The Journal of Experimental Medicine
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Published 21 June 2004. doi:10.1084/jem.20040528
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1651-1658
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Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection

Andrea K. Perry1, Edward K. Chow2, Julia B. Goodnough1, Wen-Chen Yeh4,5,6, and Genhong Cheng1,2,3

1 Department of Microbiology, Immunology, and Molecular Genetics, 2 Molecular Biology Institute, and 3 Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095
4 Advanced Medical Discovery Institute, 5 University Health Network, and 6 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada

Address correspondence to Genhong Cheng, Dept. of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, 8-240 Factor Bldg., 10833 Le Conte Ave., Los Angeles, CA 90095. Phone: (310) 825-8896; Fax: (310) 206-5553; email: genhongc{at}microbio.ucla.edu

TANK-binding kinase-1 (TBK1) and the inducible I{kappa}B kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1–/– macrophages, but defective in TBK1–/– embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1–/– embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor–mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.

Key Words: LPS • innate immunity • interferon regulatory factor-3 • viral infections • NF-{kappa}B

Abbreviations used in this paper: BMM, BM-derived macrophage; IFNAR, type I IFN {alpha}/ß receptor; IKK-i, inducible I{kappa}B kinase; IRF3, IFN regulatory factor-3; JAK, Janus kinase; KA, kinase-inactive; MEF, immortalized murine embryonic fibroblast; Q-PCR, quantitative RT-PCR; SeV, Sendai virus; STAT, signal transducer and activator of transcription; TBK1, TANK-binding kinase-1; TLR, Toll-like receptor; TRAM, TRIF-related adaptor molecule; TRIF, Toll/IL-1 receptor domain–containing adaptor-inducing IFN-ß.


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