TANK-binding kinase-1 plays an important role during in vitro and in vivo type I IFN responses to DNA virus infections.
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.
Miyahira
Andrea K
AK
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Shahangian
Arash
A
Hwang
Seungmin
S
Sun
Ren
R
Cheng
Genhong
G
D000818:Animals; D004266:DNA Virus Infections / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000276:immunology*; D012327:RNA Virus Infections / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase