Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan;313(1):25-45.
doi: 10.1111/imr.13166. Epub 2022 Nov 16.

The Factor H protein family: The switchers of the complement alternative pathway

Laura Lucientes-Continente  1 , Bárbara Márquez-Tirado  1 , Elena Goicoechea de Jorge  1
Affiliations
Review

The Factor H protein family: The switchers of the complement alternative pathway

Laura Lucientes-Continente et al. Immunol Rev. 2023 Jan.

Abstract

The factor H (FH) protein family is emerging as a complex network of proteins controlling the fate of the complement alternative pathway (AP) and dictating susceptibility to a wide range of diseases including infectious, inflammatory, autoimmune, and degenerative diseases and cancer. Composed, in man, of seven highly related proteins, FH, factor H-like 1, and 5 factor H-related proteins, some of the FH family proteins are devoted to down-regulating the AP, while others exert an opposite function by promoting AP activation. Recent findings have provided insights into the molecular mechanisms defining their biological roles and their pathogenicity, illustrating the relevance that the balance between the regulators and the activators within this protein family has in defining the outcome of complement activation on cell surfaces. In this review we will discuss the emerging roles of the factor H protein family, their impact in the complement cascade, and their involvement in the pathogenesis of complement-mediated diseases associated with the AP dysregulation.

Keywords: FHL-1; FHRs; Factor H; alternative pathway; complement.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
The FH family. (A) Genomic organization of CFH‐CFHR1‐5 within chromosome 1q32. Each gene is represented by an arrow. Large genomic duplications are depicted by colored boxes underneath. Vertical lines represent the position of exons in each gene. (B) Schematic representation of the different proteins composing the FH protein family. SCR domains are represented by circles and potential glycosylation sites (purple rhombus) are indicated for each protein. The proteins are aligned according to the conservation with FH, and the numbers above the SCRs of the FHRs indicate the percentage of amino acids that are identical to the corresponding amino acids in FH. FH and FHL‐1 are identical in their sequences, except for the last 4 amino acids (SFLT) in FHL‐1 SCR7 (grey square) that are not present in FH. FH N‐terminal SCR1‐4 domains are involved in complement regulatory activities (red box), while SCR6‐8 and the C‐terminal SCR18‐20 are domains involved in surface recognition (green boxes). Notably, the FHRs share a varying degree of conservation with the FH surface recognition domains, but none of the FHRs have homologous SCRs to the FH regulatory domains. In this panel, the two common allelic variants of FHR‐1, A and B, are depicted. (C) Alignment of FHR1, FHR‐2 and FHR‐5 shows high sequence similarity in their N‐terminal SCR1‐2 domains as illustrated by the numbers denoting the percentage of identical amino acids between proteins. SCR domains 1 and 2 in FHR‐1, −2 and − 5 contain a shared dimerization motif. (D) Alignment of FHR‐3 and FHR‐4 illustrating high amino acid sequence similarity in their C‐terminal domains
FIGURE 2
FIGURE 2
Structural features of a conserved dimerization motif in the SCR1‐2 domains of FHR‐1, −2 and – 5. (A) X‐ray crystal structure of recombinant SCR‐1 and SCR‐2 of FHR‐1 (FHR‐11–2, PDB 3zd2) demonstrates the formation of a head‐to‐tail dimer between two copies of FHR‐11–2. SCR1 domains are depicted in dark gray and SCR2 domains in light gray. Residues that play key roles in stabilizing the assembly (Tyr34, Ser36, and Tyr39) are indicated in dark blue and other interface residues are indicated in light blue. (B) Alignment of the amino acid sequences of SCR‐1 and SCR2 of FHR‐1, −2 and − 5. As above, dark blue and light blue boxes indicate the key amino acids in stabilizing the complex and other interface residues, respectively. Residues indicated in red are non‐conservative variations between the three proteins, whilst the yellow ones indicate conservative variations. (C) Mapping of the sequence variations between FHR‐1, −2 and − 5 in the crystal structure of FHR‐11–2. As above, residues depicted in red are non‐conservative variations and the yellow residues are conservative variations. Variations in the interface residues are indicated by an asterisk (*). Figures in a and c were drawn using program PyMol, www.pymol.org. (D) Schematic illustration of the potential homodimers, heterodimers and multimers of FHR‐1, −2 and − 5 that can be found in plasma. While homodimeric species of these proteins and the heterodimer between FHR‐1 and FHR‐2 are generally accepted, there is some controversy on whether FHR‐5 can form any heterodimer or whether these proteins form higher order complexes and further studies will be needed to clarify this issue,
FIGURE 3
FIGURE 3
Host ligands identified for the FH protein family. For those ligands for which the binding site within the molecules is known, the SCRs involved in the binding are indicated by horizontal lines. In the cases where the binding sites are unknown, the ligands are framed in boxes. Abbreviations are as follows: CRP, C‐reactive protein; PTX3, Pentraxin III; ECM, components of the extracellular matrix; EMR2, adhesion G protein‐coupled receptor E2; GAGs, glycosaminoglycans; HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low‐density lipoprotein; MAA, Malondialdehyde‐acetaldehyde adducts; MDA, malondialdehyde; NETs, Neutrophil Extracellular Traps; PRELP, leucine‐rich repeat protein
FIGURE 4
FIGURE 4
Schematic representation of complement alternative pathway activation in the fluid phase and on cell surfaces and its regulation by the FH family proteins. In the absence of complement regulators, activation of the alternative pathway (AP) results in the formation of C3 convertases (C3bBb) that cleave the C3 molecule, creating a self‐amplification loop and thus amplifying complement activation in fluid phase and on surfaces. On surfaces, AP amplification leads to the generation of C5 convertases (C3bBbC3b), which, in turn, cleaves C5 into C5a and C5b triggering inflammation and allowing MAC formation, respectively. Regulation of the AP amplification loop and the deposition of C3b on the surface is key for controlling homeostasis. FH is the main regulator of the AP both in the fluid phase and on cell surfaces. It acts as a cofactor for factor I proteolytic cleavage of C3b, accelerates the dissociation of the C3/C5 convertases and competes with factor B for C3b binding. While FH displays AP inhibiting activities, the FHRs may display both inhibiting and promoting AP activities. FHR‐1 and FHR‐5 have been shown to act as inhibitors of the C5 convertases, although the physiological relevance of this activity is not known. Conversely, surface‐bound FHRs such as FHR‐1, FHR‐4 and FHR‐5 have been shown to bind C3b from the fluid phase and to serve as a platform for the assembly of the C3 convertase (C3bBb) promoting AP activation. The binding of the FHRs to surfaces can be mediated through deposited‐C3 activated fragments (C3b, iC3b, C3dg, C3g). Additionally, surface‐bound FHR‐1 can recruit native C3 to the surface, increasing the local concentration of C3 and thus favoring AP activation towards the surface. Abbreviations for complement proteins depicted in the figure are: FB, factor B; FH, factor H; FHR‐1 and FHR‐5, factor H‐related protein 1 and 5; MAC, membrane attack complex. Figure created with BioRender.com
FIGURE 5
FIGURE 5
Regulation of AP activation on cell surfaces by the FH protein family under physiological and pathological conditions. The figure depicts different physiological cell surfaces such as a normal host cell and an apoptotic/necrotic cell, as well as different pathological scenarios including infections (pathogen) and the complement‐mediated renal diseases associated with AP dysregulation including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and IgA nephropathy (IgAN). On host cells, any accidental deposition of C3b is rapidly inhibited by FH, as the regulatory activity of FH is very efficient in the presence of sialic acids and is not interfered by the FHRs (they can neither deregulate FH nor promote AP activation). Apoptotic and necrotic cells require an efficient and silent removal by opsonophagocytosis without causing excessive inflammation and tissue damage. The exposure of certain molecules on its surface such as pentraxins (CRP and PTX3) and DNA, which are shared ligands between FH and FHR‐1 and FHR‐5, allows a FH/FHR competition that may be beneficial for the correct opsonization of the cells. In contrast to host surfaces, pathogens lack 2,3´sialic acid‐containing glycosaminoglycans and, hence, FH does not regulate C3b molecules that may deposit on their surface. Thus, AP activation gets amplified, and unhindered complement activation occurs to eliminate the infection. In aHUS, genetic alterations in the CFH/CFHR1‐5 cause AP dysregulation on glomerular endothelial cells. Prototypical aHUS‐associated mutations include missense mutations at the C‐terminal of either FH or FHR‐1, which results in a FH that cannot regulate efficiently surface‐bound C3b or in an FHR‐1 protein that acquires the ability to bind to sialic acids and thus, can out‐compete FH for the binding of C3b preventing FH regulation (deregulation activity). IgAN and C3G conditions reflect scenarios where host cell surfaces or host surfaces such as the glomerular basement membrane become altered because of the deposition of immune complexes or C3 activated fragments (C3b, iC3b, C3dg, C3d), which are the perfect substrates where FHRs would bind promoting AP activation. The pathogenic mechanism in these cases probably implies a functional competition between FH and the FHRs, where the regulatory activity of FH is overwhelmed by the promotion of AP activation by the FHRs. Figure created with BioRender.com
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785‐797. - PMC - PubMed
    1. Bexborn F, Andersson PO, Chen H, Nilsson B, Ekdahl KN. The tick‐over theory revisited: formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb). Mol Immunol. 2008;45(8):2370‐2379. - PMC - PubMed
    1. Harboe M, Mollnes TE. The alternative complement pathway revisited. J Cell Mol Med. 2008;12(4):1074‐1084. - PMC - PubMed
    1. Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin Exp Immunol. 2004;138(3):439‐446. - PMC - PubMed
    1. de Cordoba SR, Tortajada A, Harris CL, Morgan BP. Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology. 2012;217(11):1034‐1046. - PubMed

Publication types

MeSH terms

Substances