title: An evolutionarily conserved innate immunity protein interaction network.
abstract: 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.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, Colorado 80206, USA.
authors.forename: Lesly
authors.initials: L
authors.lastname: De Arras
authors.forename: Amara
authors.initials: A
authors.lastname: Seng
authors.forename: Brad
authors.initials: B
authors.lastname: Lackford
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Keikhaee
authors.forename: Bruce
authors.initials: B
authors.lastname: Bowerman
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.forename: Scott
authors.initials: S
authors.lastname: Alper
mesh_terms: D000818:Animals; D005075:Biological Evolution; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D060066:Protein Interaction Maps / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D029742:Caenorhabditis elegans Proteins; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4