ReviewComplement factor I in health and disease
Highlights
► FI is a 88 kDa plasma protein composed of a heavy and a light chain linked by a disulfide bond. ► FI inhibits all complement pathways via degrading activated complement proteins C3b and C4b in the presence of cofactors. ► Complete deficiency of FI is rare and leads to complement consumption resulting in recurrent severe infections. ► Incomplete FI deficiency is associated with atypical haemolytic uremic syndrome with thrombocytopenia, microangiopathic haemolytic anaemia and acute renal failure.
Introduction
The complement system plays a major role in defense against pathogens. It also identifies dying cells, immune complexes or misfolded molecules (Ricklin et al., 2009) and guides adaptive immunity (Markiewski and Lambris, 2007). The physiological relevance of complement is demonstrated by illnesses affecting complement deficient patients such as recurrent infections, autoimmune diseases and kidney diseases (Pettigrew et al., 2009, Welch and Blystone, 2009). Invading pathogens activate complement either spontaneously, due to differences in surface composition compared to host cells, or through antibody or pentraxin binding (Lambris et al., 2008). This leads to rapid initiation of a proteolytic complement cascade, release of pro-inflammatory anaphylatoxins that influence blood vessel permeability (C5a, C3a) and attract white blood cells (C5a), opsonisation of the target with C3b and finally formation of the membrane attack complex (MAC).
Complement has to be tightly regulated by both soluble and membrane bound regulators to protect self-tissues from complement-mediated damage (Sjoberg et al., 2009). Many of these inhibitors are located in chromosome 1q32 and they are collectively termed regulators of complement activation (RCA). The RCA proteins inhibit the complement system by accelerating the decay of the C3 and C5 convertases and/or by acting as a cofactor for a serine proteinase factor I (FI) in the degradation of C3b and C4b. FI inhibits all the pathways of complement by cleaving the α′-chain of the activated C3b and C4b proteins. This, however, can only occur in the presence of the following cofactors: factor H (FH), C4b-binding protein (C4BP), membrane cofactor protein (MCP; CD46) or complement receptor 1 (CR1; CD35).
Section snippets
FI
FI is an 88 kDa serum glycoprotein that is expressed in the liver by hepatocytes (Morris et al., 1982), but also by other cells such as monocytes (Whaley, 1980), fibroblasts (Vyse et al., 1996), keratinocytes (Timar et al., 2007) and human umbilical vein endothelial cells (HUVEC) (Julen et al., 1992). The average serum concentration of FI is ∼35 μg/ml and increases during inflammation since FI is an acute phase protein. Thus, the expression of factor I is upregulated by IL-6 in hepatocytes (Minta
Specificity and enzymology of FI
FI (EC 3.4.21.45) was detected in the late 1960s as an activity, which altered the properties of C3b deposited on red blood cells. At an early stage it was named Konglutinogen-Activating Factor (KAF), an activity which caused complement-reacted erythrocytes to be agglutinated by a bovine protein, conglutinin (Lachmann and Muller-Eberhard, 1968). This reaction was subsequently shown to correspond to the proteolytic cleavage of C3b deposited on the erythrocytes to form iC3b, in which a
Structural investigations of FI
In recent years significant efforts have been made to elucidate the binding sites for C3b and C4b on various cofactor proteins such as C4BP (Blom et al., 2001, Blom et al., 2003), CR1 (Krych et al., 1998), MCP (Adams et al., 1991), and FH (Wu et al., 2009). However, the mechanism by which the cofactors assist in the cleavage of C3b/C4b FI is far from clear. The substrates themselves may induce a conformational change in the FI protein that would make the active site accessible and would allow
FI deficiency
The first case of FI deficiency was described in 1971 (Abramson et al., 1971) and since then over 30 families with complete FI deficiency have been reported; reviewed in (Nilsson et al., 2009). Patients presented with recurrent infections with encapsulated microorganisms (e.g. Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae). These symptoms are similar to patients deficient in C3 and are an illustration of the importance of C3 in opsonising microorganisms, enhancing
Conclusions
FI is an unusual protease as it has no endogenous inhibitor and its activity is characterized by a narrow specificity towards two substrates, C3b and C4b, which are only cleaved in the presence of cofactors. The 3D structures of FI alone and in complex with its substrates and cofactors are long awaited particularly in the view of severe diseases affecting patients lacking FI.
Acknowledgements
The authors would like to acknowledge the financial support of the Swedish Research Council, the Swedish Foundation for Strategic Research, the Söderbergs Foundation, research grants from Region Skåne and Assistance Publique-Hôpitaux de Paris (Programme Hospitalier de Recherche Clinique [AOM 08198] 2008; INSERM (ANR, genopat; and AIRG).
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