Human factor H-related protein 5 modulates the classical and lectin complement pathways on selected host ligands

Abstract C4b-binding protein (C4BP) and factor H (FH) are the main soluble negative regulators of the classical/lectin (CP/LP) and alternative (AP) complement pathways, respectively. They do not only act in solution but also interact with host ligands such as C-reactive protein (CRP) and extracellular matrix proteins to control complement activation on surfaces. Factor H-related (FHR) proteins share structural homology with FH and modulate complement activation by competing with FH for ligands and enhancing AP activation. Due to their overlapping ligand profile with both FH and C4BP, we studied the potential effect of FHR-1, FHR-2, and FHR-5 on C4BP function and on CP/LP activation. Both FHR-1 and FHR-5 inhibited C4BP binding to surface-bound CRP and osteoadherin. This translated to reduced surface cofactor activity of C4BP on CRP in the presence of FHR-5. Unexpectedly, FHR-5 inhibited CP activation, indicated by decreased C3- and C4-fragments deposition from serum, which was due to inhibition of C1q binding on CRP and osteoadherin. FHR-1 and FHR-2 did not influence CP activation. In addition, FHR-5 inhibited LP activation by competing with ficolin-2 and ficolin-3. In conclusion, our results revealed a novel role of FHR-5 in modulating the activity of the complement CP and LP.