Molecular basis of C-reactive protein binding and modulation of complement activation by factor H-related protein 4

Hebecker, Mario; Okemefuna, Azubuike I.; Perkins, Stephen J.; Mihlan, Michael; Huber‐Lang, Markus; Józsi, Mihály

doi:10.1016/j.molimm.2009.12.005

Cited by 37 publications

(43 citation statements)

References 35 publications

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“…Previously, we have demonstrated that CFHR4 activates C2/C4-dependent pathways via its interaction with CRP (12). Here, we found that CFHR4 can initiate AP activation via the formation of active C3 convertases on CFHR4-bound C3b (Figs.…”

Section: Discussionmentioning

confidence: 57%

“…CFHR4 Activates the Alternative Complement Pathway-We have previously shown that CFHR4 activates C2/C4-dependent pathways via its interaction with CRP (12). To assess the role of CFHR4 in AP activation, we added human serum, diluted in Mg-EGTA buffer to allow AP activation only, to the immobilized CFHR4 isoforms.…”

Section: Resultsmentioning

confidence: 99%

“…3 and 4). Because complement is autoactivated in human plasma via the spontaneous hydrolysis of the thioester bond in C3 ("tick-over" mechanism) that generates trace amounts of C3b via the very short lived C3(H 2 O)Bb initial AP C3 convertase (24,25), the activation of the AP via CFHR4-bound C3b can occur independently from the activation of the classical pathway via CFHR4-bound CRP (12).…”

Section: Discussionmentioning

confidence: 99%

“…Proteins, Sera, and Antibodies-Cloning and recombinant expression of CFHR4A as well as the CFHR4A deletion mutants SCR1-3, SCR2-4, SCR4 -9, SCR5-7, and SCR8 -9 were described previously (11,12). CFHR4B, the CFHR4B mutants D221G and D221G/K290A, as well as CFHL1 were generated via gene synthesis (GenScript, Piscataway, NJ) and subcloned into the baculovirus expression vector pBSV-8His (13).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, 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).…”

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confidence: 99%

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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

Hebecker

Józsi

2012

Journal of Biological Chemistry

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102

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Section: Discussionmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Hebecker

Józsi

2012

Journal of Biological Chemistry

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102

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FHR4‐based immunoconjugates direct complement‐dependent cytotoxicity and phagocytosis towards HER2‐positive cancer cells

et al. 2019

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Directing selective complement activation towards tumour cells is an attractive strategy to promote their elimination. In the present work, we have generated heteromultimeric immunoconjugates that selectively activate the complement alternative pathway (AP) on tumour cells. We used the C4b‐binding protein C‐terminal‐α‐/β‐chain scaffold for multimerisation to generate heteromultimeric immunoconjugates displaying (a) a multivalent‐positive regulator of the AP, the human factor H‐related protein 4 (FHR4) with; (b) a multivalent targeting function directed against erbB2 (HER2); and (c) a monovalent enhanced GFP tracking function. Two distinct VHH targeting two different epitopes against HER2 and competing either with trastuzumab or with pertuzumab‐recognising epitopes [VHH(T) or VHH(P)], respectively, were used as HER2 anchoring moieties. Optimised high‐FHR4 valence heteromultimeric immunoconjugates [FHR4/VHH(T) or FHR4/VHH(P)] were selected by sequential cell cloning and a selective multistep His‐Trap purification. Optimised FHR4‐heteromultimeric immunoconjugates successfully overcame FH‐mediated complement inhibition threshold, causing increased C3b deposition on SK‐OV‐3, BT474 and SK‐BR3 tumour cells, and increased formation of lytic membrane attack complex densities and complement‐dependent cytotoxicity (CDC). CDC varies according to the pattern expression and densities of membrane‐anchored complement regulatory proteins on tumour cell surfaces. In addition, opsonised BT474 tumour cells were efficiently phagocytosed by macrophages through complement‐dependent cell‐mediated cytotoxicity. We showed that the degree of FHR4‐multivalency within the multimeric immunoconjugates was the key element to efficiently compete and deregulate FH and FH‐mediated convertase decay locally on tumour cell surface. FHR4 can thus represent a novel therapeutic molecule, when expressed as a multimeric entity and associated with an anchoring system, to locally shift the complement steady‐state towards activation on tumour cell surface.

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Factor H-Related Proteins

Józsi

Meri

2013

Methods in Molecular Biology

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Factor H-related proteins (CFHRs) are plasma glycoproteins related in structure and antigenicity to each other and to the complement inhibitory protein factor H. Such proteins are found in most mammals but their number and domain composition vary. This chapter summarizes our current knowledge on the human factor H-related proteins. In contrast to factor H, they have no strong complement inhibitory activity, although for some of them regulatory or complement modulatory activity has been reported. A common feature of CFHRs is that they bind to the C3b component of complement. Novel links between CFHRs and various diseases (C3 glomerulopathies, atypical hemolytic uremic syndrome and age-related macular degeneration) have been revealed in recent years, but we are still far from understanding their biological function.

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Molecular basis of C-reactive protein binding and modulation of complement activation by factor H-related protein 4

Cited by 37 publications

References 35 publications

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

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

FHR4‐based immunoconjugates direct complement‐dependent cytotoxicity and phagocytosis towards HER2‐positive cancer cells

Factor H-Related Proteins

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