The NS1 protein: A master regulator of host and viral functions

Krug, Robert M.; García‐Sastre, Adolfo

doi:10.1002/9781118636817.ch7

Cited by 30 publications

(45 citation statements)

References 110 publications

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“…To reconcile those findings, we considered the two major mechanisms by which NS1 proteins can reduce IFN and/or ISG induction: by silencing the RIG-I pathway or by a more general inhibition of host cell gene expression via binding of CPSF30 (20). The targeting of the two pathways has been linked to polymorphic NS1 amino acid positions 103 and 106, among others, for CPSF30 binding, and position 196, for suppressing RIG-I signaling (20).…”

Section: Discussionmentioning

confidence: 99%

“…The targeting of the two pathways has been linked to polymorphic NS1 amino acid positions 103 and 106, among others, for CPSF30 binding, and position 196, for suppressing RIG-I signaling (20). A sequence comparison correlated the asymmetric ISG control by human strains in infected and transfected cells with signature amino acids previously described to govern stable binding of NS1 to CPSF30.…”

Section: Discussionmentioning

confidence: 99%

“…The best-studied IFN antagonist expressed by IAV is the viral NS1 protein, which has evolved multiple mechanisms to inhibit the type I IFN response of the host cell (20,21). NS1 interacts not only with RNA but also with several cellular proteins, such as PKR, OAS, TRIM25, RIG-I, CPSF30, PABII, NS1-BP, NS1-I, and phosphatidylinositol 3-kinase (PI3K), in order to control maturation or translation of mRNA, suppress the cellular immune response to infection, and inhibit apoptosis of the cell (20,(22)(23)(24)(25)(26). Furthermore, strain-specific differences have been reported for the ability of NS1 proteins to inhibit IFN-␤ induction via targeting of the RIG-I signaling module and/or the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30) (27).…”

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confidence: 99%

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Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

Recum-Knepper

Sadewasser

Weinheimer

et al. 2015

J Virol

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Influenza A virus (IAV) infection provokes an antiviral response involving the expression of type I and III interferons (IFN) and Influenza A viruses (IAVs) are prototypic members of the Orthomyxoviridae family, featuring a segmented RNA genome composed of eight single-stranded RNAs that have negative polarity (1). IAVs circulate in the human population, causing periodic epidemic outbreaks and occasional pandemic waves of respiratory disease (2). Moreover, there is a large natural IAV host reservoir in wild aquatic birds, such as ducks and geese, in which the viruses cause mainly mild or no apparent symptoms. IAV strains are usually well adapted to their particular host species, which is reflected not only in the existence of stable virus lineages but also in polymorphic amino acid positions in viral proteins distinctively found in human or avian strains (3).IAVs target the epithelial cell layers lining the human respiratory tract, in which they are subject to immune control in infected cells, mediated by the antiviral type I interferon (IFN) response (4). Many of the key events and factors driving the IFN response have been identified and involve initial recognition of the viral genomic 5=-triphosphorylated RNA by the intracellular RNA helicase RIG-I, which governs a signaling module culminating in the activation of transcription factors, such as IRF-3 and NF-B, thereby inducing the transcription of type I IFN genes (5, 6). Type I IFNs comprise 14 subtypes of IFN-␣ and one IFN-␤ that are secreted from virus-infected cells and exert antiviral effects against many virus families, including IAV (4, 7). Type I IFNs secreted by

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

Recum-Knepper

Sadewasser

Weinheimer

et al. 2015

J Virol

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“…The smallest genome segment encodes the nonstructural protein 1 (NS1) protein, which is synthesized at high levels in infected cells, but is not incorporated into virus particles. The NS1 proteins of wild-type influenza A viruses range in size from 215 to 237 amino acids long and are comprised of 2 functional domains connected by a short linker: the N-terminal RNA-binding domain (RBD) (amino acids 1-73), which binds dsRNA, and the C-terminal effector domain (ED) (amino acids 85-end) (Krug and Garcia-Sastre 2013) (Fig. 1A).…”

Section: Influenza a Virus Ns1 Proteinmentioning

confidence: 99%

Viral Proteins That Bind Double-Stranded RNA: Countermeasures Against Host Antiviral Responses

Krug

2014

Journal of Interferon & Cytokine Research

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“…The major function of this RNA-binding activity is the suppression of the activation of the 2=-5=-oligo(A) synthetase/RNase L pathway (9). The effector domain (comprising amino acid 85 to the end of the protein) has been shown to bind numerous cellular proteins (10). The effector domains of NS1 proteins encoded by H3N2, H2N2, and seasonal H1N1 viruses strongly bind to the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), thereby inhibiting the 3= end processing of host pre-mRNAs and the production of mature mRNAs, including beta interferon (IFN-␤) and other antiviral mRNAs (11)(12)(13).…”

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Role of N Terminus-Truncated NS1 Proteins of Influenza A Virus in Inhibiting IRF3 Activation

Kuo

Lin

et al. 2016

J Virol

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The NS1 protein encoded by influenza A virus antagonizes the interferon response through various mechanisms, including blocking cellular mRNA maturation by binding the cellular CPSF30 3= end processing factor and/or suppressing the activation of interferon regulatory factor 3 (IRF3). In the present study, we identified two truncated NS1 proteins that are translated from internal AUGs at positions 235 and 241 of the NS1 open reading frame. We analyzed the cellular localization and function of the N-truncated NS1 proteins encoded by two influenza A virus strains, Udorn/72/H3N2 (Ud) and Puerto Rico/8/34/H1N1 (PR8). The NS1 protein of PR8, but not Ud, inhibits the activation of IRF3, whereas the NS1 protein of Ud, but not PR8, binds CPSF30. The truncated PR8 NS1 proteins are localized in the cytoplasm, whereas the full-length PR8 NS1 protein is localized in the nucleus. The infection of cells with a PR8 virus expressing an NS1 protein containing mutations of the two in-frame AUGs results in both the absence of truncated NS1 proteins and the reduced inhibition of activation of IRF3 and beta interferon (IFN-␤) transcription. The expression of the truncated PR8 NS1 protein by itself enhances the inhibition of the activation of IRF3 and IFN-␤ transcription in Ud virus-infected cells. These results demonstrate that truncated PR8 NS1 proteins contribute to the inhibition of activation of this innate immune response. In contrast, the N-truncated NS1 proteins of the Ud strain, like the full-length NS1 protein, are localized in the nucleus, and mutation of the two in-frame AUGs has no effect on the activation of IRF3 and IFN-␤ transcription. IMPORTANCEInfluenza A virus causes pandemics and annual epidemics in the human population. The viral NS1 protein plays a critical role in suppressing type I interferon expression. In the present study, we identified two novel truncated NS1 proteins that are translated from the second and third in-frame AUG codons in the NS1 open reading frame. The N-terminally truncated NS1 encoded by the H1N1 PR8 strain of influenza virus that suppresses IRF3 activation is localized primarily in the cytoplasm. We demonstrate that this truncated NS1 protein by itself enhances this suppression, demonstrating that some strains of influenza A virus express truncated forms of the NS1 protein that function in the inhibition of cytoplasmic antiviral events.

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The NS1 protein: A master regulator of host and viral functions

Cited by 30 publications

References 110 publications

Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

Fluorescence-Activated Cell Sorting-Based Analysis Reveals an Asymmetric Induction of Interferon-Stimulated Genes in Response to Seasonal Influenza A Virus

Viral Proteins That Bind Double-Stranded RNA: Countermeasures Against Host Antiviral Responses

Role of N Terminus-Truncated NS1 Proteins of Influenza A Virus in Inhibiting IRF3 Activation

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