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FHL-1/reconectin: a human complement and immune regulator with cell-adhesive function

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Abstract

A novel regulator of the alternative complement pathway with functions similar to that of factor H has been identified in human plasma. The cDNA encoding this factor H-like protein 1 (FHL-1/reconectin) was isolated several years ago. Here, Peter Zipfel and Christine Skerka describe functional analyses revealing that this novel complement regulatory protein forms a molecular link between immune defense and cell adhesion.

Section snippets

Detection of FHL-1/reconectin in plasma

Owing to their low molecular weight and their reactivity with factor H antiserum, FHL-1/reconectin and other factor H-related plasma proteins were initially considered to be degradation products of the 150 kDa factor H protein. The unambiguous identification of the 42 kDa FHL-1/reconectin protein in human plasma was hampered by the existence of a second immunologically related protein with similar mobility. However, the reported functional differences, i.e. cofactor activity in the cleavage of

Structure of FHL-1/reconectin

The isolated near full-length CHH17/pFH1.8 cDNA is 1654 bp in length, representing a 5′ untranslated region of 73 bp, an open reading frame of 1347 bp and a 3′ untranslated region of 234 bp that is followed by a polyA tail.

The 5′ 1398 nucleotides of the CHH17/pFH1.8 cDNA, which represent the 5′ untranslated region and most of the coding region, are identical to the 5′ nucleotide sequence of factor H (3, 4). The remaining 256 bp are unique and specific for the FHL-1/reconectin transcript. This

Expression and distribution of FHL-1/reconectin

The FHL-1/reconectin protein is present in human plasma at a physiological concentration of 10–50 μg ml−1. This concentration is comparable to that of factor I or clusterin; however it is about 10–50 times lower than that of factor H. Northern blot experiments show expression of a 1.8 kb CHH17/pFH1.8 transcript in human liver, demonstrating expression of the FHL-1/reconectin protein in hepatic cells. Expression of a 1.8 kb transcript hybridizing with factor H-derived cDNA probes has also been

Genomic structure and organization

FHL-1/reconectin and factor H mRNAs have identical 5′ sequences; thus, they apparently use the same transcriptional initiation site but are processed to different downstream exons to produce unique 3′ ends. The complete genomic structure of the human factor H gene has not yet been described although it is known to be located on chromosome 1 within the gene cluster encoding the regulators of complement activation (RCA)25, 26. The structure and organization of the murine factor H gene shows that

Function of FHL-1/reconectin and mapping of functional domains

The sequence overlap between FHL-1/reconectin and factor H suggests functional similarity of these two plasma proteins. Both proteins have identical regulatory roles in the alternative complement pathway as they tightly control C3 activation by displaying cofactor and decay acceleration activity10, 28, 29, 30 (Fig. 3). In addition, FHL-1/reconectin plays a unique role in cell adhesion and microbial pathogenesis that is not shared by a factor H protein purified from human plasma31. Given the

Functional comparison of FHL-1/reconectin and factor H

Both FHL-1/reconectin and factor H display regulatory activities in the alternative complement pathway, a control system that acts as an important defense mechanism against foreign cells and bacteria39, 40, 41, 42. Uncontrolled activation of this pathway results in C3b deposition and is followed by cell lysis or by opsonization and phagocytosis (Fig. 3). The alternative complement pathway is negatively controlled, i.e. its default setting is continuous activation, leading to damage of cells and

Conclusions

The FHL-1/reconectin protein is a multifunctional multidomain plasma protein that acts as a molecular link between immune defense and cell adhesion. FHL-1/reconectin has regulatory activities in the alternative complement pathways in that it acts as cofactor for factor I-mediated degradation of C3b, shows decay-accelerating activity in the dissociation of C3b, Bb convertases, provides a surface to which anchorage-dependent cells can attach and grow and also plays a role in microbial

Acknowledgements

We thank the members of our laboratory for helpful discussions, J. Hellwage for a review of the manuscript, R. Sim for sharing unpublished data on the factor H gene, and J. Lundgreen for an intriguing and fascinating perspective of light and space. The authors' work is supported by the Deutsche Forschungsgemeinschaft (DFG) and the DAAD.

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