The viral genome is depicted highlighting the 8 single-stranded RNA segments (PB2, PB1, PA, HA, NP, NA, M, and NS) organized into ribonucleoproteins and here displayed by their decreasing size. Each ribonucleoprotein complex includes one trimeric viral RNA polymerase (PB1, PB2, and PA), in addition to nucleoproteins wrapped in viral RNA. (M1—viral matrix protein; PB1—polymerase basic protein 1; PB2—polymerase basic protein 2; PA—polymerase acidic protein; M2—ion channel).

Figure 2

Ribbon and surface representations of the NS1 dimer highlighting its structural domains. Subunits 1 and 2 are represented in pink and orange, respectively; N-terminal RNA-binding domains (RBDs) are represented in dark pink and light orange (top) and effector domains (EDs) in light pink and bright orange (bottom) (PDB ID: 4OPH) [40].

Figure 3

Three X-ray crystallography NS1 structures illustrating the different conformational arrangements of the NS1 dimer: (A) “Open” conformation (PDB ID: 6O01 [53]), (B) “semi-open” conformation (PDB ID: 4OPH [41]), and (C) “closed” conformation (PDB ID: 4OPA [41]).

Figure 4

X-ray structure of RNA binding domain of NS1 bound to dsRNA (PDB ID: 2ZKO) [76] (orange, NS1-RBD monomer 1; pink, NS1-RBD monomer 2; gray, dsRNA).

Figure 5

X-ray structure of NS1 dimer bound to TRIM25′s coiled-coil domain (PDB ID: 5NT2) [80] (orange, NS1 monomer 1; pink, NS1 monomer 2; gray, TRIM25′s coiled-coil domain).

Figure 6

X-ray structure of NS1 effector domain bound to CPSF30′s F2F3 finger (PDB ID: 2RHK) [87] (orange, NS1-ED monomer 1; pink, NS1-ED monomer 2; gray, CPSF30′s F2F3 finger).

Figure 7

Graphical representation of known NS1 protein-protein and protein-RNA interactions and their respective site of interaction. (all proteins and interactions mentioned in the figure are referenced in the text).