Factor H-Related Protein 5 Interacts with Pentraxin 3 and the Extracellular Matrix and Modulates Complement Activation
Author(s)
Type
Journal Article
Abstract
The physiological roles of the factor H (FH)-related proteins are controversial and poorly understood. Based on genetic studies, FHrelated
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
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
Date Issued
2015-05-15
Date Acceptance
2015-03-11
Citation
Journal of Immunology, 2015, 194 (10), pp.4963-4973
ISSN
1550-6606
Publisher
American Association of Immunologists
Start Page
4963
End Page
4973
Journal / Book Title
Journal of Immunology
Volume
194
Issue
10
Copyright Statement
© 2015 The Authors
This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
C-REACTIVE-PROTEIN
HEMOLYTIC-UREMIC SYNDROME
GLOMERULAR IMMUNE DEPOSITS
CHRONIC KIDNEY-DISEASE
BINDING
PTX3
IDENTIFICATION
CFHR1
GLOMERULONEPHRITIS
AUTOANTIBODIES
Publication Status
Published