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

Hebecker, Mario; Józsi, Mihály

doi:10.1074/jbc.m112.364471

Cited by 77 publications

(109 citation statements)

References 30 publications

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“…Interestingly, although CFHR3 has previously been reported as a regulator of complement (in nonphysiological conditions), other experiments reported in the same article demonstrate that, as shown here for CFHR1, CFHR2, and CFHR5, CFHR3 can also deregulate CFH (15). Recently, CFHR4 was shown to be devoid of intrinsic complement activity but able to act as a platform on which complement activation could proceed unhindered (16). Therefore, if CFHR4 was able to compete for CFH ligands, then it too has the potential to deregulate CFH activity.…”

Section: Discussionmentioning

confidence: 72%

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Jorge

Caesar

Malik

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

241

374

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The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related ( CFHR ) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

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Section: Discussionmentioning

confidence: 72%

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Jorge

Caesar

Malik

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

241

374

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“…Solid-phase alternative pathway C3 convertase was assembled on immobilized C3b in microtiter plate wells, as described previously (34). Increasing concentrations of mini-FH or FH were added for 30 min at 37˚C, and the remaining intact convertase was determined using a goat antifactor B antiserum.…”

Section: C3 Convertase-decay Assaymentioning

confidence: 99%

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Hebecker

Alba-Domínguez

Roumenina

et al. 2013

The Journal of Immunology

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Complement is an essential humoral component of innate immunity; however, its inappropriate activation leads to pathology. Polymorphisms, mutations, and autoantibodies affecting factor H (FH), a major regulator of the alternative complement pathway, are associated with various diseases, including age-related macular degeneration, atypical hemolytic uremic syndrome, and C3 glomerulopathies. Restoring FH function could be a treatment option for such pathologies. In this article, we report on an engineered FH construct that directly combines the two major functional regions of FH: the N-terminal complement regulatory domains and the C-terminal surface-recognition domains. This minimal-size FH (mini-FH) binds C3b and has complement regulatory functions similar to those of the full-length protein. In addition, we demonstrate that mini-FH binds to the FH ligands C-reactive protein, pentraxin 3, and malondialdehyde epitopes. Mini-FH was functionally active when bound to the extracellular matrix and endothelial cells in vitro, and it inhibited C3 deposition on the cells. Furthermore, mini-FH efficiently inhibited complement-mediated lysis of host-like cells caused by a disease-associated FH mutation or by anti-FH autoantibodies. Therefore, mini-FH could potentially be used as a complement inhibitor targeting host surfaces, as well as to replace compromised FH in diseases associated with FH dysfunction.

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“…Finally, fH is one member of a larger family of fH-related proteins (CFHRs), whose in vivo roles are not well understood. However, CFHRs bind to C3b/C3d molecules on surfaces and may modulate fH functions in vivo (5,53). Further evaluation of the tissue-specific roles of CFHR proteins both at the mRNA and protein levels is warranted to more fully understand the role of fH and other soluble AP regulatory proteins in CAIA and other diseases.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex–Induced Arthritis

Banda

Mehta

Ferreira

et al. 2013

The Journal of Immunology

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Factor H (fH) is an endogenous negative regulator of the alternative pathway (AP) that binds polyanions as well as complement activation fragments C3b and C3d. The AP is both necessary and sufficient to develop collagen Ab–induced arthritis (CAIA) in mice; the mechanisms whereby normal control of the AP is overcome and injury develops are unknown. Although primarily a soluble circulating protein, fH can also bind to tissues in a manner dependent on the carboxyl-terminal domain containing short consensus repeats 19 and 20. We examined the role of fH in CAIA by blocking its binding to tissues through administration of a recombinant negative inhibitor containing short consensus repeats 19 and 20 (rfH19-20), which impairs fH function and amplifies surface AP activation in vitro. Administration of rfH19-20, but not control rfH3-5, significantly worsened clinical disease activity, histopathologic injury, and C3 deposition in the synovium and cartilage in wild-type and fH+/− mice. In vitro studies demonstrated that rfH19-20 increased complement activation on cartilage extracts and injured fibroblast-like synoviocytes, two major targets of complement deposition in the joint. We conclude that endogenous fH makes a significant contribution to inhibition of the AP in CAIA through binding to sites of immune complex formation and complement activation.

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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

Cited by 77 publications

References 30 publications

Dimerization of complement factor H-related proteins modulates complement activation in vivo

Dimerization of complement factor H-related proteins modulates complement activation in vivo

An Engineered Construct Combining Complement Regulatory and Surface-Recognition Domains Represents a Minimal-Size Functional Factor H

Essential Role of Surface-Bound Complement Factor H in Controlling Immune Complex–Induced Arthritis

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