Factor H–related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation

Abstract

Homozygous deletion of a 84-kb genomic fragment in human chromosome 1 that encompasses the CFHR1 and CFHR3 genes represents a risk factor for hemolytic uremic syndrome (HUS) but has a protective effect in age-related macular degeneration (AMD). Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. This activity is distinct from complement factor H, and apparently factor H and CFHR1 control complement activation in a sequential manner. As both proteins bind to the same or similar sites at the cellular surfaces, the gain of CFHR1 activity presumably is at the expense of CFH-mediated function (inhibition of the C3 convertase). In HUS, the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. These findings provide new insights into complement regulation on the cell surface and biosurfaces and likely define the role of CFHR1 in human diseases. IntroductionThe complement system is important for host innate and adaptive immunity and mounts a protective immune response to invading microbes. 1 The alternative complement pathway is spontaneously activated, and generates C3 convertases (C3bBb) that cleave the central component C3 to the anaphylactic peptide C3a and C3b. 2,3 C3b attached to a foreign surface binds factor B and generates the C3 convertase (C3bBb), which enhances further complement activation resulting in opsonization and phagocytosis of particles. Binding of an additional C3b molecule to the C3 convertase forms the C5 convertase (C3bBbC3b) of the alternative pathway. This convertase cleaves C5 and generates the potent chemoattractant C5a as well as C5b, which initiates the terminal complement pathway assembly. 4 C5b immediately undergoes conformational changes and binds C6 and C7 in a nonenzymatic manner. The assembled C5b67 complex is released from the convertase and attaches to lipid bilayers. Upon binding of C8 and C9, the lytic membrane attack complex (MAC) is formed. 3,5 Once activated, this powerful defense system is tightly controlled on host cell surfaces by both membrane-anchored and surface-attached soluble regulators. Proper and coordinated function of these regulators is essential for tissue integrity. Single gene mutations predispose to severe renal and retinal diseases, that is, hemolytic uremic syndrome (HUS; OMIM no. 235400), membranoproliferative glomerulonephritis type II (MPGN II; OMIM no. 609814), or age-related macular degeneration (AMD; OMIM no. 603075). 6,7 HUS is caused by occlusion of arterioles and capillaries in the kidney, due to endothelial cell and platelet damage. 8 MPGN II is a rare renal disease, with formation of dense deposits at the glomerular basement membrane and thickening of the peripheral capillary walls. 9 Similarly, the retinal disease AMD, which causes visual impairment of elderly people, is caused by deposits (drusen) that form on the Bruch membrane and le...

A Novel Atypical Hemolytic Uremic Syndrome–Associated Hybrid CFHR1/CFH Gene Encoding a Fusion Protein That Antagonizes Factor H–Dependent Complement Regulation

“…(1) The reciprocal hybrid FHR1/FH protein in which the C-terminal region of FHR1 is replaced by the FH C terminus, in contrast to wild-type FHR1, should compete the binding of FH to aHUS-relevant surfaces. (2) Because FHR1 is devoid of the FH complement regulatory properties (i.e., cofactor and decay-accelerating activities), 17,20,21 the hybrid FHR1/FH protein should antagonize the protection from complement damage conferred by FH. Results of competition experiments showing that purified FHR1 from heterozygous carriers of the FHR1/FH hybrid dose-dependently caused complement dysregulation on sheep erythrocytes when added to normal human serum show that the hypotheses are correct.…”

Complement in age-related macular degeneration: a focus on function

“…CFH-related 1 (CFHR1) is a complement inhibitor that inhibits C5 convertase activity and membrane attack complex assembly. 35 MCP (or CD46) is smaller than CFH, containing only four SCRs in comparison to CFH's 20, but is closely related and fulfils the function of inactivation of C3b and C4b on selfsurface membranes. 36 C4BP fulfils the same function as CFH for the lectin and classical pathway convertases.…”

“…17 CFHR3 and CFHR1 are expressed genes whose proteins have functions in the complement system that are independent of those of CFH, as shown in studies carried out in CFH-depleted serum. 35,62 CFHR1 protein inhibits the production of the C5 convertase (C3bBb3b). 35 CFHR1 contains five SCRs, the final three of which share 98% identity to the final three SCRs of CFH, which form a heparin-binding domain.…”

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…Expression of recombinant peptides CCP1‐4, CCP1‐5, CCP1‐6, CCP6‐8, CCP15‐19, CCP8‐20 and CCP18‐20 in Pichia pastoris was described elsewhere (Kühn et al , 1995; Kühn and Zipfel, 1996). Generation of the polyclonal rabbit anti‐CFHR‐1 antisera was described elsewhere (Heinen et al , 2009). …”