The Scaffolding Protein IQGAP1 Interacts with NLRC3 and Inhibits Type I IFN Production

J Immunol. 2017 Oct 15;199(8):2896-2909. doi: 10.4049/jimmunol.1601370. Epub 2017 Sep 1.


Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I IFN. One of several upstream receptors, cyclic GMP-AMP synthase, binds to cytosolic DNA and generates dicyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to stimulator of IFN genes (STING). STING recruits TNFR-associated NF-κB kinase-binding kinase 1 which acts as a critical node that allows for efficient activation of IFN regulatory factors to drive the antiviral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine-rich repeat containing protein (NLR) that negatively regulates the type I IFN pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I IFNs. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two-hybrid screening. In this article, we show that IQGAP1 associates with NLRC3 and can disrupt the NLRC3-STING interaction in the cytosol of human epithelial cells. Furthermore, knockdown of IQGAP1 in THP1 and HeLa cells causes significantly more IFN-β production in response to cytosolic nucleic acids. This result phenocopies NLRC3-deficient macrophages and fibroblasts and short hairpin RNA knockdown of NLRC3 in THP1 cells. Our findings suggest that IQGAP1 is a novel regulator of type I IFN production, possibly via interacting with NLRC3 in human monocytic and epithelial cells.

MeSH terms

  • Epithelial Cells / physiology*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunity
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interferon Type I / metabolism
  • Macrophages / physiology*
  • Membrane Proteins / metabolism
  • Nucleic Acids / immunology
  • Protein Binding
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Virus Diseases / immunology*
  • ras GTPase-Activating Proteins / metabolism*


  • IQ motif containing GTPase activating protein 1
  • Intercellular Signaling Peptides and Proteins
  • Interferon Type I
  • Membrane Proteins
  • NLRC3 protein, human
  • Nucleic Acids
  • RNA, Small Interfering
  • STING1 protein, human
  • ras GTPase-Activating Proteins