Evolutionary Dynamics of Structural and Functional Domains of Influenza a Virus Ns1 Protein

Abstract

Influenza A virus (IAV) NS1 protein is one of the key viral factors responsible for virus-host interactions. NS1 counteracts host antiviral defense, participates in the processing and export of cellular mRNAs, regulates the activity of viral RNA polymerase and the expression of viral genes, and influences the cellular signaling systems. Multiple NS1 functions are carried out due to the interactions with cellular factors, the number of which exceeds one hundred. It is noteworthy that only two segments of IAV genome - NS and NP - did not undergo reassortment and evolved in the course of genetic drift, beginning with the pandemic of 1918 to the present. This fact may indicate the importance of NS1 and its numerous interactions with cellular factors in the interspecific adaptation of the virus. The review presents data on the evolution of the human IAV NS1 protein and analysis of the amino acid substitutions in the main structural and functional domains of NS1 protein during evolution.

Mutations designed to modify the NS gene mRNA secondary structure affect influenza A pathogenicity in vivo

“…The mutations (G511A, G512A, C537G) responsible for the secondary structure changes in the RNA region 497-564 cause one amino acid substitution in NS1 (N166G) and two substitutions in NEP (V14M and A22G). Amino acid position 166 is located in the proline-rich 162-170 loop of NS1 and is not included in the known structural or functional domains of the NS1 protein [36]. Therefore, we think it is unlikely that this substitution significantly contributes to the observed differences between virus variants, although this cannot be ruled out.…”

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

“…Phylogenetically, the NS segments of all currently circulating human and swine viruses derive from a single lineage that traces back to the 1918 pandemic H1N1 strain. Since then, human and swine NS1 proteins have been evolving separately from the avian lineages and have accumulated species-specific substitutions in both protein domains and in the inter-domain linker region (systematically analyzed by Vasin et al, 2017 ). The species-associated polymorphisms with functional consequences that have been tested experimentally are summarized in Table 1 .…”

“…RNA binding depends, in part, on residues R35, R38, and K41, which also form a nuclear localization sequence essential for interaction of NS1 with importin α ( Greenspan et al, 1988 ; Melén et al, 2007 ). R35 and R38 are universally conserved, as is K41, with the exception of the human H3N2 lineage, in which a K41R mutation was observed in sequenced isolates from 1974 onward ( Vasin et al, 2017 ). In general, the dates given for the emergence of lineage-specific polymorphisms reflect their appearance in the sequences of dated isolates and not necessarily the exact years of their appearance.…”

“…In the classical swine lineage, a T91A substitution was replaced by A91S in the 2009 swine-origin pandemic strains (H1N1)pdm09. In human seasonal strains, whose NS1 proteins originate from the 1918 pandemic strain, a leucine (L) at position 95 was replaced with isoleucine (I), which became I95T in seasonal H3N2 strains since 1975, and I95V in seasonal human H1N1 strains since 2001 ( Vasin et al, 2017 ).…”

Old dog, new tricks: Influenza A virus NS1 and in vitro fibrillogenesis

“…Influenza A nonstructural protein 1 (NS1) is a multi-functional protein, with a mass of 26 kDa, which is mainly involved in suppression host immune responses. Currently, a number of mechanisms are known that involve NS1 and which prevent the induction of an interferon response [1]. Despite an important role in influenza pathogenesis, many of the mechanisms by which NS1 affects cellular factors are unclear.…”