An evolutionarily conserved innate immunity protein interaction network

Abstract

Background: Innate immunity affects infectious and inflammatory diseases. Results: Using RNAi and proteomic data, we identified a novel evolutionarily conserved protein network that modulates innate immunity. Conclusion: Studies using mutant C. elegans and mice demonstrate the utility of this network for disease investigation. Significance: This innate immunity network provides a novel set of targets for future innate immunity disease studies. The innate immune response plays a critical role in fighting infection; however, innate immunity also can affect the pathogenesis of a variety of diseases, including sepsis, asthma, cancer, and atherosclerosis. To identify novel regulators of innate immunity, we performed comparative genomics RNA interference screens in the nematode Caenorhabditis elegans and mouse macrophages. These screens have uncovered many candidate regulators of the response to lipopolysaccharide (LPS), several of which interact physically in multiple species to form an innate immunity protein interaction network. This protein interaction network contains several proteins in the canonical LPS-responsive TLR4 pathway as well as many novel interacting proteins. Using RNAi and overexpression studies, we show that almost every gene in this network can modulate the innate immune response in mouse cell lines. We validate the importance of this network in innate immunity regulation in vivo using available mutants in C. elegans and mice. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.