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Review
. 2021 Oct 4:12:693204.
doi: 10.3389/fmicb.2021.693204. eCollection 2021.

Molecular Evolution of the Influenza A Virus Non-structural Protein 1 in Interspecies Transmission and Adaptation

Danyel Evseev  1 , Katharine E Magor  1
Affiliations
Review

Molecular Evolution of the Influenza A Virus Non-structural Protein 1 in Interspecies Transmission and Adaptation

Danyel Evseev et al. Front Microbiol. .

Abstract

The non-structural protein 1 (NS1) of influenza A viruses plays important roles in viral fitness and in the process of interspecies adaptation. It is one of the most polymorphic and mutation-tolerant proteins of the influenza A genome, but its evolutionary patterns in different host species and the selective pressures that underlie them are hard to define. In this review, we highlight some of the species-specific molecular signatures apparent in different NS1 proteins and discuss two functions of NS1 in the process of viral adaptation to new host species. First, we consider the ability of NS1 proteins to broadly suppress host protein expression through interaction with CPSF4. This NS1 function can be spontaneously lost and regained through mutation and must be balanced against the need for host co-factors to aid efficient viral replication. Evidence suggests that this function of NS1 may be selectively lost in the initial stages of viral adaptation to some new host species. Second, we explore the ability of NS1 proteins to inhibit antiviral interferon signaling, an essential function for viral replication without which the virus is severely attenuated in any host. Innate immune suppression by NS1 not only enables viral replication in tissues, but also dampens the adaptive immune response and immunological memory. NS1 proteins suppress interferon signaling and effector functions through a variety of protein-protein interactions that may differ from host to host but must achieve similar goals. The multifunctional influenza A virus NS1 protein is highly plastic, highly versatile, and demonstrates a diversity of context-dependent solutions to the problem of interspecies adaptation.

Keywords: CPSF; RIG-I; adaptation; evolution; host; innate; interferon; species.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The NS1 protein. A crystal structure of the NS1 protein from A/Vietnam/1196/2004 (H5N1) is shown with the RNA-binding domain (RBD), the effector domain (ED), and the flexible interdomain linker labeled. The diagram below shows the amino acid limits of the domains. The variable lengths of the linker and the structurally disordered C-terminal tail are represented with dashed lines. Colored boxes below the schematic illustrate the approximate regions of NS1 involved in interactions with a select set of host proteins. NLS, nuclear localization sequence; PBM, PDZ-binding motif. Image was prepared with PyMol using the crystal structure from Mitra et al. (2019; PDB ID: 6O01).
Figure 2
Figure 2
Interaction between NS1 and CPSF4. (A) Crystal structure of two NS1 effector domains (red and pink) in complex with two fragments of human CPSF4, each comprising the second and third zinc fingers (white and dark gray). Zinc atoms are shown as blue spheres. The major interaction interface between the pink NS1 chain and the white CPSF4 chain is highlighted with a dashed oval. The minor interaction interface between the pink NS1 chain and the dark gray CPSF4 chain is highlighted with a dashed circle. The structure is symmetrical. (B) A view of the minor interaction interface between NS1 (pink) and CPSF4 (dark gray) showing the contributions of NS1 residues F103 and M106. (C) A view of the major interaction interface between NS1 (pink) and CPSF4 (white) showing the contributions of NS1 residues K108, D125, and D189. All three residues are making polar contacts with CPSF4 (not shown). Image was prepared with PyMol using the crystal structure from Das et al. (2008; PDB ID: 2RHK).
Figure 3
Figure 3
Interaction between NS1 and TRIM25. (A) Crystal structure of the NS1 proteins (red and pink) in complex with four fragments of human TRIM25, each comprising the coiled coil domain (white and dark gray). (B) A view of the NS1 residues E96 and E97 (colored yellow) facing away from TRIM25 and making polar contacts with neighbouring residues. Image was prepared with PyMol using the crystal structure from Koliopoulos et al. (2018; PDB ID: 5NT2).
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