Send to

Choose Destination
J Immunol. 2018 Apr 1;200(7):2280-2290. doi: 10.4049/jimmunol.1701641. Epub 2018 Feb 26.

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

Author information

Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany.
Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria.
Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Institute of Pathology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and.
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany;
Department Microbiology, Friedrich-Schiller-University, 07745 Jena, Germany.


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.


Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center