Abstract
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-κB pathways leading to activation of type I IFNs (IFNα, IFNβ) and other cytokines. In this study, induction of NF-κB 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-κB activation as well as IFNβ induction by immunostimulatory DNA. DAI also interacts with RIP3 and this interaction potentiates DAI-mediated activation of NF-κB, implicating RIP3 in regulating this RHIM-dependent pathway. The role of DAI in activation of NF-κB 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.
Original language | English (US) |
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Pages (from-to) | 6427-6434 |
Number of pages | 8 |
Journal | Journal of Immunology |
Volume | 181 |
Issue number | 9 |
DOIs | |
State | Published - Nov 1 2008 |
Externally published | Yes |
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology