title: Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing.
abstract: Controlling infectious disease without inducing unwanted inflammatory disease requires proper regulation of the innate immune response. Thus, innate immunity needs to be activated when needed during an infection, but must be limited to prevent damage. To accomplish this, negative regulators of innate immunity limit the response. Here we investigate one such negative regulator encoded by an alternative splice form of MyD88. MyD88 mRNA exists in two alternative splice forms: MyD88L, a long form that encodes a protein that activates innate immunity by transducing Toll-like receptor (TLR) signals; and a short form that encodes a different protein, MyD88S, that inhibits the response. We find that MyD88S levels regulate the extent of inflammatory cytokine production in murine macrophages. MyD88S mRNA levels are regulated by the SF3A and SF3B mRNA splicing complexes, and these mRNA splicing complexes function with TLR signaling to regulate MyD88S production. Thus, the SF3A mRNA splicing complex controls production of a negative regulator of TLR signaling that limits the extent of innate immune activation.
authors.affiliation: Integrated Department of Immunology and Integrated Center for Genes, Environment, and Health, National Jewish Health and University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Lesly
authors.initials: L
authors.lastname: De Arras
authors.forename: Scott
authors.initials: S
authors.lastname: Alper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D000072260:RNA Splicing Factors; D012333:RNA, Messenger / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics* / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D017413:Ribonucleoprotein, U2 Small Nuclear; C088050:SF3A1 protein, human; C112491:SF3B1 protein, human; D051193:Toll-Like Receptors