Xia Zhangchuan, Xu Gang, Yang Xiaodan, Peng Nanfang, Zuo Qi, Zhu Shengli, Hao Hua, Liu Shi, Zhu Ying
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China
J Immunol. 2017 May 1;198(9):3690-3704. doi: 10.4049/jimmunol.1601588. Epub 2017 Mar 29.
The innate immune response is critical for host defense and must be tightly controlled, but the molecular mechanisms responsible for its negative regulation are not yet completely understood. In this study, we report that transporter 1, ATP-binding cassette, subfamily B (TAP1), a virus-inducible endoplasmic reticulum-associated protein, negatively regulated the virus-triggered immune response. In this study, we observed upregulated expression of TAP1 following virus infection in human lung epithelial cells (A549), THP-1 monocytes, HeLa cells, and Vero cells. The overexpression of TAP1 enhanced virus replication by inhibiting the virus-triggered activation of NF-κB signaling and the production of IFNs, IFN-stimulated genes, and proinflammatory cytokines. TAP1 depletion had the opposite effect. In response to virus infection, TAP1 interacted with the TGF-β-activated kinase (TAK)1 complex and impaired the phosphorylation of TAK1, subsequently suppressing the phosphorylation of the IκB kinase complex and NF-κB inhibitor α (IκBα) as well as NF-κB nuclear translocation. Our findings collectively suggest that TAP1 plays a novel role in the negative regulation of virus-triggered NF-κB signaling and the innate immune response by targeting the TAK1 complex.
天然免疫反应对于宿主防御至关重要，必须受到严格控制，但其负调控的分子机制尚未完全明确。在本研究中，我们报告称，转运体1，ATP结合盒，B亚家族（TAP1），一种病毒诱导的内质网相关蛋白，对病毒触发的免疫反应起负调控作用。在本研究中，我们观察到在人肺上皮细胞（A549）、THP-1单核细胞、HeLa细胞和Vero细胞中，病毒感染后TAP1的表达上调。TAP1的过表达通过抑制病毒触发的NF-κB信号激活以及IFN、IFN刺激基因和促炎细胞因子的产生来增强病毒复制。TAP1的缺失则产生相反的效果。响应病毒感染时，TAP1与转化生长因子-β激活激酶（TAK）1复合物相互作用，损害TAK1的磷酸化，随后抑制IκB激酶复合物和NF-κB抑制剂α（IκBα）的磷酸化以及NF-κB的核转位。我们的研究结果共同表明，TAP1通过靶向TAK1复合物在病毒触发的NF-κB信号和天然免疫反应的负调控中发挥新作用。
