Factor H-related Protein 4 Activates Complement by Serving as a Platform for the Assembly of Alternative Pathway C3 Convertase via Its Interaction with C3b Protein

Mario Hebecker,Mihály Józsi

doi:10.1074/jbc.m112.364471

Abstract

Human complement factor H-related protein (CFHR) 4 belongs to the factor H family of plasma glycoproteins that are composed of short consensus repeat (SCR) domains. Although factor H is a well known inhibitor of the alternative complement pathway, the functions of the CFHR proteins are poorly understood. CFHR4 lacks SCRs homologous to the complement inhibitory domains of factor H and, accordingly, has no significant complement regulatory activities. We have previously shown that CFHR4 binds C-reactive protein via its most N-terminal SCR, which leads to classical complement pathway activation. CFHR4 binds C3b via its C terminus, but the significance of this interaction is unclear. Therefore, we set out to clarify the functional relevance of C3b binding by CFHR4. Here, we report a novel role for CFHR4 in the complement system. CFHR4 serves as a platform for the assembly of an alternative pathway C3 convertase by binding C3b. This is based on the sustained ability of CFHR4-bound C3b to bind factor B and properdin, leading to an active convertase that generates C3a and C3b from C3. The CFHR4-C3bBb convertase is less sensitive to the factor H-mediated decay compared with the C3bBb convertase. CFHR4 mutants containing exchanges of conserved residues within the C-terminal C3b-binding site showed significantly reduced C3b binding and alternative pathway complement activation. In conclusion, our results suggest that, in contrast to the complement inhibitor factor H, CFHR4 acts as an enhancer of opsonization by promoting complement activation.

Highlights

Complement factor H-related protein 4 (CFHR4) has been shown to interact with C3b
We described native pentameric C-reactive protein (CRP) as a ligand for CFHR4A and CFHR4B, and we showed that this interaction via a binding site in SCR1 leads to enhanced opsonization of necrotic cells with CRP and promotes complement activation via C4-dependent pathways [11, 12]
C3b Binds to the C-terminal SCR8 –9 of CFHR4A—To investigate the relevance of C3b binding to CFHR4, we first analyzed the binding of C3b to CFHR4A and compared it with the C3b binding to CFHR4B, which was previously shown to bind C3b and C3d [9, 10]

Summary

Background

Complement factor H-related protein 4 (CFHR4) has been shown to interact with C3b. Results: Binding of C3b to CFHR4 allows the formation of an active alternative pathway C3 convertase. The plasma glycoprotein factor H (FH) is the major soluble inhibitor of the alternative complement pathway (AP) [3, 4] It prevents the formation of the AP C3 convertase C3bBb by blocking the binding of factor B (FB) to C3b, and it accelerates the decay of existing C3 convertases by displacing Bb. It prevents the formation of the AP C3 convertase C3bBb by blocking the binding of factor B (FB) to C3b, and it accelerates the decay of existing C3 convertases by displacing Bb It acts as a cofactor for the serine protease factor I (FI) in the cleavage of C3b to inactive C3b (iC3b), which can no longer form a convertase [4, 5]. We described native pentameric C-reactive protein (CRP) as a ligand for CFHR4A and CFHR4B, and we showed that this interaction via a binding site in SCR1 leads to enhanced opsonization of necrotic cells with CRP and promotes complement activation via C4-dependent pathways [11, 12]. Thereby, and in marked contrast to FH, CFHR4 enhances complement activation via its interaction with C3b

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION