Receptor-interacting protein homotypic interaction motif-dependent control of NF-κB activation via the DNA-dependent activator of IFN regulatory factors

William J. Kaiser, Jason W. Upton, Edward S. Mocarski

Research output: Contribution to journalArticle

140 Scopus citations

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 languageEnglish (US)
Pages (from-to)6427-6434
Number of pages8
JournalJournal of Immunology
Volume181
Issue number9
DOIs
StatePublished - Nov 1 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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