ReviewThe human complement factor H: functional roles, genetic variations and disease associations
Introduction
The complement system is a crucial component of the innate immunity against microbial infection. It contains several plasma and membrane-associated proteins that are organized in three activation pathways: the classical, the lectin and the alternative pathways. Upon activation by molecules on the surface of the microorganisms, these pathways result in the formation of unstable protease complexes, named C3-convertases. Both, the classical/lectin pathway C3-convertase, named C4b2b, and the alternative pathway C3-convertase, named C3bBb, are able to cleave the α-chain of C3 generating C3b. Cleavage of C3 results in the exposure of an internal thiolester which is extremely reactive with nucleophiles, that provides C3b with the potential of binding covalently to biological surfaces exposing hydroxyl or amino groups (Fig. 1). C3b deposition leads to opsonization for phagocytosis by polymorphonuclear cells and macrophages. In the presence of an additional C3b molecule, the C3-convertases can function as C5-convertases, cleaving C5 and initiating the assembly of the membrane attack complex that leads to complement-mediated lysis.
The efficacy of the complement system as an innate defence mechanism against microbial infections depends on the fine control of the complement system, avoiding the wasteful consumption of its components and preventing non-specific damage to host tissues. Normally, activation of C3 in the blood is kept at a low level and deposition of C3b and further activation of complement is limited to the surface of pathogens. Not surprisingly, many complement components are regulatory proteins that modulate complement activation and protect host tissues. Several of these regulatory proteins interact with C3 or C4 derivatives and are encoded by closely linked genes that constitute the Regulator of Complement Activation (RCA) gene cluster on human chromosome 1q32. It is generally accepted that these complement regulatory genes share a common ancestor from which they originated by multiple events of gene duplication. Factor H, a plasma protein encoded by one of these RCA genes, is essential to regulate complement activation and to restrict the action of complement to activating surfaces.
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Structure and function of factor H
Factor H was first identified by Nilsson and Müeller-Eberhard (1965) as β1H globulin. Factor H is a single polypeptide chain plasma glycoprotein (155 kDa) that is present in plasma at a concentration of 110–615 μg/ml. The secreted form of the protein is composed of 20 repetitive units of 60 amino acids (Ripoche et al., 1988), named short consensus repeats (SCR) or complement control protein modules (CCP), arranged in a continuous fashion like a string of 20 beads. The SCRs have a typical
The factor H family: genes and proteins
Factor H is encoded by a single gene (HF1) located on human chromosome 1q32 within the RCA gene cluster (Rodriguez de Cordoba and Rubinstein, 1986, Rodriguez de Cordoba et al., 1999, Weis et al., 1987). HF1 is closely linked to the FHR1, FHR2, FHR3, FHR4 and FHR5 genes encoding five factor H-related human plasma proteins (Zipfel and Skerka, 1994, Zipfel et al., 1999, Diaz-Guillen et al., 1999, Perez-Caballero et al., 2001, McRae et al., 2002) (Fig. 3). Sequence analyses of the HF1/FHR1–5 gene
Factor H mutations and disease associations
In recent years a significant number of mutations has been identified in the HF1 gene (Table 2), which has revealed a very interesting association with two different renal diseases, glomerulonephritis and atypical hemolytic uremic syndrome (aHUS).
Factor H deficiencies have been described both in humans and animals. They are caused by mutations that result in truncations or amino acid substitutions that impair secretion of factor H into circulation (Ault et al., 1997, Sanchez-Corral et al., 2000
Quantitative variations and other polymorphisms
As indicated earlier, levels of factor H in human plasma vary largely (110–615 μg/ml) in the population. This variation is not a consequence of HF1 null alleles, which are extremely rare, but the result of the combined effect of genetic and environmental factors. Using variance-component methods (Almasy and Blangero, 1998) in the analysis to a family-based study including 358 individuals, we have determined that factor H plasma levels show an age-dependent increase and are decreased in smokers.
Uptake of factor H by microorganisms and tumour cells
The interaction of factor H with polyanions confers to the host cellular surfaces protection from complement activation. Similarly, factor H binding to surface molecules of pathogens and tumour cells has been demonstrated to restrict alternative pathway activation enhancing the survival and pathogenic capacity of these cells and microorganisms. Pathogenic microorganisms are normally potent activators of the complement system. Not surprisingly, many pathogens have evolved to express surface
Additional roles for factor H
Interaction of factor H with novel ligands and expression of factor H in unusual tissues under physiological or pathological conditions suggest that factor H plays a role in processes as diverse as diabetes mellitus (Pio et al., 2001b, Martinez et al., 2001), Alzheimer’s disease (Strohmeyer et al., 2002), rheumatoid arthritis or atherosclerosis (Oksjoki et al., 2003). Factor H interacts with high affinity in plasma with adrenomedullin (AM), a 52-amino acid peptide belonging to the calcitonin
Concluding remarks
We have reviewed the current knowledge of the structure and function of factor H and illustrated different situations that relate factor H with chronic or infectious disease. Abundant data are now available that define the critical role of factor H in the protection of the host cells and tissues from damage by complement activation. Furthermore, it is now well-established that the C3b/polyanions-binding site located at the C-terminal region of factor H is the most important site for preventing
Acknowledgements
We thank the helpful comments of Drs A. Corbı́ and K. E. Heath. This work was supported by the Spanish MCyT (SAF2002-1083).
References (114)
- et al.
Multipoint quantitative-trait linkage analysis in general pedigrees
Am. J. Hum. Genet.
(1998) - et al.
Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism
J. Biol. Chem.
(1997) - et al.
Solution structure of a pair of complement modules by nuclear magnetic resonance
J. Mol. Biol.
(1993) - et al.
Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome
Am. J. Hum. Genet.
(2000) - et al.
Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack
J. Biol. Chem.
(2000) - et al.
FHL-1/reconectin and factor H: two human complement regulators which are encoded by the same gene are differently expresed and regulated
Mol. Immunol.
(1999) - et al.
Functional properties of complement factor H-related proteins FHR3 and FHR4: binding to the C3d region of C3b and differential regulation by heparin
FEBS Lett.
(1999) - et al.
The complement regulator factor H binds to the surface protein OspE of Borrelia burgdorferi
J. Biol. Chem.
(2001) - et al.
The regulators of complement activation (RCA) gene cluster
Adv. Immunol.
(1989) - et al.
Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H’s cofactor activity enabling MCP-like cellular evasion of complement-mediated attack
J. Biol. Chem.
(2002)
Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function
J. Biol. Chem.
Complement factor H: sequence analysis of 221 kb of human genomic DNA containing the entire fH, FHR1 and FHR3 genes
Mol. Immunol.
Human factor H-related protein 5 (FHR5). A new complement-associated protein
J. Biol. Chem.
Factor H-related protein-5: a novel component of human glomerular immune deposits
Am. J. Kidney. Dis.
International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation
Lancet
Localization of the heparin-binding site on complement factor H
J. Biol. Chem.
Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A–I, phospholipid, and factor H-related proteins
J. Biol. Chem.
Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome
Am. J. Hum. Genet.
Molecular modelling of the C-terminal domains of factor H of human complement: a correlation between haemolytic uraemic syndrome and a predicted heparin binding site
J. Mol. Biol.
Familial hemolytic-uremic syndrome and homozygous factor H deficiency
Am. J. Kidney Dis.
Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners
J. Biol. Chem.
Cancer and diabetes: two pathological conditions in which adrenomedullin may be involved
Peptides
Combined kidney and liver transplantation for familial haemolytic uraemic syndrome
Lancet
Isolation and characterization of a novel rat factor H-related protein that is up-regulated in glomeruli under complement attack
J. Biol. Chem.
Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition
Am. J. Hum. Genet.
An integrated map of the human regulator of complement activation (RCA) gene cluster on 1q32
Mol. Immunol.
Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome
Am. J. Hum. Genet.
Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in Factor H.
Mol. Immunol.
The human factor H-related protein 4 (FHR4). A novel short consensus repeat-containing protein is associated with human triglyceride-rich lipoproteins
J. Biol. Chem.
Structural and functional analysis of the complement component factor H with the use of different enzymes and monoclonal antibodies to factor H
Biochem. J.
Solution structure of the fifth repeat of factor H: a second example of the complement control protein module
Biochemistry
Identification of the second heparin-binding domain in human complement factor H
J. Immunol.
M protein of the Group A Streptococcus binds to the seventh short consensus repeat of human complement factor H
Infect. Immun.
Identification of a heparin binding domain in the seventh short consensus repeat of complement factor H
J. Immunol.
The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20
J. Am. Soc. Nephrol.
Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease
Hum. Mol. Genet.
Role of the YadA protein in prevention of opsonization of Yersinia enterocolitica by C3b molecules
Infect. Immun.
Complement evasion by Echinococcus granulosus: sequestration of host factor H in the hydatid cyst wall
J. Immunol.
A radiation hybrid map of complement factor H and factor H-related genes
Immunogenetics
Human polymorphonuclear leukocytes adhere to complement factor H through an interaction that involves alphaMbeta2 (CD11b/CD18)
J. Immunol.
The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeats 13 to 15
Infect. Immun.
Human complement factor H: two factor H proteins are derived from alternatively spliced transcripts
Eur. J. Immunol.
Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of amplification C3 convertase of the alternative complement pathway
Proc. Natl. Acad. Sci. U.S.A.
Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer
Clin. Cancer Res.
Location of the complement factor H binding site on streptococcal M6 protein
Infect. Immun.
A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein
Eur. J. Immunol.
Identification of complement regulatory domains in human factor H
J. Immunol.
Pig complement regulator factor H: molecular cloning and functional characterization
Immunogenetics
Complement C3b/C3d and cell surface polyanions are recognized by overlapping binding sites on the most carboxyl-terminal domain of complement factor H
J. Immunol.
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