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

J Immunol. 2008 Nov 1;181(9):6427-34. doi: 10.4049/jimmunol.181.9.6427.

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-kappaB pathways leading to activation of type I IFNs (IFNalpha, IFNbeta) and other cytokines. In this study, induction of NF-kappaB 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-kappaB activation as well as IFNbeta induction by immunostimulatory DNA. DAI also interacts with RIP3 and this interaction potentiates DAI-mediated activation of NF-kappaB, implicating RIP3 in regulating this RHIM-dependent pathway. The role of DAI in activation of NF-kappaB 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / genetics
  • Adjuvants, Immunologic / physiology
  • Amino Acid Motifs / immunology
  • Cell Line
  • Cell Line, Tumor
  • Cytoplasmic Granules / enzymology
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / metabolism
  • DNA / physiology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • HeLa Cells
  • Humans
  • Interferon Regulatory Factors / metabolism*
  • Interferon Regulatory Factors / physiology
  • NF-kappa B / metabolism*
  • Protein Interaction Mapping
  • RNA-Binding Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
  • Signal Transduction / immunology

Substances

  • Adjuvants, Immunologic
  • DNA-Binding Proteins
  • Interferon Regulatory Factors
  • NF-kappa B
  • RNA-Binding Proteins
  • ZBP1 protein, human
  • DNA
  • Receptor-Interacting Protein Serine-Threonine Kinases