Large-scale analysis of influenza A virus sequences reveals potential drug target sites of non-structural proteins

Darapaneni, Vivek; Prabhaker, Varun K.; Kukol, Andreas

doi:10.1099/vir.0.011270-0

Cited by 56 publications

(44 citation statements)

References 62 publications

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“…The residues mutated in NS1-m7 reside in a region involved in NS1 interaction with eIF4G, but the functions of these residues are not known (27,38). NS1-m9 has been reported to lose the ability to suppress the E3 ligase activity of TRIM25 (21).…”

Section: Discussionmentioning

confidence: 99%

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1

Tang

Wang

Gao

2017

J Virol

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Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses. There are two ZAP isoforms arising from alternative splicing, which differ only at the C termini. It was recently reported that the long isoform (ZAPL) promotes proteasomal degradation of influenza A virus (IAV) proteins PA and PB2 through the C-terminal poly(ADP-ribose) polymerase (PARP) domain, which is missing in the short form (ZAPS), and that this antiviral activity is antagonized by the viral protein PB1. Here, we report that ZAP inhibits IAV protein expression in a PARP domain-independent manner. Overexpression of ZAPS inhibited the expression of PA, PB2, and neuraminidase (NA), and downregulation of the endogenous ZAPS enhanced their expression. We show that ZAPS inhibited PB2 protein expression by reducing the encoding viral mRNA levels and repressing its translation. However, downregulation of ZAPS only modestly enhanced the early stage of viral replication. We provide evidence showing that the antiviral activity of ZAPS is antagonized by the viral protein NS1. A recombinant IAV carrying an NS1 mutant that lost the ZAPS-antagonizing activity replicated better in ZAPS-deficient cells. We further provide evidence suggesting that NS1 antagonizes ZAPS by inhibiting its binding to target mRNA. These results uncover a distinct mechanism underlying the interactions between ZAP and IAV.IMPORTANCE ZAP is a host antiviral factor that has been extensively reported to inhibit the replication of certain viruses by repressing the translation and promoting the degradation of the viral mRNAs. There are two ZAP isoforms, ZAPL and ZAPS. ZAPL was recently reported to promote IAV protein degradation through the PARP domain. Whether ZAPS, which lacks the PARP domain, inhibits IAV and the underlying mechanisms remained to be determined. Here, we show that ZAPS posttranscriptionally inhibits IAV protein expression. This antiviral activity of ZAP is antagonized by the viral protein NS1. The fact that ZAP uses two distinct mechanisms to inhibit IAV infection and that the virus evolved different antagonists suggests an important role of ZAP in the host effort to control IAV infection and the importance of the threat of ZAP to the virus. The results reported here help us to comprehensively understand the interactions between ZAP and IAV.KEYWORDS Influenza A virus, NS1, PB2, virus-host interactions, zinc finger antiviral protein Z inc finger antiviral protein (ZAP) is a type I interferon (IFN)-inducible host factor (1-3) that inhibits the replication of certain viruses, including Sindbis virus (SINV) and Ross River virus (4), Ebola virus and Marburg virus (5), murine leukemia virus (MLV) (6), human immunodeficiency virus type 1 (HIV-1) (7), and hepatitis B virus (HBV) (8).

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Section: Discussionmentioning

confidence: 99%

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1

Tang

Wang

Gao

2017

J Virol

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“…Apart from saving time and costs in the discovery of ligands for a protein target, an additional benefit is the increased specificity of the predicted ligands, because receptor-based virtual screening is directed against a known binding site or even against a particular receptor conformation (Bruning et al, 2010). This enables the targeting of specific binding sites that are evolutionary conserved in pathogens such as the influenza virus (Darapaneni et al, 2009) or conversely, for endogenous diseases targeting of binding sites that are not conserved among homologous proteins in order to avoid side effects. Critical for the success of a virtual screening experiment is the prediction of binding affinities for the ligand to the receptor.…”

Section: Introductionmentioning

confidence: 99%

Consensus virtual screening approaches to predict protein ligands

Kukol

2011

European Journal of Medicinal Chemistry

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-In order to exploit the advantages of receptor-based virtual screening, namely time/cost saving and specificity, it is important to rely on algorithms that predict a high number of active ligands at the top ranks of a small molecule database. Towards that goal consensus methods combining the results of several docking algorithms were developed and compared against the individual algorithms. Furthermore, a recently proposed rescoring method based on drug efficiency indices was evaluated. Among AutoDock Vina 1.0, AutoDock 4.2 and GemDock, AutoDock Vina was the best performing single method in predicting high affinity ligands from a database of known ligands and decoys. The rescoring of predicted binding energies with the water/butanol partition coeffcient did not lead to an improvement averaged over all receptor targets. Various consensus algorithms were investigated and a simple combination of AutoDock and AutoDock Vina results gave the most consistent performance that showed early enrichment of known ligands for all receptor targets investigated. In case a number ligands is known for a specific target, every method proposed in this study should be evaluated.

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“…Through sequencing alignment analysis and consultation with the literature [4,16,17], five of the conserved residues (E92, W97, D120, P159, and R195) of NS1 were selected for site-directed mutagenesis study to determine which residues may be important for the binding of NS1 to NOLC1. The spacial locations of these five residues within the NS1 effector domain are shown in Fig.…”

Section: Essential Amino Acids Of Ns1-ed For Interaction With Nolc1mentioning

confidence: 99%

Identification of NS1 domains of avian H5N1 influenza virus which influence the interaction with the NOLC1 protein

et al. 2015

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Non-structural protein 1 (NS1) is an important virulence factor encoded by influenza A virus. NS1 can interact with a variety of host cell proteins to interfere with the host innate immune response and to promote effective viral replication. Our previous work has shown that only the effector domain of NS1 (amino acid residues 74-230/237) is sufficient to interact with nucleolar and coiled-body phosphoprotein 1 (NOLC1). To investigate the exact region of NS1 that interacts with NOLC1, we used only the effector domain of NS1 and constructed various mutants having different deletions, and then tested their ability to interact with NOLC1 via pull-down assay. Only the mutant containing amino acid residues 104-200 showed positive interaction with NOLC1. To further determine the key amino acids of the NS1 effector domain which are crucial for interaction with NOLC1, several mutants containing a single amino acid substitution were made and their interaction with NOLC1 was tested. Only the mutant D120A or R195A showed reduced binding with NOLC1, suggesting that D120 and R195 were crucial to the binding of NS1 to NOLC1. This study lays the foundation for further research aiming at furthering our understanding of the interaction between NS1 and host cells.

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Large-scale analysis of influenza A virus sequences reveals potential drug target sites of non-structural proteins

Cited by 56 publications

References 62 publications

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1

The Short Form of the Zinc Finger Antiviral Protein Inhibits Influenza A Virus Protein Expression and Is Antagonized by the Virus-Encoded NS1

Consensus virtual screening approaches to predict protein ligands

Identification of NS1 domains of avian H5N1 influenza virus which influence the interaction with the NOLC1 protein

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