Han Ke-Jun, Su Xiaoqin, Xu Liang-Guo, Bin Liang-Hua, Zhang Jun, Shu Hong-Bing
Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
J Biol Chem. 2004 Apr 9;279(15):15652-61. doi: 10.1074/jbc.M311629200. Epub 2004 Jan 22.
Toll-like receptor-3 is critically involved in host defense against viruses through induction of type I interferons (IFNs). Recent studies suggest that a Toll/interleukin-1 receptor domain-containing adapter protein (TRIF) and two protein kinases (TANK-binding kinase-1 (TBK1) and IkappaB kinase (IKK)-epsilon) are critically involved in Toll-like receptor-3-mediated IFN-beta production through activation of IFN regulatory factor (IRF)-3 and IRF-7. In this study, we demonstrate that TRIF interacts with both IRF-7 and IRF-3. In addition to TBK1 and IKKepsilon, our results indicate that IKKbeta can also phosphorylate IRF-3 and activate the IFN-stimulated response element. TRIF-induced IRF-3 and IRF-7 activation was mediated by TBK1 and its downstream kinases IKKbeta and IKKepsilon. TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. In addition, TRIF also induced apoptosis through a RIP/FADD/caspase-8-dependent and mitochondrion-independent pathway. Furthermore, our results suggest that the TRIF-induced IFN-stimulated response element and NF-kappaB activation and apoptosis pathways are uncoupled and provide a molecular explanation for the divergent effects induced by the adapter protein TRIF.
Toll样受体3通过诱导I型干扰素（IFN）在宿主抗病毒防御中起关键作用。最近的研究表明，一种含Toll/白细胞介素-1受体结构域的衔接蛋白（TRIF）和两种蛋白激酶（TANK结合激酶-1（TBK1）和IκB激酶（IKK）-ε）通过激活IFN调节因子（IRF）-3和IRF-7在Toll样受体3介导的IFN-β产生中起关键作用。在本研究中，我们证明TRIF与IRF-7和IRF-3都相互作用。除了TBK1和IKKε，我们的结果表明IKKβ也可以磷酸化IRF-3并激活IFN刺激反应元件。TRIF诱导的IRF-3和IRF-7激活由TBK1及其下游激酶IKKβ和IKKε介导。TRIF通过IKKβ和肿瘤坏死因子受体相关因子-6依赖性（但不是TBK1和IKKε依赖性）途径诱导NF-κB激活。此外，TRIF还通过RIP/FADD/半胱天冬酶-8依赖性和不依赖线粒体的途径诱导细胞凋亡。此外，我们的结果表明，TRIF诱导的IFN刺激反应元件、NF-κB激活和细胞凋亡途径是不相关的，并为衔接蛋白TRIF诱导的不同效应提供了分子解释。
