FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces
Tóm tắt
Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy–associated FHR21–2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild-type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface-binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures.
Từ khóa
Tài liệu tham khảo
Zipfel, 2009, Complement regulators and inhibitory proteins., Nat. Rev. Immunol., 9, 729, 10.1038/nri2620
Mathern, 2015, Molecules great and small: the complement system., Clin. J. Am. Soc. Nephrol., 10, 1636, 10.2215/CJN.06230614
Józsi, 2008, Factor H family proteins and human diseases., Trends Immunol., 29, 380, 10.1016/j.it.2008.04.008
Skerka, 2013, Complement factor H related proteins (CFHRs)., Mol. Immunol., 56, 170, 10.1016/j.molimm.2013.06.001
McRae, 2005, Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein., J. Immunol., 174, 6250, 10.4049/jimmunol.174.10.6250
Chen, 2016, Complement factor H-related 5-hybrid proteins anchor properdin and activate complement at self-surfaces., J. Am. Soc. Nephrol., 27, 1413, 10.1681/ASN.2015020212
Csincsi, 2015, Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation., J. Immunol., 194, 4963, 10.4049/jimmunol.1403121
Goicoechea de Jorge, 2013, Dimerization of complement factor H-related proteins modulates complement activation in vivo., Proc. Natl. Acad. Sci. USA, 110, 4685, 10.1073/pnas.1219260110
Kopp, 2012, Factor H: a complement regulator in health and disease, and a mediator of cellular interactions., Biomolecules, 2, 46, 10.3390/biom2010046
Oppermann, 2006, The C-terminus of complement regulator Factor H mediates target recognition: evidence for a compact conformation of the native protein., Clin. Exp. Immunol., 144, 342, 10.1111/j.1365-2249.2006.03071.x
Gordon, 1995, Identification of complement regulatory domains in human factor H., J. Immunol., 155, 348, 10.4049/jimmunol.155.1.348
Kühn, 1996, Mapping of the domains required for decay acceleration activity of the human factor H-like protein 1 and factor H., Eur. J. Immunol., 26, 2383, 10.1002/eji.1830261017
Manuelian, 2003, Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome., J. Clin. Invest., 111, 1181, 10.1172/JCI16651
Sharma, 1996, Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis., Proc. Natl. Acad. Sci. USA, 93, 10996, 10.1073/pnas.93.20.10996
Jokiranta, 2005, Binding of complement factor H to endothelial cells is mediated by the carboxy-terminal glycosaminoglycan binding site., Am. J. Pathol., 167, 1173, 10.1016/S0002-9440(10)61205-9
Gale, 2010, Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis., Lancet, 376, 794, 10.1016/S0140-6736(10)60670-8
Servais, 2007, Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome., J. Med. Genet., 44, 193, 10.1136/jmg.2006.045328
Hageman, 2005, A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration., Proc. Natl. Acad. Sci. USA, 102, 7227, 10.1073/pnas.0501536102
Edwards, 2005, Complement factor H polymorphism and age-related macular degeneration., Science, 308, 421, 10.1126/science.1110189
Zhang, 2012, Causes of alternative pathway dysregulation in dense deposit disease., Clin. J. Am. Soc. Nephrol., 7, 265, 10.2215/CJN.07900811
Gale, 2011, Regulating complement in the kidney: insights from CFHR5 nephropathy., Dis. Model. Mech., 4, 721, 10.1242/dmm.008052
Zipfel, 2007, Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome., PLoS Genet., 3, e41, 10.1371/journal.pgen.0030041
Chen, 2014, Complement factor H-related hybrid protein deregulates complement in dense deposit disease., J. Clin. Invest., 124, 145, 10.1172/JCI71866
Abrera-Abeleda, 2006, Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease)., J. Med. Genet., 43, 582, 10.1136/jmg.2005.038315
Zhai, 2016, Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy., J. Am. Soc. Nephrol., 27, 2894, 10.1681/ASN.2015010012
Westra, 2012, Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene., J. Hum. Genet., 57, 459, 10.1038/jhg.2012.57
Togarsimalemath, 2017, A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy., Kidney Int., 92, 876, 10.1016/j.kint.2017.04.025
Xiao, 2016, Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene., Mol. Immunol., 77, 89, 10.1016/j.molimm.2016.07.007
Medjeral-Thomas, 2014, A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry., Kidney Int., 85, 933, 10.1038/ki.2013.348
Weismann, 2011, Complement factor H binds malondialdehyde epitopes and protects from oxidative stress., Nature, 478, 76, 10.1038/nature10449
Veneskoski, 2011, Specific recognition of malondialdehyde and malondialdehyde acetaldehyde adducts on oxidized LDL and apoptotic cells by complement anaphylatoxin C3a., Free Radic. Biol. Med., 51, 834, 10.1016/j.freeradbiomed.2011.05.029
Binder, 2016, Innate sensing of oxidation-specific epitopes in health and disease., Nat. Rev. Immunol., 16, 485, 10.1038/nri.2016.63
Miller, 2011, Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity., Circ. Res., 108, 235, 10.1161/CIRCRESAHA.110.223875
Chang, 2004, Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory., J. Exp. Med., 200, 1359, 10.1084/jem.20031763
Tsiantoulas, 2015, Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies., J. Lipid Res., 56, 440, 10.1194/jlr.P054569
Weismann, 2012, The innate immune response to products of phospholipid peroxidation., Biochim. Biophys. Acta, 1818, 2465, 10.1016/j.bbamem.2012.01.018
Esterbauer, 1991, Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes., Free Radic. Biol. Med., 11, 81, 10.1016/0891-5849(91)90192-6
Tuma, 2002, Role of malondialdehyde-acetaldehyde adducts in liver injury., Free Radic. Biol. Med., 32, 303, 10.1016/S0891-5849(01)00742-0
Eberhardt, 2013, Human factor H-related protein 2 (CFHR2) regulates complement activation., PLoS One, 8, e78617, 10.1371/journal.pone.0078617
Chou, 2009, Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans., J. Clin. Invest., 119, 1335, 10.1172/JCI36800
Xu, 1997, Epitope characterization of malondialdehyde-acetaldehyde adducts using an enzyme-linked immunosorbent assay., Chem. Res. Toxicol., 10, 978, 10.1021/tx970069t
Amir, 2012, Peptide mimotopes of malondialdehyde epitopes for clinical applications in cardiovascular disease., J. Lipid Res., 53, 1316, 10.1194/jlr.M025445
Schindelin, 2012, Fiji: an open-source platform for biological-image analysis., Nat. Methods, 9, 676, 10.1038/nmeth.2019
Buhlmann, 2016, FHR3 blocks C3d-mediated coactivation of human B cells., J. Immunol., 197, 620, 10.4049/jimmunol.1600053
Setty, 2012, Differential expression of laminin isoforms in diabetic nephropathy and other renal diseases., Mod. Pathol., 25, 859, 10.1038/modpathol.2011.216
Miner, 2012, The glomerular basement membrane., Exp. Cell Res., 318, 973, 10.1016/j.yexcr.2012.02.031
Lauer, 2011, Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant., J. Immunol., 187, 4374, 10.4049/jimmunol.1002488
Zipfel, 1999, FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function., Immunol. Today, 20, 135, 10.1016/S0167-5699(98)01432-7
Murphy, 2002, Factor H-related protein-5: a novel component of human glomerular immune deposits., Am. J. Kidney Dis., 39, 24, 10.1053/ajkd.2002.29873
Sethi, 2009, Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway., Kidney Int., 75, 952, 10.1038/ki.2008.657
Dunér, 2010, Immune responses against aldehyde-modified laminin accelerate atherosclerosis in Apoe-/- mice., Atherosclerosis, 212, 457, 10.1016/j.atherosclerosis.2010.07.014