Complement cascade (Homo sapiens)
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In the complement cascade, a panel of soluble molecules rapidly and effectively senses a danger or damage and triggers reactions to provide a response that discriminates among foreign intruders, cellular debris, healthy and altered host cells (Ricklin D et al. 2010). Complement proteins circulate in the blood stream in functionally inactive states. When triggered the complement cascade generates enzymatically active molecules (such as C3/C5 convertases) and biological effectors: opsonins (C3b, C3d and C4b), anaphylatoxins (C3a and C5a), and C5b, which initiates assembly of the lytic membrane attack complex (MAC). Three branches lead to complement activation: the classical, lectin and alternative pathways (Kang YH et al. 2009; Ricklin D et al. 2010). The classical pathway is initiated by C1 complex binding to immune complexes, pentraxins or other targets such as apoptotic cells leading to cleavage of C4 and C2 components and formation of the classical C3 convertase, C4bC2a. The lectin pathway is activated by binding of mannan-binding lectin (MBL) to repetitive carbohydrate residues, or by binding of ficolins to carbohydrate or acetylated groups on target surfaces. MBL and ficolins interact with MBL-associated serine proteases (MASP) leading to cleavage of C4 and C2 and formation of the classical C3 convertase, C4bC2a. The alternative pathway is spontaneously activated by the hydrolysis of the internal thioester group of C3 to give C3(H2O). Alternative pathway activation involves interaction of C3(H2O) and/or previously generated C3b with factor B, which is cleaved by factor D to generate the alternative C3 convertases C3(H2O)Bb and/or C3bBb. All three pathways merge at the proteolytic cleavage of component C3 by C3 convertases to form opsonin C3b and anaphylatoxin C3a. C3b covalently binds to glycoproteins scattered across the target cell surface. This is followed by an amplification reaction that generates additional C3 convertases and deposits more C3b at the local site. C3b can also bind to C3 convertases switching them to C5 convertases, which mediate C5 cleavage leading to MAC formation. Thus, the activation of the complement system leads to several important outcomes: opsonization of target cells to enhance phagocytosis, lysis of target cells via membrane attack complex (MAC) assembly on the cell surface, production of anaphylatoxins C3a/C5a involved in the host inflammatory response, C5a-mediated leukocyte chemotaxis, and clearance of antibody-antigen complexes. The complement system is able to distinguish between pathological and physiological challenges, i.e. the outcomes of complement activation are predetermined by the trigger and are tightly tuned by a combination of initiation events with several regulatory mechanisms. These regulatory mechanisms use soluble (e.g., C4BP, CFI and CFH) and membrane-bound regulators (e.g., CR1, CD46(MCP), CD55(DAF) and CD59) and are coordinated by complement receptors such as CR1, CR2, etc. In response to microbial infection complement activation results in flagging microorganisms with opsonins for facilitated phagocytosis, formation of MAC on cells such as Gram-negative bacteria leading to cell lysis, and release of C3a and C5a to stimulate downstream immune responses and to attract leukocytes. Most pathogens can be eliminated by these complement-mediated host responses, though some pathogenic microorganisms have developed ways of avoiding complement recognition or blocking host complement attack resulting in greater virulence (Lambris JD et al. 2008; Serruto D et al. 2010). All three complement pathways (classical, lectin and alternative) have been implicated in clearance of dying cells (Mevorach D et al. 1998; Ogden CA et al. 2001; Gullstrand B et al.2009; Kemper C et al. 2008). Altered surfaces of apoptotic cells are recognized by complement proteins leading to opsonization and subsequent phagocytosis. In contrast to pathogens, apoptotic cells are believed to induce only a limited complement activation by allowing opsonization of altered surfaces but restricting the terminal pathway of MAC formation (Gershov D et al. 2000; Braunschweig A and Jozsi M 2011). Thus, opsonization facilitates clearance of dying cells and cell debris without triggering danger signals and further inflammatory responses (Fraser DA et al. 2007, 2009; Benoit ME et al. 2012). C1q-mediated complement activation by apoptotic cells has been shown in a variety of human cells: keratinocytes, human umbilical vein endothelial cells (HUVEC), Jurkat T lymphoblastoid cells, lung adenocarcinoma cells (Korb LC and Ahearn JM 1997; Mold C and Morris CA 2001; Navratil JS et al. 2001; Nauta AJ et al. 2004). In addition to C1q the opsonization of apoptotic Jurkat T cells with MBL also facilitated clearance of these cells by both dendritic cells (DC) and macrophages (Nauta AJ et al. 2004). Also C3b, iC3b and C4b deposition on apoptotic cells as a consequence of activation of the complement cascade may promote complement-mediated phagocytosis. C1q, MBL and cleavage fragments of C3/C4 can bind to several receptors expressed on macrophages (e.g. cC1qR (calreticulin), CR1, CR3, CR4) suggesting a potential clearance mechanism through this interaction (Mevorach D et al. 1998; Ogden CA et al. 2001). Apoptosis is also associated with an altered expression of complement regulators on the surface of apoptotic cells. CD46 (MCP) bound to the plasma membrane of a healthy cell protects it from complement-mediated attack by preventing deposition of C3b and C4b, and reduced expression of CD46 on dying cells may lead to enhanced opsonization (Elward K et al. 2005). Upregulation of CD55 (DAF) and CD59 on apoptotic cell surfaces may protect damaged cells against complement mediated lysis (Pedersen ED et al. 2007; Iborra A et al. 2003; Hensel F et al. 2001). In addition, fluid-phase complement regulators such as C4BP, CFH may also inhibit lysis of apoptotic cells by limiting complement activation (Trouw LA et al 2007; Braunschweig A and Jozsi M. 2011). Complement facilitates the clearance of immune complexes (IC) from the circulation (Chevalier J and Kazatchkine MD 1989; Nielsen CH et al. 1997). Erythrocytes bear clusters of complement receptor 1 (CR1 or CD35), which serves as an immune adherence receptor for C3 and/or C4 fragments deposited on IC that are shuttled to liver and spleen, where IC are transferred and processed by tissue macrophages through an Fc receptor-mediated process. Complement proteins are always present in the blood and a small percentage spontaneously activate. Inappropriate activation leads to host cell damage, so on healthy human cells any complement activation or amplification is strictly regulated by surface-bound regulators that accelerate decay of the convertases (CR1, CD55), act as a cofactor for the factor I (CFI)-mediated degradation of C3b and C4b (CR1, CD46), or prevent the formation of MAC (CD59). Soluble regulators such as C4BP, CFH and FHL1 recognize self surface pattern-like glycosaminoglycans and further impair activation. Complement components interact with other biological systems. Upon microbial infection complement acts in cooperation with Toll-like receptors (TLRs) to amplify innate host defense. Anaphylatoxin C5a binds C5a receptor (C5aR) resulting in a synergistic enhancement of the TLR and C5aR-mediated proinflammatory cytokine response to infection. This interplay is negatively modulated by co-ligation of TLR and the second C5a receptor, C5L2, suggesting the existence of complex immunomodulatory interactions (Kohl J 2006; Hajishengallis G and Lambris JD 2010). In addition to C5aR and C5L2, complement receptor 3 (CR3) facilitates TLR2 or TLR4 signaling pathways by promoting a recruitment of their sorting adaptor TIRAP (MAL) to the receptor complex (van Bruggen R et al. 2007; Kagan JC and Medzhitov R 2006). Complement may activate platelets or facilitate biochemical and morphological changes in the endothelium potentiating coagulation and contributing to homeostasis in response to injury (Oikonomopoulou K et al. 2012). The interplay of complement and coagulation also involves cleavage of C3 and C5 convertases by coagulation proteases, generating biologically active anaphylatoxins (Amara U et al. 2010). Complement is believed to link the innate response to both humoral and cell-mediated immunity (Toapanta FR and Ross TM 2006; Mongini PK et al. 1997). The majority of published data is based on experiments using mouse as a model organism. Further characterization of the influence of complement on B or T cell activation is required for the human system, since differences between murine models and the human system are not yet fully determined. Complement is also involved in regulation of mobilization and homing of hematopoietic stem/progenitor cells (HSPCs) from bone marrow to the circulation and peripheral tissue in order to accommodate blood cell replenishment (Reca R et al. 2006). Thus, the complement system orchestrates the host defense by sensing a danger signal and transmitting it into specific cellular responses while extensively communicating with associated biological pathways ranging from immunity and inflammation to homeostasis and development. Originally the larger fragment of Complement Factor 2 (C2) was designated C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. Recent literature may use the updated nomenclature and refer to the larger C2 fragment as C2b, and refer to the classical C3 convertase as C4bC2b. Throughout this pathway Reactome adheres to the original convention to agree with the current (Sep 2013) Uniprot names for C2 fragments. The complement cascade pathway is organised into the following sections: initial triggering, activation of C3 and C5, terminal pathway and regulation.
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DataNodes
Activated C1R:2x
Activated C1Sprotein
pentamer:phosphocholine:C1Qdimer:MASP2 dimer:Bacterial mannose surface
pattern:4xCa2+surface:C3b:CFHR
dimersdodecamer:MASP1 dimer:MASP2-1
dimer:4xCa2+dodecamer:MASP1 dimer:MASP2-1
dimer:4xCa2+multimer:MASP1 dimer:MASP2
dimer:4xCa2+dimer:MASP2-1 dimer:Bacterial mannose surface
pattern:4xCa2+MASPs:carbohydrate
patternsAnnotated Interactions
Activated C1R:2x
Activated C1SActivated C1R:2x
Activated C1Sprotein
pentamer:phosphocholine:C1Qdimer:MASP2 dimer:Bacterial mannose surface
pattern:4xCa2+surface:C3b:CFHR
dimersdodecamer:MASP1 dimer:MASP2-1
dimer:4xCa2+dodecamer:MASP1 dimer:MASP2-1
dimer:4xCa2+multimer:MASP1 dimer:MASP2
dimer:4xCa2+dimer:MASP2-1 dimer:Bacterial mannose surface
pattern:4xCa2+MASPs:carbohydrate
patternsN.B. Humans have two highly polymorphic loci for Complement factor 4, C4A and C4B. C4A alleles carry the Rodgers (Rg) blood group antigens while the C4B alleles carry the Chido (Ch) blood group antigens. The two loci encode non identical C4 peptides; C4 derived from C4A reacts more rapidly with the amino groups of peptide antigens while C4B allotypes react more rapidly with the hydroxyl group of carbohydrate antigens. The names of the two loci are always represented in uppercase. C4a and C4b refer to the peptide products of Complement Factor 4 cleavage.
All three pathways merge at the proteolytic cleavage of component C3 by C3 convertases to form two fragments C3b and C3a. The cleavage of component C3 exposes a reactive thioester bond on C3b, leading to the covalent attachment of C3b to glycoproteins on the target cell surface (Law SK et al. 1979; Tack BF et al. 1980). The opsonization with C3b enables the recruitment of phagocytes (Newman SL et al. 1985; Gadjeva M et al. 1998). In addition, C3b anchors the assembly of C3/C5 convertases leading to an amplification of C3 cleavage and effecting C5 activation (Fearon DT 1979; Takata Y et al 1987; Kinoshita T et al. 1988). Moreover, the activation of C3b exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF), membrane cofactor protein (MCP), complement receptor 1 (CR1) and microbial molecules such as vaccinia virus complement-control protein and staphylococcal complement inhibitor (SCIN) from Staphylococcus aureus (Forneris F et al. 2010; Morgan HP et al. 2011; Nilsson SC et al. 2010; Lambris JD et al. 1984; Medof ME et al.1984; Barilla-LaBarca ML et al. 2002; Smith BO et al. 2002; Bernet J et al. 2004; Garcia Bl et al. 2010) . C3b associates with these molecules to mediate the activation, amplification and regulation of the complement response.
C5b initiates an assembly of terminal complement components (C6-C9) leading to the formation of membrane attack complex (MAC) on the target surface (Aleshin AE et al. 2012; Hadders MA et al. 2012). MAC disrupts the cell membrane causing a subsequent cell death through osmotic lysis.
Anaphylatoxin C5a mediates pro-inflammatory and immunemodulatory signals via its receptors C5aR and C5L2. The anaphylatoxin receptors are found on surfaces of phagocytes as well as other cell types. In inflammation, they induce cytokine production, degranulation and chemotaxis of leukocytes (Monk PN et al. 2007).
C5b and C6 remains loosely bound to C3b until C5b binds to C7 and induces it to undergo a hydrophilic-amphiphilic transition. Hydrophobic binding regions for phospholipid are thereby exposed, and the trimolecular complex is endowed with a metastable membrane binding site. Membranebound
C5b-7 inflicts no harm on a cell but marks it for further assault.Ficolin-1 specifically recognizes sialic acid and can bind to acetylated compounds such as N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) (Garlatti V et al. 2007; Gout E et al. 2010; Kjaer TR et al. 2011).
CFHR3 and CFHR4 do not contain the dimerization motif seen in CFHR1, 2 and 5 but compete with factor H for binding to C3b (Hellwage et al. 1999, Fritsche et al. 2010). CFHR4 exists predominantly as a dimer in plasma (Hellwage et al. 1999).
As the main function of CFH is down-regulation of C3 activation through the alternative pathway amplification loop, CFHR dimers interfere with the C3b inhibitory actions of CFH, a process termed deregulation (de Jorge et al. 2013, Tortajada et al. 2013).
Under normal conditions, thrombin cleavage of C5 may not be a physiologically significant reaction (Bagic et al. 2015) but the combined action of thrombin and convertases appears to enhance the efficiency of the lytic pathway (Krisinger et al. 2012). Clotting-induced production of thrombin leads to cleavage of C5 at the atypical site R947 in the CUB domain. C5a can be released from the atypical C5a fragment (termed C5aT) by conventional C5 convertases; the truncated C5b fragment, termed C5bT, can form a C5bT-9 membrane attack complex that has significantly increased lytic activity (Krisinger et al. 2012).
Carboxypeptidase B2 (Plasma carboxypeptidase B, Thrombin-activable fibrinolysis inhibitor, TAF1, CPB2) also can convert C3a and C5a to C3a-desArg and C5a-desArg (Campbell et al. 2002). C3a-desArg cannot bind C3AR1, and C5a-desArg has a 90% decrease in pro-inflammatory activity compared to C5a (Sayah et al. 2003).
CPN is a tetramer comprised of two heterodimers each consisting of a CPN1 and CPN2 subunit (Levin et al. 1982, Keil et al. 2007). The catalytic CPN1 subunit ranges in size from 48 kDa to 55 kDa. This reflects processing by trypsin or plasmin, which can remove a C-terminal segment to produce the 48 kDa form, and cleave at Arg218-Arg219 to produce two peptide chains held together in an active conformation by non-covalent bonds (Levin et al. 1982, Quagraine et al. 2005). This step increases the catalytic activity of CPN towards chromogenic substrates.
Complement fragments, iC3b and C3dg, are produced in vivo due to the actions of the complement serine protease, factor I. This enzyme cleaves C3b in the presence of cofactors (factor H, MCP/CD46, complement receptor 1/CR1/CD35) to generate iC3b. CR1 acts as a cofactor for further factor I-mediated cleavage to C3dg.