Department of Microbiology and Immunology, Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida 33136, USA.
J Biol Chem. 2011 Oct 21;286(42):36592-602. doi: 10.1074/jbc.M111.283762. Epub 2011 Sep 1.
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.
病毒感染后，先天免疫反应提供第一道保护，并迅速诱导 I 型干扰素 (IFNα/β)，从而发挥强大的抗病毒作用。为了维持体内平衡并防止自身免疫，IFN 的产生受到严格调控；然而，其负调控机制仍知之甚少。在此，我们证明 A20 结合 NF-κB 抑制剂 1（ABIN1）是抗病毒信号的新型负调控因子。ABIN1 的过表达抑制了病毒感染或 poly(I:C)转染后 IFN-β 启动子的激活，而 siRNA 介导的 ABIN1 敲低则增强了病毒感染后的 IFN-β 产生。ABIN1 与 A20 调节分子 TAX1BP1 相互作用，是 poly(I:C)转染后招募 TAX1BP1 和 A20 到非经典 IκB 激酶 TBK1 和 IKKi 所必需的。ABIN1 和 TAX1BP1 共同破坏了 E3 泛素连接酶 TRAF3 与 TBK1/IKKi 的相互作用，从而减弱了 TBK1/IKKi 的赖氨酸 63 连接多泛素化。最后，ABIN1 的完整泛素结合结构域对于 ABIN1 与 TBK1/IKKi 相互作用以及抑制 poly(I:C)转染或病毒感染后的 IFN-β 产生是必需的。总之，这些结果表明 ABIN1 需要其泛素结合结构域，并与 TAX1BP1 和 A20 合作来限制抗病毒信号。
