The scaffolding protein IQGAP1 interacts with Nucleotide Binding Domain Leucine Rich Repeat CARD containing protein (NLRC3) and inhibits type I interferon production

Sensing of cytosolic nucleotides is a critical initial step in the elaboration of type I interferon. One of several upstream receptor cGAS (cyclic-GMP-AMP synthase) binds to cytosolic DNA and generates di-cyclic nucleotides that act as secondary messengers. These secondary messengers bind directly to Stimulator of Interferon Genes (STING). STING recruits TANK binding kinase 1 (TBK1) which acts as a critical node that allows for efficient activation of interferon regulatory factors (IRFs) to drive the anti-viral transcriptome. NLRC3 is a recently characterized nucleotide-binding domain, leucine rich repeat containing protein (NLR) that negatively regulates the type I interferon pathway by inhibiting subcellular redistribution and effective signaling of STING, thus blunting the transcription of type I interferons. NLRC3 is predominantly expressed in lymphoid and myeloid cells. IQGAP1 was identified as a putative interacting partner of NLRC3 through yeast two hybrid screening. Here we show that IQGAP1 associates with NLRC3 and can disrupt the NLRC3:STING interaction in the cytosol of human epithelial cells. Furthermore, knock down of IQGAP1 in THP1 and HeLa cells causes significantly more interferon-β production in response to cytosolic nucleic acids. This result phenocopies NLRC3 deficient macrophages and fibroblasts and shRNA knock down of NLRC3 in THP1 cells. Our findings suggest IQGAP1 is a novel regulator of type I interferon production possibly via interacting with NLRC3 in human monocytic and epithelial cells.