Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins

Abstract

The Influenza A virus is a continuous threat to public health that causes yearly epidemics with the ever-present threat of the virus becoming the next pandemic. Due to increasing levels of resistance, several of our previously used antivirals have been rendered useless. There is a strong need for new antivirals that are less likely to be susceptible to mutations. One strategy to achieve this goal is structure-based drug development. By understanding the minute details of protein structure, we can develop antivirals that target the most conserved, crucial regions to yield the highest chances of long-lasting success. One promising IAV target is the virulence protein non-structural protein 1 (NS1). NS1 contributes to pathogenicity through interactions with numerous host proteins, and many of the resulting complexes have been shown to be crucial for virulence. In this review, we cover the NS1-host protein complexes that have been structurally characterized to date. By bringing these structures together in one place, we aim to highlight the strength of this field for drug discovery along with the gaps that remain to be filled.

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1

“…The IAV NS1 LP between the RBD and ED is mostly made of 11 aa residues (74-85) ( Hale et al., 2008b ). The majority of IAV H5N1 isolates circulating after 2003 displayed a 5 aa deletion from residues 80 to 84 in the LP ( Figure 2A ) ( Blake et al., 2023 ). Despite that the exact role of the LP in not fully understood, studies showed that it is crucial for the distinct properties of IAV NS1 because it controls the large conformational changes required to switch from the ‘helix-open’ to ‘helix-closed’ state and vice versa ( Kerry et al., 2011 ; Hale, 2014 ).…”

“…Following host cell infection, IAV and hCoV utilize several strategies to hamper IFN expression ( Hale et al., 2008b ; Evseev and Magor, 2021 ). Most of these strategies are depending mainly on two non-structural viral protein(s), specifically IAV NS1 and hCoV non-structural protein 1 (Nsp1), that hijack, suppress, or escape the host cell innate immunity antiviral responses via several molecular strategies, including antagonism of IFN production ( Kanrai et al., 2016 ; Petersen et al., 2018 ; Khorramdelazad et al., 2021 ; Kumar et al., 2021a ; Blake et al., 2023 ).…”

“…IAV NS1 has a typical length of 230 amino acids (aa), and an approximate molecular weight of 26 kDa ( Ji et al., 2021 ). However, NS1 varies in length (202-237 aa) among different IAV subtypes and strains due to premature stop codons, or contrarily, the suppression of the most prevailing stop codon at nucleotide 688–690 that produce NS1 proteins with truncations or insertions at the disordered C-terminal tail, respectively ( Hale et al., 2008b ; Petersen et al., 2018 ; Trigueiro-Louro et al., 2019 ; Blake et al., 2023 ). Even though IAV NS1 protein has no apparent structural function in the viral particle, it contributes efficiently to viral replication and pathogenicity by suppressing IFN production and the activity of many ISGs ( Petersen et al., 2018 ; Blake et al., 2023 ).…”

“…However, NS1 varies in length (202-237 aa) among different IAV subtypes and strains due to premature stop codons, or contrarily, the suppression of the most prevailing stop codon at nucleotide 688–690 that produce NS1 proteins with truncations or insertions at the disordered C-terminal tail, respectively ( Hale et al., 2008b ; Petersen et al., 2018 ; Trigueiro-Louro et al., 2019 ; Blake et al., 2023 ). Even though IAV NS1 protein has no apparent structural function in the viral particle, it contributes efficiently to viral replication and pathogenicity by suppressing IFN production and the activity of many ISGs ( Petersen et al., 2018 ; Blake et al., 2023 ). IAV NS1 also contributes to the shut-down of host gene expression by preventing the cellular splicing and polyadenylation machineries of cellular mRNA and blocking the nuclear export of polyadenylated mature mRNAs ( Nemeroff et al., 1998 ; Ayllon and Garcia-Sastre, 2015 ; Evseev and Magor, 2021 ).…”

Research progress on the nonstructural protein 1 (NS1) of influenza a virus

“…The structure of the ED domain monomer unit of the NS1 consists of three α-helices and seven β-chains. The protein core is arranged in a long central α-helix surrounded by a twisted antiparallel β-sheet [ 24 ]. The ED structural domain interacts with innate immune response host factors induced by influenza virus infection and plays an important role in RBD localization and nuclear export of NS1.…”