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* Department of Microbiology, Immunology and Molecular Genetics,
Department of Molecular and Medical Pharmacology,
Molecular Biology Institute, and
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
TANK-binding kinase-1 (TBK1) and the inducible I
B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Research Grants R01 CA87924, R01 AI056154, and R37 AI47868. A.K.M. was supported by the Howard Hughes Medical Institute Predoctoral Fellowship (Grant 59003787) and the Warsaw Dissertation Year Fellowship. A.S. was supported by a University of California Medical Scientist Training Program training grant. S.H. was supported by University of California AIDS Institute and Center for AIDS Research (AI28697) and Universitywide AIDS Research Program Dissertation Award (D06-LA-4).
2 Address correspondence and reprint requests to Dr. Genhong Cheng, University of California, Department of Microbiology, Immunology and Molecular Genetics, 615 Charles Young Drive S., 246 BSRB, Los Angeles, CA 90095. E-mail address: genhongc{at}microbio.ucla.edu
3 Abbreviations used in this paper: IRF, IFN regulatory factor; BMM, bone marrow-derived macrophage; DAI, DNA-dependent activator of IFN-regulatory factors; DC, dendritic cell; HA, hemagglutinin; IFNAR, type I IFN 
/β receptor; IKK-i, inducible IB kinase; IP-10, IFN-
-inducible protein-10; M3FL, MHV-68 virus expressing luciferase under an M3 promoter; MEF, murine embryonic fibroblast; MHV-68, murine -herpesvirus-68; MOI, multiplicity of infection; pDC, plasmacytoid DC; Q-PCR, quantitative real-time PCR; RIG-I, retinoic acid inducible gene-I; RLR, RIG-I-like receptor; TBK1, TANK-binding kinase-1; TRAF, TNFR-associated factor; TRIF, Toll/IL-1R domain-containing adaptor inducing IFN-β; WT, wild type.
4 The online version of this article contains supplemental material.
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