2007/05/15 by Nicole A. de Weerd, Shamith Samarajiwa, Paul J. Hertzog · 1 citation
Medicine · Immunology and Microbiology · #Cytokine Signaling Pathways and Interactions #interferon and immune responses #Immune Response and Inflammation
paper · pdf · doi:10.1074/jbc.r700006200
openalex publication_date 2007/05/15 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
The type I interferon (IFN) 2The abbreviations used are: IFN, interferon; IFNAR, type I IFN receptor; IFNGR, type II IFNγ receptor; hu, human; hCR, helical cytokine receptor; ECD, extracellular domain; FBN, fibronectin; TF, tissue factor; SD, subdomain; PDB, Protein Data Bank; IL, interleukin; aa, amino acid(s); s (sIL, sIFN), soluble; JAK, Janus kinase; STAT, signal transducers and activators of transcription. receptor (IFNAR) is comprised, as other cytokine receptors, of multiple components, in this case designated IFNAR1 and IFNAR2. However it is unique among cytokine receptors in the number of cognate ligands, including 13 IFNα subtypes, β, ω, ∊, κ, and others in some species. The type I IFN receptors are distinct from those required for the type II IFNγ (IFNGR1 and IFNGR2) and type III IFNs (IFNLR and IL10Rβ). Nevertheless, genes encoding a component of each type of IFN receptor, namely IFNAR1, IFNAR2, IFNGR2, and IL10Rβ, are located on human chromosome 21q22.1 in a cytokine receptor gene cluster, as typical of functionally related genes. Although IFNs were identified 50 years ago and the existence of IFN receptors 10 years later, it was in 1990 when the first type I IFN receptor, now designated IFNAR1, was cloned. This was achieved utilizing human gene libraries expressed in murine cells and rescue of the definitive, species specific antiviral activity of human IFNα8 (1Uze G. Lutfalla G. Gresser I. Cell. 1990; 60: 225-234Abstract Full Text PDF PubMed Scopus (513) Google Scholar). IFNAR2 cloning was achieved first by identifying a human IFN binding activity in urine, peptide sequencing, and then by gene library screening with derived oligonucleotides (2Novick D. Cohen B. Rubinstein M. Cell. 1994; 77: 391-400Abstract Full Text PDF PubMed Scopus (585) Google Scholar). It was subsequently discovered that the original cDNA encoded only one isoform of the IFNAR2 gene, which also encoded a long transmembrane isoform that transduced a signal, a truncated transmembrane isoform, and a soluble/secreted isoform (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar) (Fig. 1A). Subsequently, the functions of the type I IFN receptors have been elucidated with respect to ligand interaction, mechanisms of signal transduction, and biological responses. The pioneering studies that discovered IFNARs and their mechanisms of actions in vitro have been largely validated in vivo using genetargeted mice. This body of work has highlighted the important roles of IFNARs in mediating type I IFN responses in hemopoiesis and innate and acquired immunity to infection and cancer. However, IFNs elicit many biological effects that can even be opposite in different cell types. For example, type I IFN inhibits proliferation and is proapoptotic for many cell types (4Platanias L.C. Nat. Rev. Immunol. 2005; 5: 375-386Crossref PubMed Scopus (2372) Google Scholar), yet it prolongs the survival of memory T cells (5Tough D.F. Sun S. Zhang X. Sprent J. Immunol. Rev. 1999; 170: 39-47Crossref PubMed Scopus (93) Google Scholar). Understanding the function of the IFNAR complex will elucidate how such a diversity of biological outcomes is generated. The IFNAR genes encode multiple isoforms that contribute to the potential complexity of the functional receptor (2Novick D. Cohen B. Rubinstein M. Cell. 1994; 77: 391-400Abstract Full Text PDF PubMed Scopus (585) Google Scholar, 3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar, 6Owczarek C.M. Hwang S.Y. Holland K.A. Gulluyan L.M. Tavaria M. Weaver B. Reich N.C. Kola I. Hertzog P.J. J. Biol. Chem. 1997; 272: 23865-23870Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). Two splice variants of IFNAR1 have been identified in cell lines (7Abramovich C. Ratovitski E. Lundgren E. Revel M. FEBS Lett. 1994; 338: 295-300Crossref PubMed Scopus (29) Google Scholar, 8Cook J.R. Cleary C.M. Mariano T.M. Izotova L. Pestka S. J. Biol. Chem. 1996; 271: 13448-13453Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). However, subsequent bioinformatic analyses of splice variants in expressed sequence tag (EST) data bases and rapid amplification of cDNA ends (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar′-RACE) analyses from normal cells identified only one isoform, suggesting that the former are either artifacts or aberrant transcripts found only in particular tumor cell lines. 3S. A. Samarajiwa and P. J. Hertzog, unpublished data. In contrast, four IFNAR2 transcripts encoding three isoforms are generated from the same gene by exon skipping, alternative splicing, and differential usage of polyadenylation sites (3Lutfalla G. Holland S.J. Cinato E. Monneron D. Reboul J. Rogers N.C. Smith J.M. Stark G.R. Gardiner K. Mogensen K.E. EMBO J. 1995; 14: 5100-5108Crossref PubMed Scopus (227) Google Scholar) (Fig. 1A) These transcripts encode a long trans-membrane IFNAR2c, a short transmembrane IFNAR2b chain, and a soluble sIFNAR2a chain. Transfection of human IFNAR1 and IFNAR2c, but not IFNAR2b, reconstituted the antiviral IFN response (9Cohen B. Novick D. Barak S. Rubinstein M. Mol. Cell. Biol. 1995; 15: 4208-4214Crossref PubMed Scopus (152) Google Scholar). This is consistent with data, at least in sarcomas, that IFNAR2b may act as a dominant negative regulator of IFN responses (10Gazziola C. Cordani N. Carta S. De Lorenzo E. Colombatti A. Perris R. Int. J. Oncol. 2005; 26: 129-140PubMed Google Scholar) (Fig. 1B). The mouse has been the primary model for pathophysiological studies of IFNs due to the capability of generating knockout mice, which can demonstrate cause-and-effect associations in vivo. The mouse has a comparable type I IFN system to human with multiple ligands (α, β, ∊, etc.) and Ifnar1 and Ifnar2 genes (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, 12Hardy M.P. Sanij E.P. Hertzog P.J. Owczarek C.M. Mamm. Genome. 2003; 14: 105-118Crossref PubMed Scopus (15) Google Scholar). No IFNAR2b chain has been identified in mouse, but two transcripts capable of encoding soluble isoforms (sIfnar2a and sIfnar2a′) are generated by differential splicing. The more abundant 1.5-kb sIfnar2a transcript encodes the complete IFNAR2 extracellular domain and reads through the splice site on the exon 7–7′ boundary producing a transcript encoding 12 unique and mostly hydrophobic C-terminal residues (6Owczarek C.M. Hwang S.Y. Holland K.A. Gulluyan L.M. Tavaria M. Weaver B. Reich N.C. Kola I. Hertzog P.J. J. Biol. Chem. 1997; 272: 23865-23870Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The sIfnar2a′ minor transcript is generated from a transcript missing 128 nucleotides after codon 236 of the Ifnar2 cDNA. This isoform originates by skipping the transmembrane-encoding exon 8, leading to a frameshift forming a stop codon that generates a transcript capable of producing a soluble receptor with 11 unique C-terminal amino acids (Fig. 1A). The transmembrane and soluble Ifnar2 transcripts are differentially regulated based on Northern blot analyses of expression in murine tissues. Ratios of tmIfnar2c:sIfnar2a range from >10:1 in some tissues to ∼1:1 in hemopoietic tissues (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar). Analysis of the 5′ flanking region of Ifnar2 using promoter reporter constructs identified three regulatory regions that confer basal expression, inducible expression by IFNα + IFNγ, and a negative regulatory region (11Hardy M.P. Owczarek C.M. Trajanovska S. Liu X. Kola I. Hertzog P.J. Blood. 2001; 97: 473-482Crossref PubMed Scopus (91) Google Scholar, 12Hardy M.P. Sanij E.P. Hertzog P.J. Owczarek C.M. Mamm. Genome. 2003; 14: 105-118Crossref PubMed Scopus (15) Google Scholar, 13Hardy M.P. Hertzog P.J. Owczarek C.M. Biochem. J. 2002; 365: 355-367Crossref PubMed Google Scholar). Structure-Function Relationships—Studies of type I IFN receptors prior to their cloning have indicated that most cell types bind IFNs, with large variation in the number of binding sites (200–10,000/cell) and binding affinities. Scatchard analyses of binding usually identify two types of binding sites of low (μm) and high affinity (nm–pm) (14Langer J.A. Pestka S. Immunol. Today. 1988; 9: 393-400Abstract Full Text PDF PubMed Scopus (191) Google Scholar). This pattern of binding is consistent with a multicomponent receptor containing a high affinity binding chain (often called the α or primary binding chain) and a β or signal-transducing chain that has low intrinsic ligand binding affinity and converts the affinity of interaction of ligand with α chain from moderate (nm) to high affinity (pm) (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). Recently, elegant studies using recombinant IFNAR extracellular domains (ECDs) tethered to lipid membranes have clearly demonstrated that various type I IFNs bind to IFNAR2 with Kd values mostly in the nm range (from 0.1 to 1000 nm) and bind to IFNAR1 with Kd mostly in the μm range (from 0.05 to 10 μm) (16Jaks E. Gavutis M. Uze G. Martal J. Piehler J. J. Mol. Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar). IFNAR Structures—IFNAR1 and IFNAR2 belong to the class II helical cytokine receptor (hCR) family, which includes the receptor for type II IFN, tissue factor (TF), and IL10Rβ (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). Members of the class II hCR family contain tandem ∼100 amino acid (aa) domains with a predicted topology analogous to the Ig constant domain (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar). The ECD of huIFNAR1, comprising 409 aa (403 in the murine form) contains four subdomains, referred to as SD1–SD4, each housing one fibronectin (FBN-III-like) domain (Fig. 2). SD1 contains conserved residues implicated in binding membrane glycosphingolipids (17Ghislain J. Lingwood C.A. Fish E.N. J. Immunol. 1994; 153: 3655-3663PubMed Google Scholar). SD1–SD3 appears to house the ligand binding domain; SD4 is essential for ternary complex formation (18Lamken P. Gavutis M. Peters I. Van der Heyden J. Uze G. Piehler J. J. Mol. Biol. 2005; 350: 476-488Crossref PubMed Scopus (48) Google Scholar). The SD1-SD2 pair is structurally similar to the SD3-SD4 pair with characteristic disulfide-bonding cysteine pairs (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar) and 50% sequence homology (19Uze G. Lutfalla G. Mogensen K.E. J. Interferon Cytokine Res. 1995; 15: 3-26Crossref PubMed Scopus (232) Google Scholar). NMR has been used to model huIFNAR2 structure and its interaction with huIFNα2 (20Chill J.H. Quadt S.R. R. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), which has to and from the of two of the class II hCR K. I. A. 1994; PubMed Scopus Google Scholar) and C.A. P.J. 1995; PubMed Scopus Google Scholar). predicted for class II hCR receptors (15Bazan J.F. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6934-6938Crossref PubMed Scopus (1881) Google Scholar), three have two domains with topology and two conserved C.A. P.J. 1995; PubMed Scopus Google Scholar, L. C. M. M. C. M. S. A. PubMed Scopus Google Scholar, C. X. J. P. P. PubMed Scopus Google Scholar). However, and IFNGR, which a conserved of K. I. A. 1994; PubMed Scopus Google Scholar, C.A. P.J. 1995; PubMed Scopus Google Scholar), huIFNAR2 has (20Chill J.H. Quadt S.R. R. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) (Fig. 2). on the that type I IFNs have interaction for each receptor on of the ligand L. C. M. M. C. M. S. A. PubMed Scopus Google Scholar) and on the of amino acids implicated in ligand binding on IFNAR1 and IFNAR2, a model for the human type I IFN receptor complex has been C. X. J. P. P. PubMed Scopus Google Scholar). This model that ligand the domain of IFNAR1 a the ligand C. X. J. P. P. PubMed Scopus Google Scholar). However, this to the residues of IFNAR1 implicated in binding membrane glycosphingolipids (17Ghislain J. Lingwood C.A. Fish E.N. J. Immunol. 1994; 153: 3655-3663PubMed Google Scholar) that the of IFNAR1 may the the or after ligand binding site of on IFNAR1 has been predicted from C. X. J. P. P. PubMed Scopus Google Scholar, P. S. Gavutis M. Piehler J. J. Mol. Biol. PubMed Scopus Google Scholar) and with P. J.A. G. R. J. Cytokine Google Scholar) (Fig. the may be of in ligand binding are found on the three have been identified as the residues in IFNAR1 by a P. J.A. G. R. J. Cytokine Google Scholar) and to binding C. X. J. P. P. PubMed Scopus Google Scholar). number of other residues the region have also been demonstrated to binding C. X. J. P. P. PubMed Scopus Google Scholar) (Fig. 2). from and others that IFNAR1 is for and is for the differential of the IFN ligands (16Jaks E. Gavutis M. Uze G. Martal J. Piehler J. J. Mol. Biol. 2007; 366: 525-539Crossref PubMed Scopus (166) Google Scholar, P. Gavutis M. Peters I. Van der Heyden J. Uze G. Piehler J. J. Mol. Biol. 2005; 350: 476-488Crossref PubMed Scopus (48) Google Scholar, M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar). studies have the residues of IFNAR2 in ligand with and (20Chill J.H. Quadt S.R. R. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. Gavutis M. Piehler J. J. Mol. Biol. PubMed Scopus Google Scholar, M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar) (Fig. 2). the ligand binding site of huIFNAR2 is largely of hydrophobic amino acids (20Chill J.H. Quadt S.R. R. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, K. I. A. 1994; PubMed Scopus Google Scholar, C.A. P.J. 1995; PubMed Scopus Google Scholar) (Fig. 2). the of the IFNAR2 ligand binding domain are three conserved residues and and also binding M. Mogensen K.E. Uze G. J. Mol. Biol. PubMed Scopus Google Scholar, J. G. J. Mol. Biol. 1999; PubMed Scopus Google Scholar). These residues are predicted by NMR to and largely hydrophobic on the of IFNAR2 (Fig. (20Chill J.H. Quadt S.R. R. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The interaction of is predicted to be different from IFNAR2 residues and with minor from and (Fig. J. G. J. Mol. 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This is in that it has low amino acid homology to IFNAR1 or IFNAR2 but has a based on and is a of the antiviral activity of a range of type I IFNs the species of The IFNAR complex is among cytokine receptors in mediating by more different but related type I IFN This system has been in the of the which is for genes in the characteristic antiviral However data that many more alternative are by IFNAR This diversity of may how IFNs complex biological responses. has been in the structure of the receptor However, more studies and of the potential in receptor that which elicit are to elucidate how the different biological of type I IFNs can be regulated by the