Miyahira Andrea K, Shahangian Arash, Hwang Seungmin, Sun Ren, Cheng Genhong
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
J Immunol. 2009 Feb 15;182(4):2248-57. doi: 10.4049/jimmunol.0802466.
TANK-binding kinase-1 (TBK1) and the inducible IkappaB kinase (IKK-i) have recently been shown to activate type I IFN responses elicited by intracellular detection of RNA or DNA from infecting viruses. Detection of viral RNA is mediated by retinoic acid inducible gene-I or melanoma differentiation-associated gene-5 pathways in which TBK1 and IKK-i have been demonstrated to play redundant roles in IFN activation. In this study, we have examined whether such redundancy occurs in the type I IFN response to DNA viral challenges by examining induction of IFNs and IFN-mediated signaling and gene programs in TBK1(-/-) macrophages. In contrast to the normal IFN responses in TBK1(-/-) macrophages infected with an RNA virus, IFN responses were severely abrogated during DNA virus infections in TBK1(-/-) macrophages. Because both TBK1 and IKK-i are expressed in macrophages, our studies suggest that TBK1 and IKK-i differ functionally in DNA virus-mediated IFN responses; however, they are redundant in RNA virus-mediated IFN responses. Confirmatively, reconstitution of TBK1(-/-)IKK-i(-/-) fibroblasts revealed that TBK1 rescued IFN responses to transfected B-DNA to a much stronger degree than IKK-i. Finally, we demonstrate the requirement for the TBK1-IFN regulatory factor-3 pathway in host defense against a DNA virus infection in vivo.
Tank结合激酶1（TBK1）和诱导性κB激酶（IKK-i）最近被证明可激活因细胞内检测感染病毒的RNA或DNA而引发的I型干扰素反应。病毒RNA的检测由视黄酸诱导基因I或黑色素瘤分化相关基因5途径介导，其中TBK1和IKK-i已被证明在干扰素激活中发挥冗余作用。在本研究中，我们通过检测TBK1（-/-）巨噬细胞中干扰素的诱导以及干扰素介导的信号传导和基因程序，研究了在对DNA病毒攻击的I型干扰素反应中是否存在这种冗余现象。与感染RNA病毒的TBK1（-/-）巨噬细胞中的正常干扰素反应相反，TBK1（-/-）巨噬细胞在DNA病毒感染期间干扰素反应严重缺失。由于TBK1和IKK-i都在巨噬细胞中表达，我们的研究表明，TBK1和IKK-i在DNA病毒介导的干扰素反应中功能不同；然而，它们在RNA病毒介导的干扰素反应中是冗余的。确切地说，对TBK1（-/-）IKK-i（-/-）成纤维细胞的重建显示，TBK1比IKK-i更能有效地挽救对转染B-DNA的干扰素反应。最后，我们证明了在体内宿主防御DNA病毒感染中TBK1-干扰素调节因子3途径的必要性。
