The IFNAR chain of the type I interferon (IFN)

No abstract

The type I interferon (IFN) receptor complex is assumed to be composed of multiple protein subunits. Recently, two proteins have been identified as potential receptor components, both of which share a high degree of structural homology with the immunoglobulin superfamily. One of these proteins, referred to as the human interferon ␣ receptor (IFNAR), has been shown to be involved in interferon signal transduction, but it does not bind IFN with high affinity. A second putative receptor protein, named FLP40, has been cloned from hu- Ligand-receptor cross-linking experiments (1, 2) suggest that a functional type I interferon (IFN)1 receptor complex is comprised of multiple components much like that of the previously described IFN-␥, interleukins, and granulocyte-macrophage colony-stimulating factor receptor families (3-6). However, the identity and mechanism of interaction between proteins comprising the human type I IFN receptor is unclear. Two proteins have recently been identified as potential components of the human type I IFN receptor complex (7,8). One, the human interferon ␣ receptor (IFNAR) was identified by its ability to reconstitute an antiviral response to IFN-␣8 in a murine cell line (7, 9). Monoclonal antibodies directed against the extracellular region of IFNAR have been shown to block the antiviral activity of a number of type I IFNs (10). It appears, however, that neither human IFNAR nor the purified extracellular domain of IFNAR is able to mediate high affinity binding (11,12). Although Daudi cells, from which IFNAR was cloned, bind high levels of type I IFN at 20°C, murine cells expressing human IFNAR could only be demonstrated to bind ligand at 37°C in which binding values were expressed as cellular uptake rather that direct receptor binding (7). Indeed, it was later shown that murine cells expressing IFNAR did not bind detectable levels of type I IFN when ligand binding was measured under conditions which minimized endocytosis (11). Recent studies in which human IFNAR was expressed in Xenopus laevis oocytes (13) confirmed the notion that IFNAR alone binds type I IFN with very low affinity. Finally, it has been shown that IFNAR becomes phosphorylated by IFN-␣ and IFN-␤ but not IFN-␥ in a ligand-dependent manner demonstrating again its involvement in type I IFN signaling (14).A second IFN receptor protein, P40, identified by Novick et al. (8), was purified as a soluble protein from human urine by its ability to bind to an IFN-␣2 affinity column. A variation of this protein also appears as a membrane-bound form in Daudi cells where it contains a transmembane and cytoplasmic domain (8). We refer to the membrane-bound form of this protein as full-length P40 (FLP40). Antibodies directed against the soluble form of this protein block the antiviral activity of a number of human type I IFNs on human WISH cells (8). Although P40 binds to immobilized IFN-␣2, it appears to do so with only low affinity. This is implied by the observation that the membrane-bound form of this protein when expressed on murine...