Receptor-Interacting Protein Homotypic Interaction Motif-Dependent Control of NF-κB Activation via the DNA-Dependent Activator of IFN Regulatory Factors

DNA-dependent activator of IFN regulatory factors (IRF; DAI, also known as ZBP1 or DLM-1) is a cytosolie DNA sensor that initiates IRF3 and NF-kappa B pathways leading to activation of type I IFNs (IFN alpha, IFN beta) and other cytokines. In this study, induction of NF-kappa B is shown to depend on the adaptor receptor-interacting protein kinase (RIP)I, 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 IFN beta 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 Journal of Immunology, 2008, 181: 6427-6434.