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.
Highlights
Significance of GPI-anchored protein enrichment in lipid rafts, which requires PGAP3-mediated structural remodeling of GPI, remains unclear
It was widely accepted that GPI-anchored proteins (GPI-APs) in PGAP3-deficient cells lose their characteristic nature and that GPI-AP Thy-1 is not enriched in lipid rafts in T cells from PGAP3Ϫ/Ϫ mice [2, 6, 7], we re-confirmed that this is the case with another GPI-AP, CD14, in PGAP3Ϫ/Ϫ mice before going into the detailed analysis of the mechanisms
CD14 was mainly detected in the detergent-resistant membrane (DRM) fraction in cells from PGAP3ϩ/ϩ and PGAP3ϩ/Ϫ mice, whereas it was mainly detected in the non-DRM fraction in cells from PGAP3Ϫ/Ϫ mice (Fig. 1), confirming that in the absence of fatty acid remodeling catalyzed by PGAP3 GPI-APs are localized outside lipid rafts in primary cells
Summary
Significance of GPI-anchored protein enrichment in lipid rafts, which requires PGAP3-mediated structural remodeling of GPI, remains unclear. 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. The replacement of the GPI anchor with a transmembrane peptide is another way to reduce the affinity of GPI-APs to lipid rafts, but only a few molecules can be examined in one study, and application for in vivo studies is difficult To overcome these problems, we generated PGAP3 knock-out mice. We report that GPI-AP enrichment in lipid rafts induced by PGAP3-dependent fatty acid remodeling of the GPI anchor has a significant role in the control of autoimmunity possibly by regulating apoptotic cell clearance and the Th1/Th2 balance
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