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The Journal of Immunology, 2008, 181, 6427 -6434
Copyright © 2008 by The American Association of Immunologists, Inc.
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Receptor-Interacting Protein Homotypic Interaction Motif-Dependent Control of NF-{kappa}B Activation via the DNA-Dependent Activator of IFN Regulatory Factors1

William J. Kaiser, Jason W. Upton and Edward S. Mocarski2

Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322

DNA-dependent activator of IFN regulatory factors (IRF; DAI, also known as ZBP1 or DLM-1) is a cytosolic DNA sensor that initiates IRF3 and NF-{kappa}B pathways leading to activation of type I IFNs (IFN{alpha}, IFNβ) and other cytokines. In this study, induction of NF-{kappa}B is shown to depend on the adaptor receptor-interacting protein kinase (RIP)1, acting via a RIP homotypic interaction motif (RHIM)-dependent interaction with DAI. DAI binds to and colocalizes with endogenous RIP1 at characteristic cytoplasmic granules. Suppression of RIP1 expression by RNAi abrogates NF-{kappa}B activation as well as IFNβ induction by immunostimulatory DNA. DAI also interacts with RIP3 and this interaction potentiates DAI-mediated activation of NF-{kappa}B, implicating RIP3 in regulating this RHIM-dependent pathway. The role of DAI in activation of NF-{kappa}B in response to immunostimulatory DNA appears to be analogous to sensing of dsRNA by TLR3 in that both pathways involve RHIM-dependent signaling that is mediated via RIP1, reinforcing a central role for this adaptor in innate sensing of intracellular microbes.

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 by Public Health Service Grant R01 AI20211 (to E.S.M.) and T32 HL069769 (to J.W.U.) as well as a grant from the Georgia Cancer Coalition.

2 Address correspondence and reprint requests to Dr. Edward S. Mocarski, Department of Microbiology and Immunology, Emory Vaccine Center, 1462 Clifton Road NE, Emory University School of Medicine, Atlanta, GA 30322. E-mail address: mocarski{at}emory.edu

3 Abbreviations used in this paper: IRF, IFN regulatory factor; TANK, TNFR-associated factor family member-associated NF-{kappa}B activator; TBK, TANK-binding kinase; IKK, I{kappa}B kinase; TRIF, TIR domain-containing adaptor-inducing IFNβ; RLH, retinoic acid-inducible gene I-like helicase; DD, death domain; RHIM, RIP homotypic interaction motif; RIP, receptor-interacting protein kinase; MCMV, murine CMV; RLR, RHIM-like repeat; shRNA, short hairpin RNA; I{kappa}B{alpha}-SR, I{kappa}B{alpha}-super repressor; KD, kinase dead; EV, empty vector; IB, immunoblot.






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