期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 42, 页码 36592-36602出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.283762
关键词
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资金
- National Institutes of Health [PO1CA128115, RO1GM083143]
- United Kingdom Medical Research Council
- Association for International Cancer Research [AICR 03-297]
- MRC [MC_U117584209] Funding Source: UKRI
- Medical Research Council [U117532003, MC_U117584209] Funding Source: researchfish
Upon virus infection, the innate immune response provides the first line of protection and rapidly induces type I interferons (IFN alpha/beta), 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-kappa B 1 (ABIN1) is a novel negative regulator of antiviral signaling. Overexpression of ABIN1 inhibited IFN-beta promoter activation in response to virus infection or poly(I:C) transfection, whereas siRNA-mediated knockdown of ABIN1 enhanced IFN-beta 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 I kappa B 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-beta 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.
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