Factor H-related protein 5 interacts with pentraxin 3 and the extracellular matrix and modulates complement activation.

Abstract

The physiological roles of the factor H (FH)-related proteins are controversial and poorly understood. Based on genetic studies, FH-related protein 5 (CFHR5) is implicated in glomerular diseases, such as atypical hemolytic uremic syndrome, dense deposit disease, and CFHR5 nephropathy. CFHR5 was also identified in glomerular immune deposits at the protein level. For CFHR5, weak complement regulatory activity and competition for C3b binding with the plasma complement inhibitor FH have been reported, but its function remains elusive. In this study, we identify pentraxin 3 (PTX3) as a novel ligand of CFHR5. Binding of native CFHR5 to PTX3 was detected in human plasma and the interaction was characterized using recombinant proteins. The binding of PTX3 to CFHR5 is of ∼2-fold higher affinity compared with that of FH. CFHR5 dose-dependently inhibited FH binding to PTX3 and also to the monomeric, denatured form of the short pentraxin C-reactive protein. Binding of PTX3 to CFHR5 resulted in increased C1q binding. Additionally, CFHR5 bound to extracellular matrix in vitro in a dose-dependent manner and competed with FH for binding. Altogether, CFHR5 reduced FH binding and its cofactor activity on pentraxins and the extracellular matrix, while at the same time allowed for enhanced C1q binding. Furthermore, CFHR5 allowed formation of the alternative pathway C3 convertase and supported complement activation. Thus, CFHR5 may locally enhance complement activation via interference with the complement-inhibiting function of FH, by enhancement of C1q binding, and by activating complement, thereby contributing to glomerular disease.

• Authors: Ádám I Csincsi, Anne Kopp, Miklós Zöldi, Zsófia Bánlaki, Barbara Uzonyi, Mario Hebecker, Joseph J E Caesar, Matthew C Pickering, Kenji Daigo, Takao Hamakubo, Susan M Lea, Elena Goicoechea de Jorge, Mihály Józsi
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 10 Pg. 4963-73 (May 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25855355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors.

Chemical References

• CFHR5 protein, human
• Ligands
• Recombinant Proteins
• Serum Amyloid P-Component
• PTX3 protein
• Complement System Proteins
• C-Reactive Protein

Topics

• C-Reactive Protein (metabolism)
• Complement Activation (physiology)
• Complement System Proteins (metabolism)
• Extracellular Matrix (metabolism)
• Humans
• Ligands
• Protein Binding
• Recombinant Proteins
• Serum Amyloid P-Component (metabolism)