FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces

Journal of Immunology - Tập 200 Số 7 - Trang 2280-2290 - 2018
Ramona B. Rudnick1, Qian Chen1, Emma Diletta Stea1, Andrea Hartmann1, Nikolina Papac-Miličević2,3, Fermín Person4, Michael S. Wiesener5, Christoph J. Binder2,3, Thorsten Wiech4, Christine Skerka1, Peter F. Zipfel1,6
1*Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany;
2†Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria;
3Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
4§Institute of Pathology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany;
5¶Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and
6‖Department Microbiology, Friedrich-Schiller-University, 07745 Jena, Germany

Tóm tắt

Abstract 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.

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Tài liệu tham khảo

Zipfel, 2009, Complement regulators and inhibitory proteins., Nat. Rev. Immunol., 9, 729, 10.1038/nri2620

Sarma, 2011, The complement system., Cell Tissue Res., 343, 227, 10.1007/s00441-010-1034-0

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

Tortajada, 2017, Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy., Kidney Int., 92, 953, 10.1016/j.kint.2017.03.041

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Journal of Immunology

Tập 200 Số 7

2280-2290

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