title: Complement Factor H-Related 5-Hybrid Proteins Anchor Properdin and Activate Complement at Self-Surfaces.
abstract: C3 glomerulopathy (C3G) is a severe kidney disease for which no specific therapy exists. The causes of C3G are heterogeneous, and defective complement regulation is often linked to C3G pathogenesis. Copy number variations in the complement factor H-related (CFHR) gene cluster on chromosome 1q32 and CFHR5 mutant proteins associate with this disease. Here, we identified CFHR5 as a pattern recognition protein that binds to damaged human endothelial cell surfaces and to properdin, the human complement activator. We found the two N-terminal short consensus repeat domains of CFHR5 contact properdin and mediate dimer formation. These properdin-binding segments are duplicated in two mutant CFHR5 proteins, CFHR2-CFHR5Hyb from German patients with C3G and CFHR5Dup from Cypriot patients with C3G. Each of these mutated proteins assembled into large multimeric complexes and, compared to CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local complement activation. This enhanced surface binding and properdin recruitment was further evidenced in the mesangia of a transplanted and explanted kidney from a German patient with a CFHR2-CFHR5Hyb protein. Enhanced properdin staining correlated with local complement activation with C3b and C5b-9 deposition on the mesangial cell surface in vitro This gain of function in complement activation for two disease-associated CFHR5 mutants describes a new disease mechanism of C3G, which is relevant for defining appropriate treatment options for this disorder.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany;
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany;
authors.forename: Melanie
authors.initials: M
authors.lastname: Manzke
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, Germany;
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: University Hospital Regensburg, Regensburg, Germany; and.
authors.forename: Diana
authors.initials: D
authors.lastname: Pauly
authors.affiliation: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Wiesener
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany;
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; Friedrich Schiller University, Jena, Germany peter.zipfel@leibniz-hki.de.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D002462:Cell Membrane; D003167:Complement Activation; D003165:Complement System Proteins / Q000502:physiology*; D006801:Humans; D007674:Kidney Diseases / Q000276:immunology; D007678:Kidney Glomerulus; D011414:Properdin / Q000502:physiology*
chemical_list: C432223:CFHR5 protein, human; D011414:Properdin; D003165:Complement System Proteins
keywords: ESRD; complement; glomerulopathy; immune deficiency; pathology; pediatric nephrology