Abstract
Upon virus infection, the innate immune response provides the first line of protection and rapidly induces type I interferons (IFNα/β), which mediate potent antiviral effects. To maintain homeostasis and prevent autoimmunity, IFN production is tightly regulated; however, the mechanisms of negative regulation are poorly understood. Herein, we demonstrate that the A20 binding inhibitor of NF-κB 1 (ABIN1) is a novel negative regulator of antiviral signaling. Overexpression of ABIN1 inhibited IFN-β promoter activation in response to virus infection or poly(I:C) transfection, whereas siRNA-mediated knockdown of ABIN1 enhanced IFN-β production upon virus infection. ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IκB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. Finally, an intact ubiquitin binding domain of ABIN1 was essential for ABIN1 to interact with TBK1/IKKi and inhibit IFN-β production upon poly(I:C) transfection or virus infection. Together, these results suggest that ABIN1 requires its ubiquitin binding domain and cooperates with TAX1BP1 and A20 to restrict antiviral signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Humans
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Interferon Inducers / pharmacology
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Interferon-beta / biosynthesis
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Interferon-beta / genetics
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Knockout
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Poly I-C / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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Signal Transduction*
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TNF Receptor-Associated Factor 3 / genetics
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TNF Receptor-Associated Factor 3 / metabolism
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Tumor Necrosis Factor alpha-Induced Protein 3
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Virus Diseases / genetics
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Virus Diseases / metabolism*
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Viruses / genetics
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Viruses / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Interferon Inducers
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Intracellular Signaling Peptides and Proteins
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Neoplasm Proteins
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Nuclear Proteins
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TAX1BP1 protein, human
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TAX1BP1 protein, mouse
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TNF Receptor-Associated Factor 3
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TNIP1 protein, human
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Tnip2 protein, mouse
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Ubiquitin
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Interferon-beta
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Tbk1 protein, mouse
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Protein Serine-Threonine Kinases
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TBK1 protein, human
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse
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Poly I-C