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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ramona B RudnickPeter F Zipfel

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 ...Continue Reading

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Citations

Jun 10, 2020·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Jun NakamuraScott J Bultman
Jan 26, 2020·Journal of the American Society of Nephrology : JASN·Peter F ZipfelChristine Skerka
Apr 24, 2020·Proceedings of the National Academy of Sciences of the United States of America·Lejla AlicChristoph J Binder
Nov 24, 2019·Seminars in Immunology·Marcell CserhalmiMihály Józsi
Jul 2, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Frederick Gyapon-QuastMatthew C Pickering
Oct 7, 2021·Cell and Tissue Research·Peter F ZipfelChristine Skerka
Nov 26, 2021·Frontiers in Immunology·Nicole SchäferDiana Pauly

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