Fibrinogen-like protein 2 (FGL2), also known as fibroleukin, was first cloned from cytotoxic T lymphocytes and was classified as a member of the fibrinogen superfamily due to its homology (36%) with fibrinogen β and γ chains (Koyama et al., PNAS, 1987). The fgl2 gene, which has been localized to chromosome 7 and 5 in humans and mice, is composed of two exons that are separated by one intron. The fgl2 promoter contains cis element consensus sequences for the binding of various transcription factors, including Ets, AP1, Sp1, TCF1, Ikaros and CEBP (Yuwaraj et al., Genomics, 2001).
The fgl2 gene encodes a protein of 432 amino acids in mice and 439 amino acids in humans. The deduced protein sequence contains a predicted signal peptide, five N-linked glycosylation sites and conserved cysteine residues. Under non-reducing conditions the molecular mass of the protein is 250-300 kDa and in reducing condition it is 64-70 kDa, indicating that FGL2 in its natural state forms a tetrameric complex (Liu et al., Eur. J. Immunol., 2008; Marazzi et al., J. Immunol., 1998). Based on sequence and structural analysis, it is predicted that the encoded protein is composed of two major regions, the N-terminal domain and the carboxyl-terminus. The N-terminal domain is proposed to have a linear conformation due to the presence of α-helical region and several conserved cysteine residues, which can promote coiled-coil formation. The 229-amino-acidlong carboxyl-terminus consists of a highly conserved globular domain, known as the fibrinogen-related domain (FRED) that is characteristic of the fibrinogenrelated protein superfamily. The overall identity between the mouse and human FGL2 is 78%, but within the FRED domain the two proteins share 90% homology (Levy et al., Am. J. Pathol., 2000).
In reticuloendothelial (macrophages and endothelial cells), FGL2 is expressed as a membrane-associated protein, which acts as a prothrombinase enzyme with the ability to generate thrombin directly from prothrombin (Chan et al., J. Immunol., 2002). By a combination of site-directed mutagenesis and production of truncated proteins, it was shown that the serine 89 residue of the N-terminal domain is critical for the procoagulant function of the molecule (Chan et al., J. Immunol., 2002). FGL2 prothrombinase activity has been implicated in the pathogenesis of various human and experimental models (Clark et al., Mol. Hum. Reprod., 2004; Ghanekar et al., J. Immunol., 2004; Marsden et al., JCI, 2003; Mendicino et al., Circulation, 2005).
FGL2 also exists as a secreted form expressed by regulatory T cells that down-regulates DC activity and induces B cell apoptosis (Chan et al., J. Immunol., 2003; Marazzi et al., J. Immunol., 1998; Shalev et al., J. Immunol., 2008; Shalev et al., Hepatology, 2009). The C terminal globular portion of FGL2 has been suggested to account for the immunomodulatory function of the molecule (Chan et al., J. Immunol., 2003). FGL2 exerts its regulatory activity by binding to the Fc gamma receptors (FcγR) that are expressed on antigen presenting cells (Liu et al., Eur. J. Immunol. 2008). The regulatory activity of FGL2 has been implicated in inhibition of allograft rejection (Liu et al., 2008) and autoimmunity (Shalev et al., J. Immunol. 2008) and the pathogenesis of experimental and human viral infections, including in patients with HIV, SARS and hepatitis B and C virus (Chen et al.,Clin. Infect. Dis., 2006; Li et al., J. Immunol., 2009; Marsden et al., JCI, 2003; Shalev et al., Hepatology, 2009, Foerster et., J. Hepatology, 2010).