b Receptor

IFN/ Receptor S. Jaharul Haque1,2 and B. R. G. Williams1,* 1

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA 2 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA * corresponding author tel: 216-445-9652, fax: 216-444-3164, e-mail: [email protected] DOI: 10.1006/rwcy.2000.18002.

SUMMARY Interferons (IFNs) comprise a family of secreted proteins produced by a variety of vertebrate cells in response to viral and other microbial infections, and function as antiviral, antiproliferative, and immunomodulatory agents. IFNs bind to specific receptors on the surface of target cells and activate multiple intracellular signaling cascades including the JAK/STAT pathway which in turn activates the transcription of IFN-stimulated genes. Type I IFNs, including , , and !, bind to the same receptor that comprises two transmembrane subunits (IFNAR-1 and IFNAR-2) that are classified as type II cytokine receptors based on their amino acid sequence and structural features. These two proteins function in a species-specific fashion. IFNAR-1 and IFNAR-2 physically associate with TYK2 and JAK1 respectively that catalyze the tyrosyl phosphorylation of IFN-signaling proteins including JAK1, TYK2, IFNAR-1, IFNAR-2, STAT1, STAT2, and STAT3. Mice lacking the IFNAR-1 are completely unresponsive to type I IFNs and unable to combat viral infection.

BACKGROUND Interferons (IFNs) belong to the cytokine superfamily of secreted proteins that were originally identified as antiviral agents in 1957 by Isaacs and Lindenmann. Subsequent studies revealed that IFNs exert pleiotropic biological effects, all mediated through the activation of specific receptors on the cell surface (Pestka et al., 1987; Sen and Lengyel, 1992; Darnell et al., 1994; Uze et al., 1995; Domanski and Colamonici,

1996; Haque and Williams, 1998; Stark et al., 1998). IFNs are divided into two types: human type I IFNs include 13 nonallelic isoforms of IFN, one IFN , and one IFN! (Weissmann and Weber, 1986; Pestka et al., 1987; Sen and Lengyel, 1992; Haque and Williams, 1998). All type I IFNs compete for binding to the same receptor on the cell surface, known as type I IFN receptor or IFN/ receptor (Aguet et al., 1984; Merlin et al., 1985; Pestka et al., 1987; Uze et al., 1995; Haque and Williams, 1998). IFN binds to a distinct transmembrane receptor (Aguet et al., 1984; Pestka et al., 1987; Uze et al., 1995; Haque and Williams, 1998; Merlin et al., 1985). IFNs exhibit a high level of species-specificity with a few exceptions (Stwert, 1979; Uze et al., 1990; Novick et al., 1994; Domanski and Colamonici, 1996). Binding of IFNs to their receptors initiates signals that are transmitted from cell surface to the nucleus, resulting in the rapid induction of a number of IFN-stimulated genes (ISGs) in the absence of de novo protein synthesis (Sen and Lengyel, 1992; Darnell et al., 1994; Levy, 1995; Ihle, 1996; Haque and Williams, 1998). Each type of IFN induces a distinct set of genes with a certain degree of overlap (Sen and Lengyel, 1992; Darnell et al., 1994; Haque and Williams, 1998; Stark et al., 1998). Most of the IFN/ -responsive genes contain an enhancer element, termed the IFN-stimulated response element (ISRE) that binds to the transcription factor IFN-stimulated gene factor 3 (ISGF3), which is induced through an IFN/ -dependent activation of the Janus kinase/ signal transducer and activator of transcription (JAK/STAT) signal transduction pathway (Darnell et al., 1994; Levy, 1995; Ihle, 1996; Haque and Williams, 1998; Stark et al., 1998). The SH2 domaincontaining proteins STAT1 and STAT2 are

1846 S. Jaharul Haque and B. R. G. Williams phosphorylated at unique tyrosine residues by a pair of activated JAKs that are physically associated with the IFN receptor subunits (Darnell et al., 1994; Stark et al., 1998). This results in an SH2 domain± phosphotyrosine interaction-mediated formation of a STAT1/STAT2 heterodimer that migrates to the nucleus and binds with a member of the IFN regulatory factor (IRF) family protein p48 (ISFG3- ) to form the functional trimeric complex ISGF3 that binds to an ISRE to activate transcription (Darnell et al., 1994; Stark et al., 1998). A second set of genes, including major histocompatibility complexes, is induced as a delayed response that requires new protein synthesis (Pestka et al., 1987; Sen and Lengyel, 1992; Haque and Williams, 1998; Stark et al., 1998). The mechanisms of this delayed response to IFNs are not well understood, but in some cases IFNs may regulate gene expression at the posttranscriptional level (Stark et al., 1998). The proteins encoded by the IFN-regulated genes mediate multiple biological activities attributed to IFNs (Stark et al., 1998).

Discovery Early investigations using radiolabeled recombinant type I IFNs revealed the cell surface expression of both low-affinity and high-affinity receptors for type I IFNs (Aguet and Blanchard, 1981; Branca and Baglioni, 1981; Joshi et al., 1982; Hannigan et al., 1983, 1984, 1986; Aguet et al., 1984; Merlin et al., 1985; Raziuddin and Gupta, 1985; Zhang et al., 1986; Pestka et al., 1987; Vanden Broecke and Pfeffer, 1988; Sen and Lengyel, 1992; Faltynek et al., 1993). Studies on binding and crosslinking of radiolabeled IFNs to the cell surface suggested the existence of the multisubunit structure for the type I IFN receptors (Joshi et al., 1982; Aguet et al., 1984; Merlin et al., 1985; Raziuddin and Gupta, 1985; Hannigan et al., 1986; Zhang et al., 1986; Pestka et al., 1987; Vanden Broecke and Pfeffer, 1988; Sen and Lengyel, 1992; Faltynek et al., 1993). The existence of the multisubunit structure was later demonstrated using specific monoclonal antibodies to receptor subunits (Colamonici et al., 1990, 1992). The first receptor subunit to be cloned was the human IFNAR-1 (formerly known as IFN receptor  chain) (Uze et al., 1990). The cDNA encoding the human IFNAR-1 was isolated by an expression cloning strategy utilizing the species-specific recognition property of type I IFNs. This protein conferred resistance to vesicular stomatitis virus replication in mouse cells in the presence of human IFN8 (Uze et al., 1990). However, when the human IFNAR-1

cDNA was expressed in mouse cells, the protein could only bind to IFN8 at 37 C, but not to the other type I IFNs of human origin (Uze et al., 1990). The human IFN8 was later found to possess some binding affinity for mouse receptor (Domanski and Colamonici, 1996). Therefore, IFNAR-1 was not sufficient to confer responsiveness to all the type I IFNs, indicating that another species-specific ligandbinding receptor subunit was required for signal transduction (Uze et al., 1990; Domanski and Colamonici, 1996). The purification of human IFN-binding protein from urine and its amino acid sequence analyses led to the isolation of an 1.5 kb cDNA for a novel subunit of type I IFN receptor encoding 331 amino acids (Novick et al., 1994). However, this novel protein of 331 amino acids termed IFNAR-2B ( S subunit) was not a functional receptor subunit. A longer form of human IFNAR-2 encoding 515 amino acids, termed IFNAR-2C ( L subunit) was identified as the universal ligand-binding subunit of the type I IFN receptor (Zhang et al., 1986; Bazan, 1990; Colamonici et al., 1990, 1992; Domanski et al., 1995; Lutfalla et al., 1995).

Alternative names The receptor for the type I IFNs is also referred to as type I IFNR, IFNR, IFNR, and IFN/ R (Uze et al., 1995; Domanski and Colamonici, 1996). The first cloned subunit of the type I IFN receptor is IFNAR-1, which was initially termed IFNAR by Uze et al. (1990). It is identical to IFNR of the Colamonici group (Uze et al. 1995). The second subunit of type I IFN receptor, originally cloned by Novick et al. (1994), is IFNAR-2, which is also known as IFNR (Domanski et al., 1995). This subunit has three isoforms: IFNAR-2A, IFNAR-2B (also termed IFNR S), and IFNAR-2C, which is also known as IFNR L (Domanski et al., 1995; Lutfalla et al. 1995; Domanski and Colamonici, 1996).

Structure Cytokine receptors are transmembrane proteins with a single membrane-spanning region. Based on the amino acid sequence and structural features, cytokine receptors are divided into two classes (Bazan, 1990; Kishimoto et al., 1994; Heldin, 1995; Haque and Williams, 1998). While the majority of the cytokine receptors fall into class I, the receptors for IFN/ , IFN , and IL-10 as well as the tissue factor (a membrane receptor for the coagulation protease factor VII)

IFN/ Receptor 1847 belong to the class II cytokine receptor family (Bazan, 1990). The cytokine receptors contain one or two characteristic external domain structures (D200) consisting of two homologous subdomains (SD100) of  100 amino acids, each of which adopts an immunoglobulin-like fold with seven strands (s1±s7) organized into two sheets (Bazan, 1990). While the D200 module of class I receptors contains a set of four conserved cysteine residues and a WSXWS motif, the class II cytokine receptors share one cysteine pair with class I and contain an additional conserved cysteine pair, and several conserved proline and tryptophan residues, but lack the WSXWS motif (Bazan, 1990). The INFAR-1 chain of the receptor contains two D200 modules, while IFNAR-2 has one (Bazan, 1990; Gaboriaud et al., 1990; Thoreau et al., 1991). Human IFN2 binds to the human IFNAR-1 with low affinity, while it exhibits moderate binding affinity towards the bovine homolog of IFNAR-1. This has facilitated the analysis of IFN binding to IFNAR-1 (Rehberg et al., 1982; Zoon et al., 1982; Lundgren and Langer, 1997; Goldman et al., 1998). Binding of human IFN2 to bovine/human IFNAR-1 chimeras reveals that bovine SD2 and SD3 contain residues necessary but not sufficient for moderate-affinity ligand binding; SD1 and SD4 also contribute either directly or indirectly to ligand binding (Goldman et al., 1998). Mapping of epitopes for neutralizing monoclonal antibodies to IFNAR-1 also implicates direct roles for amino acid residues in all four subdomains of the IFNAR-1 molecule (Eid and Tovey, 1995; Goldman et al., 1998; Lu et al., 1998). The human IFNAR-2 binds to type I IFNs with moderate affinity (2±8 nmol/L; Novick et al., 1994; Domanski and Colamonici, 1996; Lewerenz et al., 1998). Mutant IFNAR-2 proteins generated by alanine substitutions of selected amino acids in two loop regions (amino acids 71±75 in s3±s4 and amino acids 103±106 in s5±s6) in the N-terminal subdomain confer complete resistance to IFN but not IFN binding when expressed in IFNAR-2-null human cell line U5A (Lewerenz et al., 1998). In contrast, unlike IFN, IFN binding to IFNAR-2 is sensitive to an alanine substitution of Try127 located in the intersubdomain link of the IFNAR-2 molecule (Lewerenz et al., 1998). Cytokines in general contain four main  helices labeled A through D connected by two long loops (AB and CD) and a short loop (BC) with an upup-down-down arrangement (Uze et al., 1995; Mitsui and Senda, 1997). IFNs having an additional helix (E) instead of CD loop constitute a subclass of cytokine with an up-up-down-up-down arrangement (Uze et al., 1995; Mitsui and Senda, 1997). At the amino

acid levels, different IFN  subtypes are  80% homologous, while the homology between the  subtypes and the subtype is about 35% (Pestka et al., 1987). The AB loop, C helix, and D helix are important for functional IFN binding to its receptors (Runkel et al., 1998). Mutational studies reveal that substitutions of amino acids that are highly conserved in the AB loop and D helix reduce the binding of IFN compared with that of IFN , suggesting a differential interaction of  and IFNs with their receptor (Runkel et al., 1998). It is evident that both IFN and IFN need to make physical contact with IFNAR-1 and IFNAR-2 for intracellular signal transduction, although IFNAR-1 seems to engage IFN quite differently than IFN (Novick et al., 1994; Cohen et al., 1995; Domanski et al., 1995; Lutfalla et al., 1995; Cutrone and Langer, 1997; Karpusas et al., 1997; Rani et al., 1996). This suggests that there are some functional differences between these two subtypes of IFNs at the level of receptor recognition. The three-dimensional structure of the cytoplasmic domain of cytokine receptors is not currently available. Most of the information on structure±function relationship has been derived from the receptor mutagenesis studies. Cytoplasmic domains of cytokine receptors are of variable lengths (Bazan, 1990; Uze et al., 1990; Kishimoto et al., 1994; Novick et al., 1994; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Domanski and Colamonici, 1996; Haque and Williams, 1998; Leonard and O'Shea, 1998; Stark et al., 1998). Many cytokine receptors contain two membrane proximal loosely conserved motifs, Box 1 and Box 2 (Bazan, 1990; Kishimoto et al., 1994; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Leonard and O'Shea, 1998).

Main activities and pathophysiological roles Protein tyrosine phosphorylation is a key reaction in the activation of cytokine and growth factor receptors (Velazquez et al., 1992; MuÈller et al., 1993; Watling et al., 1993; Kishimoto et al., 1994; Heldin, 1995; Ihle, 1995, 1996; Ihle and Kerr, 1995; Ihle et al., 1995; Krowlewski, 1995; Levy, 1995; Domanski and Colamonici, 1996; Haque and Williams, 1998; Leonard and O'Shea, 1998; Stark et al., 1998). Unlike most growth factor receptors, the cytokine receptors do not possess any cytoplasmic tyrosine kinase domain, rather they constitutively associate with members of Janus family tyrosine kinases that provide tyrosine kinase activity necessary for receptor activation and subsequent signal transduction

1848 S. Jaharul Haque and B. R. G. Williams (Velazquez et al., 1992; MuÈller et al., 1993; Watling et al., 1993; Kishimoto et al., 1994; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Domanski and Colamonici, 1996; Haque and Williams, 1998; Leonard and O'Shea, 1998; Stark et al., 1998;). After being activated by JAK-mediated tyrosine phosphorylation cytokine receptor subunits recruit a number of downstream signaling components through protein±protein interactions (Velazquez et al., 1992; MuÈller et al., 1993; Watling et al., 1993; Kishimoto et al., 1994; Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Domanski and Colamonici, 1996; Haque and Williams, 1998; Leonard and O'Shea, 1998; Stark et al., 1998). The type I IFN receptor subunits IFNAR-1 and IFNAR-2 constitutively associate with the Janus kinases TYK2 and JAK1 respectively (Velazquez et al., 1992; MuÈller et al., 1993; Watling et al., 1993; Domanski and Colamonici, 1996; Haque and Williams, 1998; Stark et al., 1998). TYK2 was the first member of the JAK family to be identified as an essential component of IFN signaling by the use of somatic cell genetic studies and subsequent investigations established the role of other JAKs in cytokine signaling (Velazquez et al., 1992). The C-terminal kinase domain (JH1) of JAKs shares sequence homology with the catalytic domains of other protein tyrosine kinases within the defined conserved (Ihle, 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Krowlewski, 1995; Wilks, 1995; Hanks et al., 1988; Leonard and O'Shea, 1998). Adjacent to the kinase domain JAKs have a pseudokinase (i.e. kinaserelated) domain (JH2) that has a number of sequence motifs characteristic of a catalytic domain but is missing some conserved amino acids including the catalytic aspartic acid (Ihle et al., 1995; Leonard and O'Shea, 1998). The precise function of the pseudokinase domain is not clear yet. The N-terminal half of the JAKs contains five regions (JH3±7) that share sequence homology among the Janus family members. In contrast, however, the extreme N-terminal region of each JAK protein is unique, and may confer the specificity in binding to the membrane-proximal regions of cytokine receptors (Ihle, 1995; Ihle et al., 1995; Leonard and O'Shea, 1998). TYK2-binding domain in IFNAR-1 protein has been mapped to a  33 amino acids membraneproximal region that comprises the Box 1 and Box 2 motifs (Domanski and Colamonici, 1996; Yan et al., 1996a). Almost all phylogenetically conserved residues in this region of IFNAR-1 are essential for TYK2 recognition (Domanski and Colamonici, 1996; Yan et al., 1996a). In contrast to other cytokine receptors, the Box 1 motif, which is not well conserved in IFNAR-1, does not play a critical role

in this protein±protein interaction (Domanski and Colamonici, 1996). The three amino acid residues Ile504, Leu505, and Glu506 in IFNAR-1 are essential for TYK2 binding (Colamonici et al., 1994a, 1994b; Domanski and Colamonici, 1996; Yan et al., 1996a). In vitro binding studies suggest that the N-terminal  600 amino acids containing JH7 to JH3 comprise the major binding site of TYK2 to the IFNAR-1 protein (Yan et al., 1998). Glutathione S-transferaseTYK2-JH3 or JH6 domain physically interacts in vitro with the IFNAR-1 protein, suggesting that JH3 and JH6 are the major sites of interaction of TYK2 with IFNAR-1 (Yan et al., 1998). A truncated TYK2 protein containing amino acids 1±601 can function in vivo as a dominant negative mutant kinase inhibiting IFN-dependent JAK/STAT signaling (Yan et al., 1998). Further mutagenesis studies have revealed that JH7 and a part of the JH6 domain containing amino acids 22±221 are essential for TYK2 binding to IFNAR-1 (Richter et al., 1998). Tyr466 and, to some extent, Tyr481 on human IFNAR-1 are phosphorylated by TYK2 and phospho-Tyr466 serves as a docking site for STAT2 (Krishnan et al., 1996, 1998; Yan et al., 1996b; Li et al., 1997; Richter et al., 1998; Nadeau et al., 1999). The SH2-containing protein tyrosine phosphatase SHP-2 preassociates with IFNAR-1 and is phosphorylated in response to IFN/ (David et al., 1995a). In transient transfection assays a dominant negative mutant SHP-2 inhibits IFN/ -induced expression of an ISRE-driven reporter gene, suggesting that SHP-2 may function as a positive regulator of type IFN signaling (David et al., 1995a). In contrast, SHP-1 negatively controls IFN/ signaling. Bone marrow-derived macrophages from viable moth-eaten mice (expressing mutant SHP-1 with substantially reduced phosphatase activity) exhibit enhanced IFN/ signaling compared with normal littermate control (David et al., 1995a). SHP-1 physically associates with IFNAR-1 in a ligand-regulated fashion (David et al., 1995a). Mutation of tyrosines to phenylalanines at positions 527 and 538 of IFNAR-1 enhances IFN signaling, suggesting that IFN/ signaling is negatively regulated through this region of IFNAR-1 (Gibbs et al., 1996). The cytoplasmic domains of IFNAR-2B and IFNAR-2C are divergent after the membrane-proximal 15 amino acids. Human IFNAR-2B contains two tyrosine residues (269 and 321) and no characteristic motifs of cytokine receptors and it does not interact with JAK1 (Domanski et al., 1995; Lutfalla et al., 1995; Domanski and Colamonici, 1996). Like IFNAR-2A, IFNAR-2B probably functions as decoy

IFN/ Receptor 1849 receptor for type I IFNs. In contrast, the cytoplasmic domain of human IFNAR-2C contains a Box 1 motif and seven tyrosine residues (269, 306, 316, 337, 411, and 512) and a number of acidic residues (Domanski et al., 1995; Lutfalla et al., 1995; Domanski and Colamonici, 1996). The JAK1-interaction domain of IFNAR-2 has been mapped to amino acids 300±346 (Domanski et al., 1996). The Box 1 motif in IFNAR-2 plays a minor role in JAK1 binding (Domanski et al., 1995; Lutfalla et al., 1995; Domanski and Colamonici, 1996). It has been demonstrated by indirect approaches using a JAK1±JAK2 chimeric protein that the JH3± JH7 of JAK1 is involved in the physical association with IFNAR-2 to elicit biological responses of type I IFNs (Kohlhuber et al., 1997). Both STAT1 and STAT2 physically associate with the IFNAR-2C protein in unstimulated cells, but the biological significance of the interaction is not clear (Stancato et al., 1996; Stark et al., 1998). Murine cells expressing human IFNAR-2C truncated at amino acid 417 show a marked decrease in IFN -mediated antiviral response without any defect in JAK/STAT signaling by both IFN and IFN (Platanias et al., 1998). Protein tyrosine phosphatase activity associated with the distal region of IFNAR-2C has been implicated in the negative regulation of the growth-inhibitory action of type I IFNs (Platanias et al., 1998). The mitogen-activated protein kinase (MAPK) is activated by IFN/ treatment of cells and ERK2 (p42-MAPK) associates with IFNAR-1 both in vitro and in vivo (David et al., 1995b). Binding of type I IFNs to receptor causes tyrosine phosphorylation of insulin receptor substrate 1 and subsequent activation of the phosphatidylinositol 3-kinase pathway, which requires functional JAK1 and TYK2 proteins (Pfeffer et al., 1997). However, the contribution of the PI-3 kinase pathway to the biological outcome of type I IFN action is not yet known (Wang et al., 1997). STAT3 is activated by type I IFNs and may serve as an adapter for the recruitment of PI-3 kinase in Daudi cells (Burfoot et al., 1997). Stimulation of cells with IFN causes a JAK1-dependent phosphorylation of cytosolic phospholipase A2 (cPLA2) and pretreatment of cells with inhibitors of cPLA2 inhibits the activation of ISGF3 but not GAF (STAT1 homodimer) formation (Flati et al., 1996). Moreover, JAK1 and cPLA2 can be co-immunoprecipitated from IFN-treated cell lysate (Flati et al., 1996). Type I IFNs also activate p38 mitogen-activated kinase (p38 MAPK) and this is essential for cPLA2-dependent ISGF3 formation (Goh et al., 1999; Uddin et al., 1999). IFNAR-1, IFNAR-2C, JAK1, and TYK2 are known to form the functional type I IFN receptor

complex (Darnell et al., 1994; Uze et al., 1995; Domanski and Colamonici, 1996; Haque and Williams, 1998; Stark et al., 1998). However, differences have been observed between cell signaling by IFN and IFN . Interestingly, U1A cells which are completely defective in response to recombinant IFN1, IF-2, or a mixture of natural IFNs, retain a partial response to IFN (Pellegrini et al., 1989). But none of the mutant cell lines lacking JAK1, STAT1, or STAT2 exhibits any IFN response, suggesting that TYK2 activity is not absolutely required for IFN signaling (Stark et al., 1998). U1A cells express low levels of IFNAR-1 which is not stably maintained at the plasma membrane. Therefore, in U1A cells IFN likely signals through the IFNAR-2 dimer (Lewerenz et al., 1998). Reconstitutions of U1A cells with mutant TYK2 proteins reveal that TYK2 N-terminal domain is required to maintain functional IFNAR-1, JH2 (pseudokinase) domain is necessary for high-affinity ligand binding and JH1(kinase) domain phosphorylates IFNAR-1 which is dispensable for JAK/STAT signaling by IFN or IFN (Pellegrini et al., 1989; Velazquez et al., 1992; Richter et al., 1998; Rani et al., 1999). Recently it has been demonstrated that the IFNAR-1 and TYK2 expression is coordinately regulated in cells (Gauzzi et al., 1997). This is consistent with the model that IFN interacts with the receptor in a manner that is different from that of IFN (Pellegrini et al., 1989; Velazquez et al., 1992; Lewerenz et al., 1998; Stark et al., 1998; Rani et al., 1999). IFN2 and IFN may require distinct cytoplasmic regions of IFNAR-2C to elicit an antiviral response. IFNAR-2C is phosphorylated at comparable levels in response to IFN and IFN ; however, the IFNAR1/ IFNAR-2C complex can be immunoprecipitated only from the IFN -treated but not IFN-treated cells (Croze et al., 1996; Platanias et al., 1996). Identification of the -R1 gene which shows a selective induction by IFN compared with IFN by Rani et al. has provided further evidence that IFN may use a distinct pathway for cell signaling (Rani et al., 1996). IFN shares only 35% identity with the IFN subtypes, and appears to engage the / receptor differently. This can result in the activation of selective subsets of genes by IFN (Der et al., 1998), even though it binds and activates the same receptor. Apparently distinctive structural differences are transmitted through the membrane to the cytoplasmic domains of the receptors that then mediate a differential response. Mutant cell lines lacking TYK2 which are completely defective in their response to IFN2 still respond to IFN or 8, albeit with reduced activity. In fact, using these and other mutant

1850 S. Jaharul Haque and B. R. G. Williams cell lines reconstituted with different mutant proteins, three distinct modes of type I interactions with receptor subunits have been discerned: IFN with IFNAR-1 and IFNAR-2, IFN with IFNAR-1, and IFNAR-2 and IFN with IFNAR-2 only (Lewerenz et al., 1998). Thus IFN and signal differently through their receptors because they interact with the receptor in different ways. There is a tight correlation between receptor occupancy and the transcriptional response to IFN (Hannigan and Williams, 1986). The degree of receptor occupancy is a ratelimiting step in determining the transcriptional response to IFN which is transient and is accompanied by the downregulation of receptors on the cell surface. Downregulation of type I IFN receptors is also seen in vivo on peripheral blood lymphocytes following IFN therapy (Lau et al., 1986). This is a temporary state and receptors reappear on the surface over 24±48 hours.

GENE

Accession numbers Human IFNAR-1 cDNA: J03171 Human IFNAR-1 gene: X60459 Mouse IFNAR-1 cDNA: M89641 Bovine IFNAR-1 cDNA: L06320 Sheep IFNAR-1 cDNA: U65978 Human IFNAR-2.2 cDNA: L41942 Mouse IFNAR-2 cDNA: Y09813 Mouse IFNAR-2B cDNA: Y09864 Mouse IFNAR-2C cDNA: Y09865 Sheep IFNAR-2 cDNA: U65979

Chromosome location and linkages The human IFNAR-1 gene comprises 11 exons covering a 32.9 kb region on chromosome 21q22.1 (Lutfalla et al., 1990, 1992). The human IFNAR-2 gene is also located on human chromosome 21q22.1 (Lutfalla et al., 1995). The murine IFNAR gene is located on chromosome 16. The genes encoding two other members of the class II cytokine receptors, namely IFNGR-2 and CRF2±4, are also mapped to chromosome 21q22.1 within a  300 kb span (Hertzog et al., 1994; Rubinstein et al., 1998). IFNGR-2 is the second chain of IFN receptor and recently the orphan receptor CRF2±4 has been shown to encode the second chain of IL-10 receptor (Spencer et al., 1998; Reboul et al., 1999).

PROTEIN

Accession numbers Bovine IFNAR-2: Q95141 Human IFNAR-2: P48551 Sheep IFNAR-2: Q95207 Human IFNAR-1: P17181 Sheep IFNAR-1: Q28589, Q95206 Bovine IFNAR-1: Q04790 Mouse IFNAR-1: P33896

Description of protein See Structure. Both N- and O-linked glycosylation of the IFNAR1 has been demonstrated (Novick et al., 1992; Platanias et al., 1993; Constantinescu et al., 1995; Ling et al., 1995).

Relevant homologies and species differences The receptor subunits are species-specific (Uze et al., 1990; Domanski and Colamonici, 1996; Stark et al., 1998).

Affinity for ligand(s) See Structure.

Cell types and tissues expressing the receptor The IFNAR subunits are expressed in all tissues. Soluble IFNAR-1 and IFNAR-2 are present in human body fluids (Novick et al., 1992, 1994).

Regulation of receptor expression Recent study shows that TYK2 protein can regulate the expression and ligand-binding activity of IFNAR-1 protein (Gauzzi et al., 1997). Binding studies with iodinated IF2 and Scatchard plot analysis reveal that monocyte differentiation to macrophages results in a 3- to 4-fold increase in cell surface receptors with no change in their affinity (Eantuzzi et al., 1997).

IFN/ Receptor 1851

BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY

Phenotypes of receptor knockouts and receptor overexpression mice Mice lacking the IFNAR-1 were completely unresponsive to type I IFNs. These animals showed no overt abnormalities but were unable to cope with viral infection (Muller et al., 1994; Steinhoff et al., 1995; Van den Broek et al., 1995a, 1995b). Despite compelling evidence for modulation of cell proliferation and differentiation by type I IFNs, there were no gross signs of abnormal fetal development or morphological changes in adult IFNAR-1-deficient mice (Hwang et al., 1995). However, abnormalities of hematopoietic cells were detected in these animals.

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