title: Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity.
abstract: The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, Colorado 80206 Integrated Center for Genes, Environment and Health, National Jewish Health and University of Colorado, Denver, Colorado 80206.
authors.forename: Lesly
authors.initials: L
authors.lastname: De Arras
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts 02118.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Laws
authors.affiliation: Integrated Center for Genes, Environment and Health, National Jewish Health and University of Colorado, Denver, Colorado 80206.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Leach
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, Colorado 80206 Integrated Center for Genes, Environment and Health, National Jewish Health and University of Colorado, Denver, Colorado 80206.
authors.forename: Kyle
authors.initials: K
authors.lastname: Pontis
authors.affiliation: Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina 27709.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
authors.affiliation: Integrated Center for Genes, Environment and Health, National Jewish Health and University of Colorado, Denver, Colorado 80206 Department of Medicine, University of Colorado, Aurora, Colorado 80045.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.affiliation: Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, Colorado 80206 Integrated Center for Genes, Environment and Health, National Jewish Health and University of Colorado, Denver, Colorado 80206.
authors.forename: Scott
authors.initials: S
authors.lastname: Alper
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D055028:Comparative Genomic Hybridization; D007113:Immunity, Innate / Q000235:genetics*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D010445:Peptide Elongation Factors / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics / Q000276:immunology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D053594:Myeloid Differentiation Factor 88; D010445:Peptide Elongation Factors; D017415:Ribonucleoprotein, U5 Small Nuclear
keywords: C. elegans; LPS; MyD88; complex genetics; complex immunity; infection; innate immunity; macrophage; resistance; tolerance