IRF3 and IRF7 Phosphorylation in Virus-infected Cells Does Not Require Double-stranded RNA-dependent Protein Kinase R or IκB Kinase but Is Blocked by Vaccinia Virus E3L Protein

Smith, Eric; Marié, Isabelle; Prakash, Arun; Garcı́a-Sastre, Adolfo; Levy, David E.

doi:10.1074/jbc.m008717200

Cited by 220 publications

(180 citation statements)

References 68 publications

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“…These studies have led to the characterization of new inducers of IRF-3 activity as well as the intracellular signaling pathways leading to IRF-3 activation (38,42,43,55,56). Notably, two IKK homologs, IKKi and TBK1, were shown to be involved in IRF-3 phosphorylation and activation (12)(13)(14)(15)(16)57).…”

Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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Activation of the innate arm of the immune system following pathogen infection relies on the recruitment of latent transcription factors involved in the induction of a subset of genes responsible for viral clearance. One of these transcription factors, IFN regulatory factor 3 (IRF-3), is targeted for proteosomal degradation following virus infection. However, the molecular mechanisms involved in this process are still unknown. In this study, we show that polyubiquitination of IRF-3 increases in response to Sendai virus infection. Using an E1 temperature-sensitive cell line, we demonstrate that polyubiquitination is required for the observed degradation of IRF-3. Inactivation of NEDD8-activating E1 enzyme also results in stabilization of IRF-3 suggesting the NEDDylation also plays a role in IRF-3 degradation following Sendai virus infection. In agreement with this observation, IRF-3 is recruited to Cullin1 following virus infection and overexpression of a dominant-negative mutant of Cullin1 significantly inhibits the degradation of IRF-3 observed in infected cells. We also asked whether the C-terminal cluster of phosphoacceptor sites of IRF-3 could serve as a destabilization signal and we therefore measured the half-life of C-terminal phosphomimetic IRF-3 mutants. Interestingly, we found them to be short-lived in contrast to wild-type IRF-3. In addition, no degradation of IRF-3 was observed in TBK1−/− mouse embryonic fibroblasts. All together, these data demonstrate that virus infection stimulates a host cell signaling pathway that modulates the expression level of IRF-3 through its C-terminal phosphorylation by the IκB kinase-related kinases followed by its polyubiquitination, which is mediated in part by a Cullin-based ubiquitin ligase.

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Section: Discussionmentioning

confidence: 99%

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Bibeau-Poirier¹,

Gravel²,

Clément³

et al. 2006

The Journal of Immunology

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“…The NS1 protein inhibits activation of NF-jB and induction of . Activation of IRF3 and IRF7 is inhibited by influenza A virus NS1 protein [27,28]. Here we present the first report that influenza A virus encodes an immunomodulatory function, which directly interferes with IFN-c-stimulated signal transduction via the Jak/ Stat pathway and enables the virus to inhibit IFN-c-inducible gene expression.…”

mentioning

confidence: 90%

“…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-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].…”

Section: Introductionmentioning

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%

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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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Requirement of type I interferon signaling for arthritis triggered by double‐stranded RNA

Magnusson

Zare

Tarkowski

2005

Arthritis & Rheumatism

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Objective. Arthralgias and overt arthritides are often associated with viral infections. Viral infections expose the infected host to proinflammatory doublestranded RNA (dsRNA), which can cause joint inflammation and is a potent activator of interferon-␣ (IFN␣). The aim of this study was to determine the role of IFN␣ and dsRNA-related signaling molecules in the onset of joint inflammation induced by viral dsRNA.Methods. IFN␣ and different forms of RNA were injected into the knee joints of wild-type mice, mice lacking the type I interferon receptor (IFNAR ؊/؊ ), and mice deficient in dsRNA-dependent protein kinase (PKR ؊/؊ ). Histologic evidence of joint damage and the ability of splenocytes to produce cytokines in response to dsRNA or IFN␣ were assessed.Results. Viral dsRNA, but not short singlestranded RNA, induced arthritis.

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IRF3 and IRF7 Phosphorylation in Virus-infected Cells Does Not Require Double-stranded RNA-dependent Protein Kinase R or IκB Kinase but Is Blocked by Vaccinia Virus E3L Protein

Cited by 220 publications

References 68 publications

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

Involvement of the IκB Kinase (IKK)-Related Kinases Tank-Binding Kinase 1/IKKi and Cullin-Based Ubiquitin Ligases in IFN Regulatory Factor-3 Degradation

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

Requirement of type I interferon signaling for arthritis triggered by double‐stranded RNA

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