title: Significance of glycosylphosphatidylinositol-anchored protein enrichment in lipid rafts for the control of autoimmunity.
abstract: Glycosylphosphatidylinositols (GPI) are complex glycolipids that are covalently linked to the C terminus of proteins as a post-translational modification and tether proteins to the plasma membrane. One of the most striking features of GPI-anchored proteins (APs) is their enrichment in lipid rafts. The biosynthesis of GPI and its attachment to proteins occur in the endoplasmic reticulum. In the Golgi, GPI-APs are subjected to fatty acid remodeling, which replaces an unsaturated fatty acid at the sn-2 position of the phosphatidylinositol moiety with a saturated fatty acid. We previously reported that fatty acid remodeling is critical for the enrichment of GPI-APs in lipid rafts. To investigate the biological significance of GPI-AP enrichment in lipid rafts, we generated a PGAP3 knock-out mouse (PGAP3(-/-)) in which fatty acid remodeling of GPI-APs does not occur. We report here that a significant number of aged PGAP3(-/-) mice developed autoimmune-like symptoms, such as increased anti-DNA antibodies, spontaneous germinal center formation, and enlarged renal glomeruli with deposition of immune complexes and matrix expansion. A possible cause for this was the impaired engulfment of apoptotic cells by resident peritoneal macrophages in PGAP3(-/-) mice. Mice with conditional targeting of PGAP3 in either B or T cells did not develop such autoimmune-like symptoms. In addition, PGAP3(-/-) mice exhibited the tendency of Th2 polarization. These data demonstrate that PGAP3-dependent fatty acid remodeling of GPI-APs has a significant role in the control of autoimmunity, possibly by the regulation of apoptotic cell clearance and Th1/Th2 balance.
authors.affiliation: From the Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, and.
authors.forename: Yetao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, and.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, and Laboratory of Molecular Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 and.
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
authors.affiliation: the Technology and Development Team for Mouse Phenotype Analysis, Japan Mouse Clinic, RIKEN Bioresource Center, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.affiliation: Department of Molecular Immunology, Research Institute for Microbial Diseases, and Laboratory of Molecular Immunology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.affiliation: From the Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, and.
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: From the Department of Immunoregulation, Research Institute for Microbial Diseases, and Laboratory of Immunoglycobiology, WPI Immunology Frontier Research Center, and. Electronic address: ymaeda@biken.osaka-u.ac.jp.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017261:Glycosylphosphatidylinositols / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007105:Immune Complex Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000974:Antibodies, Antinuclear; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D002265:Carboxylic Ester Hydrolases; C571153:PGAP3 protein, mouse
keywords: Autoimmunity; Glycosylphosphatidylinositol Anchors; Lipid Raft; Lipid Structure; PGAP3; Phagocytosis