title: FAS mRNA editing in Human Systemic Lupus Erythematosus.
abstract: FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human Systematic Lupus Erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNF receptor (TNFR) family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T-cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases.
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA. jmwu@umn.edu
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Fenglong
authors.initials: F
authors.lastname: Xie
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Gibson
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D015854:Up-Regulation; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C491901:FAS protein, human; D012333:RNA, Messenger; D019014:fas Receptor