Virus infection induces an innate antiviral host response mediated by the cytoplasmic pattern recognition receptors RIG-I and MDA-5 that sense viral RNAs. RIG-I/MDA5 trigger downstream signaling events involving the mitochondrial adaptor molecule MAVS, the kinases TBK1/IKKi and the transcription factors IRF3 and IRF7. IRF3 and IRF7 directly activate the transcription of the type I interferon-(IFN) a and genes tha play critical antiviral roles. This pathway is tightly regulated by key inhibitory proteins that orchestrate the downregulation of antiviral signaling upon viral clearance to ensure homeostasis and prevent tissue damage and uncontrolled inflammation. Dysregulation of the balance between activation and inhibition of the RIG-I/MDA-5 pathway may result in the uncontrolled production of type I IFN that may lead to autoimmune disease. TAX1BP1 was first identified as an anti-apoptotic protein that interacts with the A20 zinc finger protein. TAX1BP1 has since been characterized as an adaptor molecule for A20, and together these two proteins inhibit the stimulus-induced activation of the NF-?B transcription factor in inflammatory signaling pathways. We have demonstrated that TAX1BP1 and A20 also cooperate to inhibit the RIG-I/MDA-5 pathway and restrict the activation of type I IFN triggered by virus infection. However, whether the anti-apoptotic function of TAX1BP1 plays a role in the host response to virus infection is unknown. It is also unclear what the precise roles of TAX1BP1 are in vivo during the course of a respiratory virus infection such as influenza and the specific cell types where TAX1BP1 attenuates viral-induced production of proinflammatory cytokines and type I IFN. In preliminary studies we provide evidence that TAX1BP1 serves as a novel substrate of the IKKi kinase during virus infection. The phosphorylation of TAX1BP1 by IKKi triggers its proteasomal degradation and apoptotic death of virus-infected cells. Consequently, TAX1BP1-deficient cells are highly sensitive to virus-induced cell death and cytopathic effects, suggesting that the anti-apoptotic function of TAX1BP1 is unmasked by its degradation and further supporting the notion that TAX1BP1 couples antiviral signaling to cell death pathways. The central hypothesis driving the proposed investigations is that TAX1BP1 is a key regulator of innate antiviral signaling and cell survival in the context of virus infection. We will test this hypothesis experimentally with te following specific aims: (1) determine the mechanisms of IKKi-induced TAX1BP1 phosphorylation and degradation and; (2) elucidate the role of cell-type specific TAX1BP1 in regulating influenza virus infection. Completion of the proposed studies will provide important insight into the host mechanisms that are essential to restrict virus replication and may pave the way for the identification of novel antiviral drugs or vaccines for influenza infection.

Public Health Relevance

The respiratory virus influenza A is responsible for seasonal epidemics and recurring pandemics that represent a major threat to public health and the global economy. The host innate immune response provides the first line of defense against virus infection and also marshals the adaptive immune response to eliminate virus- infected cells. The goals of this proposal are to elucidate the mechanisms of TAX1BP1 regulation of virus-induced type I interferon production and cell death that serve to restrict virus replication, and Cell-type specific roles of TAX1BP1 in regulating influenza virus replication will be uncovered using conditional TAX1BP1- deficient mice.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Immunity and Host Defense Study Section (IHD)
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Palker, Thomas J
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Mao, Renfang; Yang, Riyun; Chen, Xia et al. (2017) Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses. Cell Mol Immunol 14:412-422
Choi, Young Bong; Shembade, Noula; Parvatiyar, Kislay et al. (2017) TAX1BP1 Restrains Virus-Induced Apoptosis by Facilitating Itch-Mediated Degradation of the Mitochondrial Adaptor MAVS. Mol Cell Biol 37: