Journal
JOURNAL OF IMMUNOLOGY
Volume 182, Issue 4, Pages 2248-2257Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0802466
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Funding
- National Institutes of Health Research [R01 CA87924, R01 A1056154, \R37 A147868]
- Howard Hughes Medical Institute Predoctoral Fellowship [59003787]
- Warsaw Dissertation Year Fellowship
- University of California Medical Scientist Training Program
- University of California AIDS Institute
- Center for AIDS Research [A128697]
- Universitywide AIDS Research Program Dissertation Award
- [D06-LA-4]
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TANK-binding kinase-1 (TBK1) and the inducible I kappa 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 TBKI-/- 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 TBKI-/-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 Journal of Immunology, 2009,182: 2248-2257.
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