IQGAP1 inhibits type I interferon production via interactions with NLRC3

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (1_Supplement), p.129-129.18
• Main Authors: Davis, Beckley K, Roberts, David Michael, Tocker, Aaron M, Troiani, Zachary, Jacob, Kimberly, Trieschman, Kate, Durocher, Emily, Rechnitzer, Alma, Talento, Suzanna Marie
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.129.18

Nucleotide binding domain, leucine rich repeat CARD containing protein 3 (NLRC3) is a member of the NLR gene family. Members of this family have been associated with human inflammatory diseases such as Crohn’s disease and cryopyrin-associated periodic syndrome. Although NLRC3 is not associated with human diseases, it is expressed preferentially in the immune system and functions in pathogen detection. NLRC3 is an intracellular protein involved in the sensing of lipopolysaccharide and cytosolic nucleic acids. NLRC3 is hypothesized to act as a negative regulator in response to bacterial and viral infection, suggesting that the vertebrate immune system has evolved specific inhibitors to limit the inflammatory response. We performed an unbiased yeast two-hybrid screen using an amino terminal fragment of NLRC3 to identify putative interacting proteins that might help elucidate the mechanism by which NLRC3 might inhibit inflammatory responses. To this end, we identified several interacting proteins. One protein, in particular, IQGAP1, acts as a scaffold important in regulating the cytoskeleton, cell adhesion and proliferation. Structure function analysis has localized the domains necessary and sufficient for interacting with NLRC3. Confocal microscopy demonstrates that these two proteins co-localize in transformed human epithelial cells. Functionally, in the absence of IQGAP1, human monocytic cells are hyperactive in response to cytosolic nucleotides, phenocopying NLRC3 deficiencies. These data suggest that NLRC3 can interact with novel proteins to facilitate squelching of cellular responses to cytosolic nucleotides.