The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3

Qian, Wei; Wei, Xiaojian; Guo, Kelei; Li, Yongtao; Lin, Xian; Zou, Zhong; Jin, Meilin

doi:10.3389/fimmu.2017.00779

Cited by 30 publications

(24 citation statements)

References 56 publications

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“…This type of regulation is reported in RIG-I ubiquitination by an E3 ligase, TRIM25 that is targeted by NS1 to suppress IFN production (53). The NS1 C-terminal aa 126 to 225 of avian H5N1 was recently reported to downregulate RIG-I-mediated IFN signaling through interacting with TRAF3 and inhibiting the K63linked ubiquitination of TRAF3 (54). This shows that the inhibitory functions of the NS1 C terminus on the host immunity is not limited to the suppression of the NLRP3 inflammasome.…”

Section: Discussionmentioning

confidence: 95%

NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

Park

Liu

Raman

et al. 2018

J Virol

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The inflammasome represents a molecular platform for innate immune regulation and controls proinflammatory cytokine production. The NLRP3 inflammasome is comprised of NLRP3, ASC, and procaspase-1. When the NLRP3 inflammasome is activated, it causes ASC speck formation and caspase-1 activation, resulting in the maturation of interleukin-1β (IL-1β). The NLRP3 inflammasome is regulated at multiple levels, with one level being posttranslational modification. Interestingly, ubiquitination of ASC has been reported to be indispensable for the activation of the NLRP3 inflammasome. Influenza A virus (IAV) infection induces NLRP3 inflammasome-dependent IL-1β secretion, which contributes to the host antiviral defense. However, IAVs have evolved multiple antagonizing mechanisms, one of which is executed by viral NS1 protein to suppress the NLRP3 inflammasome. In this study, we compared IL-1β production in porcine alveolar macrophages in response to IAV infection and found that the 2009 pandemic H1N1 induced less IL-1β than swine influenza viruses (SIVs). Further study revealed that the NS1 C terminus of pandemic H1N1 but not that of SIV was able to significantly inhibit NLRP3 inflammasome-mediated IL-1β production. This inhibitory function was attributed to impaired ASC speck formation and suppression of ASC ubiquitination. Moreover, we identified two target lysine residues, K110 and K140, which are essential for both porcine ASC ubiquitination and NLRP3 inflammasome-mediated IL-1β production. These results revealed a novel mechanism by which the NS1 protein of the 2009 pandemic H1N1 suppresses NLRP3 inflammasome activation. Influenza A virus (IAV) infection activates the NLRP3 inflammasome, resulting in the production of IL-1β, which contributes to the host innate immune response. ASC, an adaptor protein of NLRP3, forms specks that are critical for inflammasome activation. Here, we report that the NS1 C terminus of the 2009 pandemic H1N1 has functions to suppress porcine IL-1β production by inhibiting ASC speck formation and ASC ubiquitination. Furthermore, the ubiquitination sites on porcine ASC were identified. The information gained here may contribute to an in-depth understanding of porcine inflammasome activation and regulation in response to different IAVs, helping to further enhance our knowledge of innate immune responses to influenza virus infection in pigs.

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Section: Discussionmentioning

confidence: 95%

NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

Park

Liu

Raman

et al. 2018

J Virol

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“…Recently, NS1 was also found to bind cellular dsDNA and prevent the loading of transcriptional machinery onto the DNA, thus attenuating expression of antiviral genes [ 82 ]. Meanwhile, the C-terminal domain of NS1 blocked IFN-beta production by targeting TNF receptor-associated factor 3 (TRAF-3) [ 83 ], while other domains of the protein inhibited interferon regulatory transcription factor 3 (IRF3) [ 84 ] and RNA-dependent protein kinase (PKR) activation [ 85 ]. Another IAV protein, neuraminidase (NA), was shown to remove sialic acid residues from NKp46, resulting in reduced recognition of HA and enhancing immune evasion of NK cells [ 86 ].…”

Section: Immune Evasion By Respiratory Virusesmentioning

confidence: 99%

Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host

Zheng

Perlman

2018

Current Opinion in Virology

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Respiratory viruses, especially influenza A viruses and coronaviruses such as MERS-CoV, represent continuing global threats to human health. Despite significant advances, much needs to be learned. Recent studies in virology and immunology have improved our understanding of the role of the immune system in protection and in the pathogenesis of these infections and of co-evolution of viruses and their hosts. These findings, together with sophisticated molecular structure analyses, omics tools and computer-based models, have helped delineate the interaction between respiratory viruses and the host immune system, which will facilitate the development of novel treatment strategies and vaccines with enhanced efficacy.

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“…NS1 is a major inhibitor of host innate immune response. For example, it suppresses the production and signaling of type I interferons (IFNs) ( 24 ). In addition, NS1 can trigger the apoptosis of human airway epithelial cells via a caspase-dependent mechanism during the IAV infection ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

Host Immune Response to Influenza A Virus Infection

et al. 2018

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Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.

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The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-β Production by Targeting TNF Receptor-Associated Factor 3

Cited by 30 publications

References 56 publications

NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

NS1 Protein of 2009 Pandemic Influenza A Virus Inhibits Porcine NLRP3 Inflammasome-Mediated Interleukin-1 Beta Production by Suppressing ASC Ubiquitination

Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host

Host Immune Response to Influenza A Virus Infection

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