The NS1 protein of influenza A virus suppresses interferon-regulated activation of antigen-presentation and immune-proteasome pathways

Tisoncik, Jennifer R.; Billharz, Rosalind; Burmakina, Svetlana; Belisle, Sarah E.; Proll, Sean; Korth, Marcus J.; García‐Sastre, Adolfo; Katze, Michael G.

doi:10.1099/vir.0.84873-0

Cited by 9 publications

(10 citation statements)

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“…Viruses, such as the influenza virus and the coronavirus, elicit cellular innate immunity [48][49][50][51][52]. We have previously shown that G6PD-knockdown cells are more susceptible to viral infection [13,14].…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

Chiu

Lin

et al. 2015

Viruses

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Glucose-6-phosphate dehydrogenase (G6PD)-deficient cells are highly susceptible to viral infection. This study examined the mechanism underlying this phenomenon by measuring the expression of antiviral genes—tumor necrosis factor alpha (TNF-α) and GTPase myxovirus resistance 1 (MX1)—in G6PD-knockdown cells upon human coronavirus 229E (HCoV-229E) and enterovirus 71 (EV71) infection. Molecular analysis revealed that the promoter activities of TNF-α and MX1 were downregulated in G6PD-knockdown cells, and that the IκB degradation and DNA binding activity of NF-κB were decreased. The HSCARG protein, a nicotinamide adenine dinucleotide phosphate (NADPH) sensor and negative regulator of NF-κB, was upregulated in G6PD-knockdown cells with decreased NADPH/NADP+ ratio. Treatment of G6PD-knockdown cells with siRNA against HSCARG enhanced the DNA binding activity of NF-κB and the expression of TNF-α and MX1, but suppressed the expression of viral genes; however, the overexpression of HSCARG inhibited the antiviral response. Exogenous G6PD or IDH1 expression inhibited the expression of HSCARG, resulting in increased expression of TNF-α and MX1 and reduced viral gene expression upon virus infection. Our findings suggest that the increased susceptibility of the G6PD-knockdown cells to viral infection was due to impaired NF-κB signaling and antiviral response mediated by HSCARG.

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Section: Discussionmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

Chiu

Lin

et al. 2015

Viruses

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“…Accordingly, expression of the NS1 protein antagonizes IAV-induced NF-κB activation and subsequent IFN synthesis. Several studies show that the IFN antagonizing function of the NS1 protein depends on the IAV genotype [97,98]. For example, a virus containing the 1918 pandemic NS1 gene was more efficient at blocking the IFN response than its parental IAV [97].…”

Section: Iav Inhibiting Functions Of Nf-κbmentioning

confidence: 99%

“…The relative contribution of the alternative NF-κB signaling pathway for IAV replication is not clear, as infection with IAV strains expressing the NS1 protein only modestly activates the noncanonical NF-κB pathway [99,100]. The NS1 protein was also reported to impair the transcriptional activity of other transcription factors such as p53 [101] and immune-proteasome pathways [98]. It is conceivable that NS1 will affect more cellular signaling steps, as interactome screens have shown numerous cellular binding partners for this viral protein including members of the PI3K (phosphoinositide-3-kinase) and AKT signaling pathways [102,103].…”

Section: Iav Inhibiting Functions Of Nf-κbmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

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“…Reduced production of infectious particles, in the face of enhance viral protein production, may therefore be a consequence of either limiting host factors or disruption of viral protein/host factor stoichiometry required for assembly of viable viral particles. Of interest, the viral cytophathic effect was greatly enhanced upon IFITM3 depletion in the presence or absence of the virulence factor NS1, a viral protein known to block many of the innate immunity responses [15][16][17][18][19] (figure 2F, G). However, deletion of NS1 results in complete failure of infectious particle production even upon IFITM3 depletion ( Figure 2H).…”

Section: Resultsmentioning

confidence: 99%

Host Modulators of H1N1 Cytopathogenicity

et al. 2012

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Influenza A virus infects 5–20% of the population annually, resulting in ∼35,000 deaths and significant morbidity. Current treatments include vaccines and drugs that target viral proteins. However, both of these approaches have limitations, as vaccines require yearly development and the rapid evolution of viral proteins gives rise to drug resistance. In consequence additional intervention strategies, that target host factors required for the viral life cycle, are under investigation. Here we employed arrayed whole-genome siRNA screening strategies to identify cell-autonomous molecular components that are subverted to support H1N1 influenza A virus infection of human bronchial epithelial cells. Integration across relevant public data sets exposed druggable gene products required for epithelial cell infection or required for viral proteins to deflect host cell suicide checkpoint activation. Pharmacological inhibition of representative targets, RGGT and CHEK1, resulted in significant protection against infection of human epithelial cells by the A/WS/33 virus. In addition, chemical inhibition of RGGT partially protected against H5N1 and the 2009 H1N1 pandemic strain. The observations reported here thus contribute to an expanding body of studies directed at decoding vulnerabilities in the command and control networks specified by influenza virulence factors.

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The NS1 protein of influenza A virus suppresses interferon-regulated activation of antigen-presentation and immune-proteasome pathways

Cited by 9 publications

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Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

Glucose-6-Phosphate Dehydrogenase Enhances Antiviral Response through Downregulation of NADPH Sensor HSCARG and Upregulation of NF-κB Signaling

The intricate interplay between RNA viruses and NF-κB

Host Modulators of H1N1 Cytopathogenicity

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