title: Regulation of toll-like receptor signaling by the SF3a mRNA splicing complex.
abstract: The innate immune response plays a key role in fighting infection by activating inflammation and stimulating the adaptive immune response. However, chronic activation of innate immunity can contribute to the pathogenesis of many diseases with an inflammatory component. Thus, various negatively acting factors turn off innate immunity subsequent to its activation to ensure that inflammation is self-limiting and to prevent inflammatory disease. These negatively acting pathways include the production of inhibitory acting alternate proteins encoded by alternative mRNA splice forms of genes in Toll-like receptor (TLR) signaling pathways. We previously found that the SF3a mRNA splicing complex was required for a robust innate immune response; SF3a acts to promote inflammation in part by inhibiting the production of a negatively acting splice form of the TLR signaling adaptor MyD88. Here we inhibit SF3a1 using RNAi and subsequently perform an RNAseq study to identify the full complement of genes and splicing events regulated by SF3a in murine macrophages. Surprisingly, in macrophages, SF3a has significant preference for mRNA splicing events within innate immune signaling pathways compared with other biological pathways, thereby affecting the splicing of specific genes in the TLR signaling pathway to modulate the innate immune response.
authors: Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America; Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America; Department of Biomedical Research, National Jewish Health, Denver, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, United States of America.
authors: Brian P
authors: BP
authors: O'Connor
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors: Thomas
authors: T
authors: Danhorn
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors: Lesly
authors: L
authors: De Arras
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America; Department of Biomedical Research, National Jewish Health, Denver, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, United States of America.
authors: Brenna R
authors: BR
authors: Flatley
authors: Department of Pediatrics, National Jewish Health, Denver, Colorado, United States of America; Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors: Roland A
authors: RA
authors: Marcus
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors: Eveline
authors: E
authors: Farias-Hesson
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America.
authors: Sonia M
authors: SM
authors: Leach
authors: Integrated Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, United States of America; Department of Biomedical Research, National Jewish Health, Denver, Colorado, United States of America; Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado, United States of America.
authors: Scott
authors: S
authors: Alper
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D017398:Alternative Splicing / Q000235:genetics* / Q000276:immunology; D000818:Animals; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007438:Introns / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology
chemical_list: D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017413:Ribonucleoprotein, U2 Small Nuclear; C088050:SF3A1 protein, human; D051197:Toll-Like Receptor 4