Influenza Virus NS1 Protein Counteracts PKR-Mediated Inhibition of Replication

Bergmann, Michael; García‐Sastre, Adolfo; Carnero, Elena; Pehamberger, Hubert; Wolff, Klaus; Palese, Peter; Muster, Thomas

doi:10.1128/jvi.74.13.6203-6206.2000

Cited by 328 publications

(241 citation statements)

References 36 publications

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“…The influenza virus-encoded NS1 has been shown to inhibit the host-cell antiviral responses [1,15,[23][24][25][26][27][28]. To elucidate the mechanism by which influenza A virus infection inhibits IFN-c-induced tyrosine phosphorylation of Stat1, we next analyzed the effect of NS1 protein on the Stat1 phosphorylation.…”

Section: Ns1 Does Not Inhibit Ifn-c-induced Tyrosine Phosphorylation mentioning

confidence: 99%

“…The influenza A NS1 protein, which is known to be an IFN antagonist [1,15,[23][24][25][26][27][28], did not affect IFN-c-induced tyrosine phosphorylation of Stat1. However, surprisingly, there was a dramatic decrease of Jak1 and IFNGR1 proteins in influenza A virus-infected cells, indicating that this is the cause of a disruption of the IFN-c signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

“…The influenza-virus-encoded nonstructural protein 1 (NS1), which binds dsRNA and forms dimers in vivo, has been shown to inhibit the host cell antiviral response by multiple mechanisms. These mechanisms include the inhibition of the IFN-inducible dsRNA activated-protein kinase (PKR) [24,25] and the blocking of IFN-b production by preventing nuclear factor (NF)-jB [26], IRF3 [27], and IRF7 activation [28]. Influenza virus infection induces the local production of IFN-c by T cells and NK cells in the respiratory tract [29].…”

mentioning

confidence: 99%

“…Two distinct types of antigenic variation that occur in influenza A viruses allow them to evade preexisting immunity [2,3]. The NS1 protein of influenza A virus counteracts PKR-mediated phosphorylation to prevent the establishment of an antiviral state [24,25]. The NS1 protein inhibits activation of NF-jB and induction of .…”

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confidence: 99%

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Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-c is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-c as evidenced by studies using anti-IFN-c Ab and IFN-c -/-mice. Thus, we hypothesized that IFN-c is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-c. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-c to detect IFN-c-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-c-induced up-regulation of HLA-DRa mRNA and the IFN-c induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1a upon IFN-c stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1a. Thus, influenza A virus subverts antiviral host defense mediated by IFN-c through effects on the intracellular signaling pathways. IntroductionInfluenza A viruses are negative-strand RNA viruses that have a segmented genome with a coding capacity for 11 polypeptides. The virus genome is composed of eight different RNA segments, which are tightly associated with the viral nucleoprotein and polymerases in ribonucleoprotein complexes [1]. Influenza A viruses, causing acute infections, continuously escape from recognition by virus neutralizing Ab as a result of accumulation of mutations in their surface glycoproteins hemagglutinin and neuraminidase (antigenic drift) or by introduction of new subtypes of these glycoproteins (antigenic shift) [2,3]. Recent outbreaks of highly pathogenic avian influenza A virus infections in poultry and in humans have raised concerns that a new influenza pandemic will occur in the near future [4]. Thus, prediction of the severity of continuously emerging human influenza virus strains remains a high public health priority, but it is limited by our incomplete understanding of the molecular determinants of pathogenicity in this disease. Although factors dictating the severity of virus disease are complex, interaction between inherent viral properties and host cellular response ultimately determines disease outcome. The first site of viral contact with the host and main target of infection and inflammation is the airway mucosal epithelium. Epithelial cells at the airway mucosal surface have a variety of inflammatory and immune defense mechanisms to deal with virus, including Eur. J. Immunol. 2008. 38: 1559-1573 Immunity to infection expression of cytokines with chemoattractant and proinflammatory functions [5], intercellular adhesion molecule-1 (ICAM-1) [6], IFN regulatory factor 1 (IRF-1) [7], nitric oxide synthase 2 (NOS2) [8], and MHC ...

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Section: Ns1 Does Not Inhibit Ifn-c-induced Tyrosine Phosphorylation mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

et al. 2008

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“…Out of the 10 to 11 viral proteins encoded by influenza A virus, one of the most functionally diverse is the nonstructural viral protein NS1, which has been associated with numerous roles during influenza infection, including the modulation of viral RNA (vRNA) replication (3)(4)(5)(6), general inhibition of the nuclear export of mRNAs carrying polyadenylated tails (7,8), inhibition of the transcriptional elongation of host genes (9), regulation of host and viral protein synthesis (recently reviewed by Yanguez and Nieto [10]), and the neutralization of the activity of some of the interferon (IFN)-induced antiviral proteins, such as 2=,5=-oligoadenylate synthetase (OAS)/RNase L (11) and the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) (12)(13)(14)(15)(16)(17)(18). However, the main function attributed to NS1 is the neutralization of the initial signaling pathway leading to the production of type I IFN (reviewed by Krug et al and Hale et al [19,20]).…”

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SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Santos

Pal

Chacon

et al. 2013

J Virol

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Our pioneering studies on the interplay between the small ubiquitin-like modifier (SUMO) and influenza A virus identified the nonstructural protein NS1 as the first known SUMO target of influenza virus and one of the most abundantly SUMOylated influenza virus proteins. Here, we further characterize the role of SUMOylation for the A/Puerto Rico/8/1934 (PR8) NS1 protein, demonstrating that NS1 is SUMOylated not only by SUMO1 but also by SUMO2/3 and mapping the main SUMOylation sites in NS1 to residues K219 and K70. Furthermore, by using SUMOylatable and non-SUMOylatable forms of NS1 and an NS1-specific artificial SUMO ligase (ASL) that increases NS1 SUMOylation ϳ4-fold, we demonstrate that SUMOylation does not affect the stability or cellular localization of PR8 NS1. However, NS1's ability to be SUMOylated appears to affect virus multiplication, as indicated by the delayed growth of a virus expressing the non-SUMOylatable form of NS1 in the interferon (IFN)-competent MDCK cell line. Remarkably, while a non-SUMOylatable form of NS1 exhibited a substantially diminished ability to neutralize IFN production, increasing NS1 SUMOylation beyond its normal levels also exerted a negative effect on its IFN-blocking function. This observation indicates the existence of an optimal level of NS1 SUMOylation that allows NS1 to achieve maximal activity and suggests that the limited amount of SUMOylation normally observed for most SUMO targets may correspond to an optimal level that maximizes the contribution of SUMOylation to protein function. Finally, protein cross-linking data suggest that SUMOylation may affect NS1 function by regulating the abundance of NS1 dimers and trimers in the cell.

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NF90 is a novel influenza A virus NS1‐interacting protein that antagonizes the inhibitory role of NS1 on PKR phosphorylation

Zhu

et al. 2016

FEBS Letters

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NF90 is a novel host antiviral factor that regulates PKR activation and stress granule formation in influenza A virus (IAV)-infected cells, but the precise mechanisms by which it operates remain unclear. We identified NF90 as a novel interacting protein of IAV nonstructural protein 1 (NS1). The interaction was dependent on the RNA-binding properties of NS1. NS1 associated with NF90 and PKR simultaneously; however, the interaction between NF90 and PKR was restricted by NS1. Knockdown of NF90 promoted inhibition of PKR phosphorylation induced by NS1, while coexpression of NF90 impeded reduction of PKR phosphorylation and stress granule formation triggered by NS1. In summary, NF90 exerts its antiviral activity by antagonizing the inhibitory role of NS1 on PKR phosphorylation.

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Influenza Virus NS1 Protein Counteracts PKR-Mediated Inhibition of Replication

Cited by 328 publications

References 36 publications

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

NF90 is a novel influenza A virus NS1‐interacting protein that antagonizes the inhibitory role of NS1 on PKR phosphorylation

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