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Complement Factor H Related Proteins (Cfhrs)

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Complement Factor H Related Proteins (Cfhrs) G Model MIMM-4208; No. of Pages 11 ARTICLE IN PRESS Molecular Immunology xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Molecular Immunology jo urnal homepage: www.elsevier.com/locate/molimm Review Complement factor H related proteins (CFHRs) a,∗ a b,c b,d,e Christine Skerka , Qian Chen , Veronique Fremeaux-Bacchi , Lubka T. Roumenina a Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany b Centre de Recherche des Cordeliers, INSERM UMRS 872, Paris, France c Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France d Université Paris Descartes Sorbonne Paris-Cité, Paris, France e Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France a b s t r a c t a r t i c l e i n f o Factor H related proteins comprise a group of five plasma proteins: CFHR1, CFHR2, CFHR3, CFHR4 and Article history: CFHR5, and each member of this group binds to the central complement component C3b. Mutations, Received 1 May 2013 genetic deletions, duplications or rearrangements in the individual CFHR genes are associated with a Accepted 8 May 2013 Available online xxx number of diseases including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathies (C3 glomerulonephritis (C3GN), dense deposit disease (DDD) and CFHR5 nephropathy), IgA nephropathy, age related macular degeneration (AMD) and systemic lupus erythematosus (SLE). Although complement regulatory functions were attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and the exact contribution to disease pathology is still unclear. Recent publications show that CFHR proteins form homo- as well as heterodimers. Genetic abnormalities within the CFHR gene locus can result in hybrid proteins with affected dimerization or recognition domains which cause defective functions. Here we summarize the recent data about CFHR genes and proteins in order to better understand the role of CFHR proteins in complement activation and in complement associated diseases. © 2013 Elsevier Ltd. All rights reserved. 1. The complement system further C3 molecules, generate C3a and amplify C3b deposition. Further complement activation leads to the C5 convertase forma- The complement system is a central immune surveillance sys- tion and cleavage of C5 to C5b and C5a. A fourth complement path- tem of the vertebrate organism as complement recognizes and way directly activates C3 and C5 due to convertase independent eliminates foreign particles and modified host cells. Upon infection cleavage by thrombin (Huber-Lang et al., 2006). C5b initiates the with microorganisms, complement is activated to induce inflam- terminal complement complex (TCC) on foreign surfaces resulting mation and to allow their elimination. In case of altered self cell in cytolysis (Muller-Eberhard, 1986; Bhakdi and Tranum-Jensen, material, complement assures a silent, non inflammatory clear- 1988; Morgan, 1999; Ward, 2009) The cleavage products C3a and ance by phagocytic cells (Zipfel and Skerka, 2009; Ricklin et al., C5a are potent anaphylatoxins that are chemotactic for immune 2010). In addition, the activated complement system interacts with cells, such as macrophages and neutrophils and that modulate via the coagulation cascade and contributes to the regulation of the receptor binding the immune response. In addition C3a, but not C5a adaptive immune response and T cell differentiation (Kemper and displays anti microbial activity (Diaz-Guillen et al., 1999). Atkinson, 2007). Surface recognition is mediated by deposition of Once activated, the complement system needs tight control, C3b (alternative pathway), antibody binding or surfactant proteins as newly generated complement activation products can induce (the classical pathway), or by mannose binding lectins (the lectin severe inflammation and cell damage. A number of soluble as well pathway). All three pathways converge into the generation of a C3 as membrane bound complement regulators ensure regulation of convertase, which cleaves the central complement component C3 complement activation at the surface of self cells and control dif- into the activation product C3b, which forms together with factor B ferent activation phases and sites of action (Walport, 2001a,b). the C3 convertase (C3bBb) (Fig. 1). These convertases rapidly cleave Abnormalities in any of these regulators can lead to pathological reactions (Zipfel and Skerka, 2009). ∗ Corresponding author at: Department of Infection Biology, Leibniz Institute 2. The factor H/CFHR gene family for Natural Product Research and Infection Biology, Hans Knoell Institute, Beuten- bergstrasse 11, D-07745 Jena, Germany. Tel.: +49 0 3641 5321164; The factor H/CFHR family comprises a group of highly related fax: +49 0 3641 5320807. E-mail address: [email protected] (C. Skerka). proteins that includes the five Complement Factor H Related 0161-5890/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molimm.2013.06.001 Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001 G Model MIMM-4208; No. of Pages 11 ARTICLE IN PRESS 2 C. Skerka et al. / Molecular Immunology xxx (2013) xxx–xxx Fig. 1. Complement activation pathways Complement is activated via three main pathways, the alternative, classical and lectin pathways. All pathways result in the assembly of an active C3 convertase and C3b amplification loop, leading to opsonization via C3b and iC3b for enhanced phagocytosis, to C5a generation and inflammatory reactions as well as to the assembly of the terminal complement complex. proteins, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, factor H and the cesses that result in rearrangements within this chromosomal spliced variant factor H-like protein 1 (FHL-1). Each single gene of region with diverse outcomes. Deletions as well as duplications the family members (CFHR1, CFHR2, CFHR3, CFHR4, CFHR5 and fac- of chromosomal fragments were identified, which harbor either tor H) is located on a distinct segment on human chromosome 1q32 complete CFHR genes, or gene fragments. Such recombination within the RCA (Regulation of Complement Activation) gene cluster processes can lead to loss of single or several CFHR genes, but also (Fig. 2) (Diaz-Guillen et al., 1999; Male et al., 2000). The five CFHR form new gene-compositions including in some cases also the genes are located downstream of the factor H gene and each CFHR factor H gene and their translations into the corresponding proteins. gene codes for a plasma protein that is exclusively composed out of All five CFHR proteins show a high degree of sequence iden- short consensus repeat domains. The entire chromosomal segment tity in their two N-terminal regions (36–94%). The two C-terminal with the CFHR genes is characterized by several large genomic SCR domains of the CFHRs are very similar to the factor H C- repeat regions, which have a high degree of sequence identity. terminus (36–100%). Such sequence homology suggests conserved These repeat regions allow non-homologous recombination pro- domains as well as related functional roles of the proteins. The Fig. 2. The CFHR protein family The genes of the factor H family encode proteins that are composed exclusively of short consensus repeat (SCR) domains. The complement regulatory region in factor H SCRs 1–4 (Reg I) is not conserved in the CFHR proteins, but CFHR proteins harbor three regions that show high identity to factor H. The N-terminal SCR domains of CFHR proteins share sequence homologies to SCRs 6–9 (Reg II), SCRs 10–14 (Reg III) of factor H and the C-terminal SCRs of the CFHRs to the C-terminus of factor H SCRs 18–20 (Reg IV). The CFHR proteins are presented in two groups. CFHR1, CFHR2, CFHR5 are members of group I, as these molecules form homo-dimers via their N-terminal two SCR domains. CFHR1 likely also forms heterodimers with CFHR5. The second group, group II, includes CFHR3 and CFHR4, that do not express the dimerization motif in the N-terminus. The colors of the SCR domains reflect the degree of amino acid identity to factor H. Please cite this article in press as: Skerka, C., et al., Complement factor H related proteins (CFHRs). Mol. Immunol. (2013), http://dx.doi.org/10.1016/j.molimm.2013.06.001 G Model MIMM-4208; No. of Pages 11 ARTICLE IN PRESS C. Skerka et al. / Molecular Immunology xxx (2013) xxx–xxx 3 Fig. 3. CFHR proteins in human plasma (Western blot) Due to the high sequence identity to factor H and to each other the CFHR plasma proteins show immune crossreactivity with polyclonal antiserum. Normal human plasma was separated by SDS gel electrophoresis and blotted to a membrane. Incubation with polyclonal antiserum or monoclonal antibodies to the CFHR proteins (as indicated by numbers, see table lower panel) reveals a specific detection pattern (upper panel). The CFHR proteins are often detected as multiple bands because of different glycosylated forms as indicated. Plasma probes were separated by SDS PAGE (12%) and immunoblotted with indicated antibodies. high amino acid identity among the family members is also to factor H, discriminate between self and non self cell surfaces reflected by the fact that antibodies raised against factor H detect (Hellwage et al., 1999; McRae et al., 2005; Heinen et al., 2009; also different CFHRs in plasma and that the antibodies gener- Eberhardt et al., 2009; Goicoechea de Jorge et al., 2013; Tortajada ated against CFHRs crossreact with other CFHRs (Fig. 3). Moreover, et al., 2013). The C-terminal SCRs in all CFHR proteins that corre- auto-antibodies against factor H in aHUS recognize not only fac- spond to SCR19 in factor H are highly conserved, while the most tor H but also certain CFHRs (Kopp et al., 2012; Blanc et al., C-terminal SCRs which correspond to SCR20 in factor H (Fig.
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