IFNa/b Receptor

10 Pages·0.106 MB·English

IFN(cid:11)/(cid:12) Receptor
S. Jaharul Haque1,2 and B. R. G. Williams1,*
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid
Avenue, Cleveland, OH 44195, USA
2DepartmentofPulmonaryandCriticalCareMedicine,ClevelandClinicFoundation,9500EuclidAvenue,
Cleveland, OH 44195, USA
*corresponding author tel: [phone], fax: [phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.18002.
SUMMARY 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(cid:11), one IFN(cid:12),
Interferons (IFNs) comprise a family of secreted pro-
and one IFN! (Weissmann and Weber, 1986; Pestka
teins produced by a variety of vertebrate cells in
et al., 1987; Sen and Lengyel, 1992; Haque and
response to viral and other microbial infections, and
Williams, 1998). All type I IFNs compete for binding
function as antiviral, antiproliferative, and immuno-
to the same receptor on the cell surface, known as
modulatoryagents.IFNsbindtospecificreceptorson
typeIIFNreceptororIFN(cid:11)/(cid:12) receptor(Aguetetal.,
the surface of target cells and activate multiple intra-
1984;Merlinetal.,1985;Pestkaetal.,1987;Uzeetal.,
cellular signaling cascades including the JAK/STAT
1995; Haque and Williams, 1998). IFN(cid:13) binds to a
pathway which in turn activates the transcription of
distinct transmembrane receptor (Aguet et al., 1984;
IFN-stimulated genes. Type I IFNs, including (cid:11), (cid:12),
Pestka et al., 1987; Uze et al., 1995; Haque and
and !, bind to the same receptor that comprises two
Williams, 1998; Merlin et al., 1985).
transmembrane subunits (IFNAR-1 and IFNAR-2)
IFNs exhibit a high level of species-specificity with
that are classified as type II cytokine receptors based
a few exceptions (Stwert, 1979; Uze et al., 1990;
on their amino acid sequence and structural features.
Novick et al., 1994; Domanski and Colamonici,
These two proteins function in a species-specific
1996). Binding of IFNs to their receptors initiates
fashion.IFNAR-1andIFNAR-2physicallyassociate
signals that are transmitted from cell surface to the
with TYK2 and JAK1 respectively that catalyze the
nucleus, resulting in the rapid induction of a number
tyrosyl phosphorylation of IFN-signaling proteins
of IFN-stimulated genes (ISGs) in the absence of
including JAK1, TYK2, IFNAR-1, IFNAR-2,
de novo protein synthesis (Sen and Lengyel, 1992;
STAT1, STAT2, and STAT3. Mice lacking the
Darnell et al., 1994; Levy, 1995; Ihle, 1996; Haque
IFNAR-1arecompletelyunresponsivetotypeIIFNs
and Williams, 1998). Each type of IFN induces a dis-
and unable to combat viral infection.
tinctsetofgeneswithacertaindegreeofoverlap(Sen
and Lengyel, 1992; Darnell et al., 1994; Haque and
Williams,1998;Starketal.,1998).MostoftheIFN(cid:11)/
BACKGROUND
(cid:12)-responsive genes contain an enhancer element,
termed the IFN-stimulated response element (ISRE)
Interferons(IFNs)belongtothecytokinesuperfamily that binds to the transcription factor IFN-stimulated
of secreted proteins that were originally identified as gene factor 3 (ISGF3), which is induced through an
antiviral agents in 1957 by Isaacs and Lindenmann. IFN(cid:11)/(cid:12)-dependent activation of the Janus kinase/
Subsequent studies revealed that IFNs exert pleio- signal transducer and activator of transcription
tropicbiologicaleffects,allmediatedthroughtheacti- (JAK/STAT) signal transduction pathway (Darnell
vationofspecificreceptorsonthecellsurface(Pestka et al., 1994; Levy, 1995; Ihle, 1996; Haque and
et al., 1987; Sen and Lengyel, 1992; Darnell et al., Williams, 1998; Stark et al., 1998). The SH2 domain-
1994; Uze et al., 1995; Domanski and Colamonici, containing proteins STAT1 and STAT2 are
1846 S. Jaharul Haque and B. R. G. Williams
phosphorylated at unique tyrosine residues by a pair cDNAwasexpressedinmousecells,theproteincould
of activated JAKs that are physically associated with onlybindtoIFN(cid:11)8at37(cid:14)C,butnottotheothertype
the IFN receptor subunits (Darnell et al., 1994; Stark IIFNsofhumanorigin(Uzeetal.,1990).Thehuman
et al., 1998). This results in an SH2 domain– IFN(cid:11)8 was later found to possess some binding
phosphotyrosine interaction-mediated formation of affinity for mouse receptor (Domanski and
a STAT1/STAT2 heterodimer that migrates to the Colamonici, 1996). Therefore, IFNAR-1 was not
nucleus and binds with a member of the IFN regu- sufficient to confer responsiveness to all the type I
latory factor (IRF) family protein p48 (ISFG3-(cid:13)) to IFNs, indicating that another species-specific ligand-
form the functional trimeric complex ISGF3 that binding receptor subunit was required for signal
binds to an ISRE to activate transcription (Darnell transduction (Uze et al., 1990; Domanski and
et al., 1994; Stark et al., 1998). Colamonici, 1996).
A second set of genes, including major histocom- The purification of human IFN(cid:11)-binding protein
patibility complexes,is inducedas a delayedresponse from urine and its amino acid sequence analyses led
that requires new protein synthesis (Pestka et al., totheisolationofan1.5kbcDNAforanovelsubunit
1987; Sen and Lengyel, 1992; Haque and Williams, of type I IFN receptor encoding 331 amino acids
1998; Stark et al., 1998). The mechanisms of this (Novick et al., 1994). However, this novel protein of
delayed response to IFNs are not well understood, 331 amino acids termed IFNAR-2B ((cid:12) subunit) was
S
but in some cases IFNs may regulate gene expression not a functional receptor subunit. A longer form of
at the posttranscriptional level (Stark et al., 1998). human IFNAR-2 encoding 515 amino acids, termed
The proteins encoded by the IFN-regulated genes IFNAR-2C ((cid:12) subunit) was identified as the uni-
L
mediate multiple biological activities attributed to versal ligand-binding subunit of the type I IFN
IFNs (Stark et al., 1998). receptor(Zhangetal.,1986;Bazan,1990;Colamonici
et al., 1990, 1992; Domanski et al., 1995; Lutfalla
et al., 1995).
Discovery
Alternative names
Early investigations using radiolabeled recombinant
type I IFNs revealed the cell surface expression of
both low-affinity and high-affinity receptors for type Thereceptor forthetypeI IFNsis also referredtoas
I IFNs (Aguet and Blanchard, 1981; Branca and type I IFNR, IFNR, IFN(cid:11)R, and IFN(cid:11)/(cid:12)R (Uze
Baglioni, 1981; Joshi et al., 1982; Hannigan et al., et al., 1995; Domanski and Colamonici, 1996). The
1983, 1984, 1986; Aguet et al., 1984; Merlin et al., first cloned subunit of the type I IFN receptor is
1985;RaziuddinandGupta,1985;Zhangetal.,1986; IFNAR-1,whichwasinitiallytermedIFNARbyUze
Pestkaetal.,1987;VandenBroeckeandPfeffer,1988; et al. (1990). It is identical to IFNR(cid:11) of the
SenandLengyel,1992;Faltyneketal.,1993).Studies Colamonici group (Uze et al. 1995). The second
on binding and crosslinking of radiolabeled IFNs to subunit of type I IFN receptor, originally cloned by
the cell surface suggested the existence of the multi- Novick et al. (1994), is IFNAR-2, which is also
subunit structure for the type I IFN receptors (Joshi known as IFNR(cid:12) (Domanski et al., 1995). This sub-
et al., 1982; Aguet et al., 1984; Merlin et al., 1985; unit has three isoforms: IFNAR-2A, IFNAR-2B
Raziuddin and Gupta, 1985; Hannigan et al., 1986; (alsotermedIFNR(cid:12) ),andIFNAR-2C,whichisalso
S
Zhang et al., 1986; Pestka et al., 1987; Vanden known as IFNR(cid:12) (Domanski et al., 1995; Lutfalla
L
Broecke and Pfeffer, 1988; Sen and Lengyel, 1992; et al. 1995; Domanski and Colamonici, 1996).
Faltynek et al., 1993). The existence of the multi-
subunit structure was later demonstrated using spe-
Structure
cific monoclonal antibodies to receptor subunits
(Colamonici et al., 1990, 1992).
The first receptor subunit to be cloned was the Cytokine receptors are transmembrane proteins with
humanIFNAR-1(formerlyknownasIFNreceptor(cid:11) a single membrane-spanning region. Based on the
chain) (Uze et al., 1990). The cDNA encoding the aminoacidsequenceandstructuralfeatures,cytokine
human IFNAR-1 was isolated by an expression receptors are divided into two classes (Bazan, 1990;
cloning strategy utilizing the species-specific recogni- Kishimoto et al., 1994; Heldin, 1995; Haque and
tion property of type I IFNs. This protein conferred Williams, 1998). While the majority of the cytokine
resistance to vesicular stomatitis virus replication in receptors fall into class I, the receptors for IFN(cid:11)/(cid:12),
mouse cells in the presence of human IFN(cid:11)8 (Uze IFN(cid:13), and IL-10 as well as the tissue factor (a mem-
et al., 1990). However, when the human IFNAR-1 branereceptorforthecoagulationproteasefactorVII)
IFN(cid:11)/(cid:12) Receptor 1847
belongtotheclassIIcytokinereceptorfamily(Bazan, acidlevels,differentIFN(cid:11)subtypesare(cid:24)80%homol-
1990). ogous, while the homology between the (cid:11) subtypes
The cytokine receptors contain one or two char- and the (cid:12) subtype is about 35% (Pestka et al., 1987).
acteristic external domain structures (D200) consist- The AB loop, C helix, and D helix are important for
ing of two homologous subdomains (SD100) of functional IFN(cid:11) binding to its receptors (Runkel
(cid:24)100aminoacids,eachofwhichadoptsanimmuno- et al., 1998). Mutational studies reveal that substitu-
globulin-like fold with seven (cid:12) strands (s1–s7) organ- tions of amino acids that are highly conserved in the
ized into two (cid:12) sheets (Bazan, 1990). While the D200 AB loop and D helix reduce the binding of IFN(cid:11)
module of class I receptors contains a set of four comparedwiththatofIFN(cid:12),suggestingadifferential
conservedcysteine residues and aWSXWSmotif, the interaction of (cid:11) and (cid:12) IFNs with their receptor
class II cytokine receptors share one cysteine pair (Runkeletal.,1998).ItisevidentthatbothIFN(cid:11)and
with class I and contain an additional conserved IFN(cid:12) need to make physical contact with IFNAR-1
cysteine pair, and several conserved proline and and IFNAR-2 for intracellular signal transduction,
tryptophan residues, but lack the WSXWS motif although IFNAR-1 seems to engage IFN(cid:12) quite
(Bazan, 1990). differently than IFN(cid:11) (Novick et al., 1994; Cohen
The INFAR-1 chain of the receptor contains two et al., 1995; Domanski et al., 1995; Lutfalla et al.,
D200modules,whileIFNAR-2hasone(Bazan,1990; 1995; Cutrone and Langer, 1997; Karpusas et al.,
Gaboriaudetal.,1990;Thoreauet al.,1991).Human 1997; Rani et al., 1996). This suggests that there are
IFN(cid:11)2 binds to the human IFNAR-1 with low some functional differences between these two
affinity, while it exhibits moderate binding affinity subtypes of IFNs at the level of receptor recognition.
towards the bovine homolog of IFNAR-1. This has The three-dimensional structure of the cytoplasmic
facilitated the analysis of IFN(cid:11) binding to IFNAR-1 domain of cytokine receptors is not currently avail-
(Rehberg et al., 1982; Zoon et al., 1982; Lundgren able. Most of the information on structure–function
and Langer, 1997; Goldman et al., 1998). Binding of relationship has been derived from the receptor
human IFN(cid:11)2 to bovine/human IFNAR-1 chimeras mutagenesis studies. Cytoplasmic domains of cyto-
reveals that bovine SD2 and SD3 contain residues kine receptors are of variable lengths (Bazan, 1990;
necessary but not sufficient for moderate-affinity Uzeetal.,1990;Kishimotoetal.,1994;Novicketal.,
ligand binding; SD1 and SD4 also contribute either 1994;Ihle,1995;IhleandKerr,1995;Ihleetal.,1995;
directly or indirectly to ligand binding (Goldman Domanski and Colamonici, 1996; Haque and
et al., 1998). Mapping of epitopes for neutralizing Williams, 1998; Leonard and O’Shea, 1998; Stark
monoclonal antibodies to IFNAR-1 also implicates et al., 1998). Many cytokine receptors contain two
direct roles for amino acid residues in all four sub- membrane proximal loosely conserved motifs, Box 1
domains of the IFNAR-1 molecule (Eid and Tovey, and Box 2 (Bazan, 1990; Kishimoto et al., 1994; Ihle,
1995; Goldman et al., 1998; Lu et al., 1998). 1995; Ihle and Kerr, 1995; Ihle et al., 1995; Leonard
The human IFNAR-2 binds to type I IFNs with and O’Shea, 1998).
moderate affinity (2–8nmol/L; Novick et al., 1994;
Domanski and Colamonici, 1996; Lewerenz et al.,
1998). Mutant IFNAR-2 proteins generated by ala- Main activities and
ninesubstitutionsofselectedaminoacidsintwoloop
pathophysiological roles
regions (amino acids 71–75 in s3–s4 and amino acids
103–106ins5–s6)intheN-terminalsubdomainconfer
complete resistance to IFN(cid:11) but not IFN(cid:12) binding Protein tyrosine phosphorylation is a key reaction in
when expressed in IFNAR-2-null human cell line the activation of cytokine and growth factor recep-
U5A (Lewerenz et al., 1998). In contrast, unlike tors (Velazquez et al., 1992; Mu¨ller et al., 1993;
IFN(cid:11), IFN(cid:12) binding to IFNAR-2 is sensitive to an Watling et al., 1993; Kishimoto et al., 1994; Heldin,
alanine substitution of Try127 located in the inter- 1995;Ihle,1995,1996;IhleandKerr,1995;Ihleetal.,
subdomain link of the IFNAR-2 molecule (Lewerenz 1995; Krowlewski, 1995; Levy, 1995; Domanski and
et al., 1998). Cytokines in general contain four main Colamonici, 1996; Haque and Williams, 1998;
(cid:11)helices labeled A throughD connectedby two long Leonard and O’Shea, 1998; Stark et al., 1998).
loops(ABandCD)andashortloop(BC)withanup- Unlike most growth factor receptors, the cytokine
up-down-down arrangement (Uze et al., 1995; Mitsui receptors do not possess any cytoplasmic tyrosine
andSenda,1997).IFNshavinganadditionalhelix(E) kinase domain, rather they constitutively associate
instead of CD loop constitute a subclass of cytokine with members of Janus family tyrosine kinases that
with an up-up-down-up-down arrangement (Uze providetyrosinekinaseactivitynecessaryforreceptor
et al., 1995; Mitsui and Senda, 1997). At the amino activation and subsequent signal transduction
1848 S. Jaharul Haque and B. R. G. Williams
(Velazquez et al., 1992; Mu¨ller et al., 1993; Watling in this protein–protein interaction (Domanski and
et al., 1993; Kishimoto et al., 1994; Ihle, 1995; Ihle Colamonici, 1996). The three amino acid residues
and Kerr, 1995; Ihle et al., 1995; Domanski and Ile504, Leu505, and Glu506 in IFNAR-1 are essen-
Colamonici, 1996; Haque and Williams, 1998; tial for TYK2 binding (Colamonici et al., 1994a,
Leonard and O’Shea, 1998; Stark et al., 1998;). After 1994b; Domanski and Colamonici, 1996; Yan et al.,
being activated by JAK-mediated tyrosine phosphor- 1996a).
ylation cytokine receptor subunits recruit a number In vitro bindingstudies suggest that the N-terminal
of downstream signaling components through pro- (cid:24)600 amino acids containing JH7 to JH3 comprise
tein–protein interactions (Velazquez et al., 1992; the major binding site of TYK2 to the IFNAR-1
Mu¨ller et al., 1993; Watling et al., 1993; Kishimoto protein (Yan et al., 1998). Glutathione S-transferase-
etal.,1994;Ihle,1995;IhleandKerr,1995;Ihleetal., TYK2-JH3 or JH6 domain physically interacts
1995; Domanski and Colamonici, 1996; Haque and in vitro with the IFNAR-1 protein, suggesting that
Williams, 1998; Leonard and O’Shea, 1998; Stark JH3 and JH6 are the major sites of interaction of
et al., 1998). TYK2with IFNAR-1(Yan et al., 1998).A truncated
The type I IFN receptor subunits IFNAR-1 and TYK2 protein containing amino acids 1–601 can
IFNAR-2 constitutively associate with the Janus function in vivo as a dominant negative mutant
kinases TYK2 and JAK1 respectively (Velazquez kinase inhibiting IFN(cid:11)-dependent JAK/STAT sig-
et al., 1992; Mu¨ller et al., 1993; Watling et al., 1993; naling (Yan et al., 1998). Further mutagenesis
Domanski and Colamonici, 1996; Haque and studies have revealed that JH7 and a part of the
Williams, 1998; Stark et al., 1998). TYK2 was the JH6 domain containing amino acids 22–221 are
first member of the JAK family to be identified as an essential for TYK2 binding to IFNAR-1 (Richter
essential component of IFN(cid:11) signaling by the use of et al., 1998).
somatic cell genetic studies and subsequent investiga- Tyr466 and, to some extent, Tyr481 on human
tions established the role of other JAKs in cytokine IFNAR-1 are phosphorylated by TYK2 and phos-
signaling (Velazquez et al., 1992). pho-Tyr466 serves as a docking site for STAT2
The C-terminal kinase domain (JH1) of JAKs (Krishnan et al., 1996, 1998; Yan et al., 1996b; Li
shares sequence homologywiththe catalytic domains et al., 1997; Richter et al., 1998; Nadeau et al., 1999).
of other protein tyrosine kinases within the defined The SH2-containing protein tyrosine phosphatase
conserved(Ihle,1995; IhleandKerr,1995;Ihleet al., SHP-2 preassociates with IFNAR-1 and is phos-
1995; Krowlewski, 1995; Wilks, 1995; Hanks et al., phorylated in response to IFN(cid:11)/(cid:12) (David et al.,
1988; Leonard and O’Shea, 1998). Adjacent to the 1995a). In transient transfection assays a dominant
kinasedomainJAKshaveapseudokinase(i.e.kinase- negative mutant SHP-2 inhibits IFN(cid:11)/(cid:12)-induced
related) domain(JH2) that hasa number of sequence expression of an ISRE-driven reporter gene, suggest-
motifs characteristic of a catalytic domain but is ingthatSHP-2mayfunctionasapositiveregulatorof
missing some conserved amino acids including the type IFN signaling (David et al., 1995a). In contrast,
catalytic aspartic acid (Ihle et al., 1995; Leonard and SHP-1 negatively controls IFN(cid:11)/(cid:12) signaling. Bone
O’Shea, 1998). The precise function of the pseudo- marrow-derivedmacrophagesfromviablemoth-eaten
kinasedomainisnotclearyet.TheN-terminalhalfof mice (expressing mutant SHP-1 with substantially
the JAKs contains five regions (JH3–7) that share reduced phosphatase activity) exhibit enhanced
sequence homology among the Janus family mem- IFN(cid:11)/(cid:12) signaling compared with normal littermate
bers. In contrast, however, the extreme N-terminal control (David et al., 1995a). SHP-1 physically
regionofeachJAKproteinisunique,andmayconfer associates with IFNAR-1 in a ligand-regulated
the specificity in binding to the membrane-proximal fashion (David et al., 1995a). Mutation of tyrosines
regions of cytokine receptors (Ihle, 1995; Ihle et al., to phenylalanines at positions 527 and 538 of
1995; Leonard and O’Shea, 1998). IFNAR-1 enhances IFN(cid:11) signaling, suggesting that
TYK2-binding domain in IFNAR-1 protein has IFN(cid:11)/(cid:12) signaling is negatively regulated throughthis
been mapped to a (cid:24)33 amino acids membrane- region of IFNAR-1 (Gibbs et al., 1996).
proximal region that comprises the Box 1 and Box 2 The cytoplasmic domains of IFNAR-2B and
motifs (Domanski and Colamonici, 1996; Yan et al., IFNAR-2C are divergent after the membrane-pro-
1996a). Almost all phylogenetically conserved resi- ximal 15 amino acids. Human IFNAR-2B contains
dues in this region of IFNAR-1 are essential for two tyrosine residues (269 and 321) and no char-
TYK2 recognition (Domanski and Colamonici, acteristic motifs of cytokine receptors and it does not
1996; Yan et al., 1996a). In contrast to other cyto- interact with JAK1 (Domanski et al., 1995; Lutfalla
kine receptors, the Box 1 motif, which is not well et al., 1995; Domanski and Colamonici, 1996). Like
conserved in IFNAR-1, does not play a critical role IFNAR-2A, IFNAR-2B probably functions as decoy
IFN(cid:11)/(cid:12) Receptor 1849
receptorfortypeIIFNs.Incontrast,thecytoplasmic complex (Darnell et al., 1994; Uze et al., 1995;
domainofhumanIFNAR-2CcontainsaBox1motif Domanski and Colamonici, 1996; Haque and
and seven tyrosine residues (269, 306, 316, 337, 411, Williams, 1998; Stark et al., 1998). However, dif-
and 512) and a number of acidic residues (Domanski ferenceshavebeenobservedbetweencellsignalingby
et al., 1995; Lutfalla et al., 1995; Domanski and IFN(cid:11) and IFN(cid:12). Interestingly, U1A cells which are
Colamonici, 1996). The JAK1-interaction domain of completely defective in response to recombinant
IFNAR-2 has been mapped to amino acids 300–346 IFN(cid:11)1, IF-(cid:11)2, or a mixture of natural IFN(cid:11)s, retain
(Domanskietal.,1996).TheBox1motifinIFNAR-2 a partial response to IFN(cid:12) (Pellegrini et al., 1989).
playsaminorroleinJAK1binding(Domanskietal., But none of the mutant cell lines lacking JAK1,
1995; Lutfalla et al., 1995; Domanski and STAT1, or STAT2 exhibits any IFN(cid:12) response,
Colamonici, 1996). suggesting that TYK2 activity is not absolutely
It has been demonstrated by indirect approaches required for IFN(cid:12) signaling (Stark et al., 1998). U1A
using a JAK1–JAK2 chimeric protein that the JH3– cells express low levels of IFNAR-1 which is not
JH7 of JAK1 is involved in the physical association stably maintained at the plasma membrane. There-
with IFNAR-2 to elicit biological responses of type I fore, in U1A cells IFN(cid:12) likely signals through the
IFNs (Kohlhuber et al., 1997). Both STAT1 and IFNAR-2 dimer (Lewerenz et al., 1998). Recon-
STAT2 physically associate with the IFNAR-2C stitutions of U1A cells with mutant TYK2 proteins
protein in unstimulated cells, but the biological sig- reveal that TYK2 N-terminal domain is required to
nificanceoftheinteractionisnotclear(Stancatoetal., maintain functional IFNAR-1, JH2 (pseudokinase)
1996; Stark et al., 1998). Murine cells expressing domain is necessary for high-affinity ligand binding
humanIFNAR-2Ctruncatedataminoacid417show and JH1(kinase) domain phosphorylates IFNAR-1
a marked decrease in IFN(cid:12)-mediated antiviral which is dispensable for JAK/STAT signaling by
response without any defect in JAK/STAT signaling IFN(cid:11) or IFN(cid:12) (Pellegrini et al., 1989; Velazquez
by both IFN(cid:11) and IFN(cid:12) (Platanias et al., 1998). et al., 1992; Richter et al., 1998; Rani et al., 1999).
Protein tyrosine phosphatase activity associated with Recentlyithasbeendemonstratedthat theIFNAR-1
thedistalregionofIFNAR-2Chasbeenimplicatedin and TYK2 expression is coordinately regulated in
the negative regulation of the growth-inhibitory cells (Gauzzi et al., 1997). This is consistent with the
action of type I IFNs (Platanias et al., 1998). model that IFN(cid:12) interacts with the receptor in a
The mitogen-activated protein kinase (MAPK) is mannerthatisdifferentfromthatofIFN(cid:11)(Pellegrini
activated by IFN(cid:11)/(cid:12) treatment of cells and ERK2 et al., 1989; Velazquez et al., 1992; Lewerenz et al.,
(p42-MAPK) associates with IFNAR-1 both in vitro 1998; Stark et al., 1998; Rani et al., 1999).
and in vivo (David et al., 1995b). Binding of type I IFN(cid:11)2 and IFN(cid:12) may require distinct cytoplasmic
IFNs to receptor causes tyrosine phosphorylation of regions of IFNAR-2C to elicit an antiviral response.
insulinreceptorsubstrate1andsubsequentactivation IFNAR-2Cisphosphorylatedatcomparablelevelsin
of the phosphatidylinositol 3-kinase pathway, which response toIFN(cid:11)and IFN(cid:12); however,the IFNAR1/
requiresfunctionalJAK1andTYK2proteins(Pfeffer IFNAR-2Ccomplexcanbeimmunoprecipitatedonly
et al., 1997). However, the contribution of the PI-3 from the IFN(cid:12)-treated but not IFN(cid:11)-treated cells
kinase pathway to the biological outcome of type I (Croze et al., 1996; Platanias et al., 1996). Iden-
IFN action is not yet known (Wang et al., 1997). tification of the (cid:12)-R1 gene which shows a selective
STAT3 is activated by type I IFNs and may serve as induction by IFN(cid:12) compared with IFN(cid:11) by Rani
an adapter for the recruitment of PI-3 kinase in et al. has provided further evidence that IFN(cid:12) may
Daudicells (Burfootet al.,1997).Stimulationofcells use a distinct pathway for cell signaling (Rani et al.,
with IFN(cid:11) causes a JAK1-dependent phosphoryla- 1996).
tion of cytosolic phospholipase A (cPLA ) and IFN(cid:12) shares only 35% identity with the IFN(cid:11)
2 2
pretreatment of cells with inhibitors of cPLA2 subtypes, and appears to engage the (cid:11)/(cid:12) receptor
inhibits the activation of ISGF3 but not GAF differently. This can result in the activation of selec-
(STAT1 homodimer) formation (Flati et al., 1996). tive subsets of genes by IFN(cid:12) (Der et al., 1998), even
Moreover, JAK1 and cPLA2 can be co-immunopre- though it binds and activates the same receptor.
cipitated from IFN-treated cell lysate (Flati et al., Apparently distinctive structural differences are
1996). Type I IFNs also activate p38 mitogen-acti- transmittedthroughthemembranetothecytoplasmic
vated kinase (p38 MAPK) and this is essential for domains of the receptors that then mediate a dif-
cPLA -dependentISGF3formation(Gohetal.,1999; ferential response. Mutant cell lines lacking TYK2
2
Uddin et al., 1999). which are completely defective in their response to
IFNAR-1, IFNAR-2C, JAK1, and TYK2 are IFN(cid:11)2 still respond to IFN(cid:12) or (cid:11)8, albeit with
known to form the functional type I IFN receptor reducedactivity.Infact,usingtheseandothermutant
1850 S. Jaharul Haque and B. R. G. Williams
celllinesreconstitutedwithdifferentmutantproteins, PROTEIN
three distinct modes of type I interactions with
receptor subunits have been discerned: IFN(cid:11) with
Accession numbers
IFNAR-1 and IFNAR-2, IFN(cid:12) with IFNAR-1, and
IFNAR-2 and IFN(cid:12) with IFNAR-2 only (Lewerenz
Bovine IFNAR-2: Q95141
et al., 1998). Thus IFN(cid:11) and (cid:12) signal differently
Human IFNAR-2: P48551
through their receptors because they interact with
Sheep IFNAR-2: Q95207
the receptor in different ways. There is a tight cor-
Human IFNAR-1: P17181
relation between receptor occupancy and the tran-
Sheep IFNAR-1: Q28589, Q95206
scriptionalresponsetoIFN(HanniganandWilliams,
Bovine IFNAR-1: Q04790
1986). The degree of receptor occupancy is a rate-
Mouse IFNAR-1: P33896
limiting step in determining the transcriptional
response to IFN which is transient and is accom-
panied by the downregulation of receptors on the
Description of protein
cell surface. Downregulation of type I IFN receptors
is also seen in vivo on peripheral blood lymphocytes
See Structure.
following IFN therapy (Lau et al., 1986). This is a
BothN-andO-linkedglycosylationoftheIFNAR-
temporary state and receptors reappear on the sur-
1 has been demonstrated (Novick et al., 1992;
face over 24–48 hours.
Platanias et al., 1993; Constantinescu et al., 1995;
Ling et al., 1995).
GENE
Relevant homologies and species
Accession numbers
differences
Human IFNAR-1 cDNA: J03171
The receptor subunits are species-specific (Uze et al.,
Human IFNAR-1 gene: X60459
1990; Domanski and Colamonici, 1996; Stark et al.,
Mouse IFNAR-1 cDNA: M89641
1998).
Bovine IFNAR-1 cDNA: L06320
Sheep IFNAR-1 cDNA: U65978
Human IFNAR-2.2 cDNA: L41942 Affinity for ligand(s)
Mouse IFNAR-2 cDNA: Y09813
Mouse IFNAR-2B cDNA: Y09864
See Structure.
Mouse IFNAR-2C cDNA: Y09865
Sheep IFNAR-2 cDNA: U65979
Cell types and tissues expressing
the receptor
Chromosome location and linkages
The IFNAR subunits are expressed in all tissues.
The human IFNAR-1 gene comprises 11 exons
Soluble IFNAR-1 and IFNAR-2 are present in
covering a 32.9kb region on chromosome 21q22.1
human body fluids (Novick et al., 1992, 1994).
(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
Regulation of receptor expression
located on chromosome 16.
The genes encoding two other members of the
class II cytokine receptors, namely IFNGR-2 and Recent study shows that TYK2 protein can regu-
CRF2–4, are also mapped to chromosome 21q22.1 late the expression and ligand-binding activity of
within a (cid:24)300kb span (Hertzog et al., 1994; IFNAR-1 protein (Gauzzi et al., 1997). Binding
Rubinstein et al., 1998). IFNGR-2 is the second studies with iodinated IF(cid:11)2 and Scatchard plot anal-
chain of IFN(cid:13) receptor and recently the orphan ysis reveal that monocyte differentiation to macro-
receptor CRF2–4 has been shown to encode the phages results in a 3- to 4-fold increase in cell surface
second chain of IL-10 receptor (Spencer et al., 1998; receptors with no change in their affinity (Eantuzzi
Reboul et al., 1999). et al., 1997).
IFN(cid:11)/(cid:12) Receptor 1851
BIOLOGICAL CONSEQUENCES Colamonici,O.R.,Uyttendaele,H.,Domanski,P.,Yan,H.,and
Krolewski, J. J. (1994b). p135tyk2, an interferon-alpha-acti-
OF ACTIVATING OR INHIBITING
vated tyrosine kinase, is physically associated with an inter-
RECEPTOR AND feron-alphareceptor.J.Biol.Chem.269,3518–3522.
Constantinescu, S.N.,Croze,E.,Murti,A.,Wang,C.,Basu,L.,
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Martinez, V., Mullersman, J. E., and Pfeffer, L. M. (1995).
Expression and signaling specificity of the IFNAR chain of
Phenotypes of receptor knockouts
the type I interferon receptor complex. Proc. Natl Acad. Sci.
and receptor overexpression mice USA92,10487–10491.
Croze,E.,Russell-Harde,D.,Wagner,T.C.,Pu,H.,Pfeffer,L.M.,
andPerez,H.D.(1996).ThehumantypeIinterferonreceptor.
Mice lacking the IFNAR-1 were completely unre- Identificationoftheinterferonbeta-specificreceptor-associated
sponsive to type I IFNs. These animals showed no phosphoprotein.J.Biol.Chem.271,33165–33168.
Cutrone,E.C.,andLanger,J.A.(1997).Contributionsofcloned
overtabnormalitiesbutwereunabletocopewithviral
typeIinterferonreceptorsubunitstodifferentialligandbinding.
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and differentiation by type I IFNs, there were no andotherextracellularproteins.Science264,1415–1421.
David,M.,Chen,H.E.,Goelz,S.,Larner,A.C.,andNeel,B.G.
gross signs of abnormal fetal development or mor-
(1995a). Differential regulation of the alpha/beta interferon-
phological changes in adult IFNAR-1-deficient mice
stimulated Jak/Stat pathway by the SH2 domain-containing
(Hwang et al., 1995). However, abnormalities of tyrosinephosphataseSHPTP1.Mol.CellBiol.15,7050–7058.
hematopoietic cells were detected in these animals. David,M.,PetricoinIII,E.,Benjamin,C.,Pine,R.,Weber,M.J.,
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