|Coordinate||91,383,899 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||interferon (alpha and beta) receptor 2|
|Chromosomal Location||91,372,783-91,405,589 bp (+)|
|MGI Phenotype||Mice with mutations of this gene have defects in immune responses involving, variously, NK cells, CD4+ and CD8+ T cells and B cells in response to induced and transplanted tumors, viruses, and double stranded DNA. These defects include diminished secretion of type I and type II interferons.,NO_PHENOTYPE|
|Amino Acid Change||Methionine changed to Valine|
|Institutional Source||Beutler Lab|
M1V in Ensembl: ENSMUSP00000023693 (fasta)
|Gene Model||not available|
|Phenotypic Category||adenovirus infection of macrophages - increased, immune system, impaired response to dsDNA- type I IFN production by macrophages, influenza proliferation in macrophages - increased, MCMV proliferation in macrophages - increased, RVFV proliferation in macrophages - increased, RVFV susceptibility|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice, Sperm, gDNA|
|Last Updated||2017-04-11 2:19 PM by Katherine Timer|
Macro-2 was discovered in an ex vivo macrophage screen for control of viral infection. Macrophages from ENU-mutagenized G3 mice were infected with mouse cytomegalovirus (MCMV), influenza virus, Rift Valley Fever virus (RVFV), and an adenoviral vector and examined for effective viral clearance. Peritoneal macrophages from Macro-2 mice were found to be permissive to all viral infections (Figure 1A). Macro-2 macrophages are also defective in producing type I interferon (IFN) in response to double-stranded DNA (Double-stranded DNA Macrophage Screen) (Figure 1B).
|Nature of Mutation|
The Ifnar2 gene on chromosome 16 of macro-2 mice was sequenced, and an A to G transition was identified in exon 2 (of 9 total exons) at position 221 of the Ifnar2 cDNA.
The mutated nucleotide is indicated in red lettering, and results in a conversion of the methionine start site to a valine of the IFNAR2 protein.
The IFNAR receptor is typical of class II hCRs and lacks intrinsic kinase activity. Instead, the intracellular domains of the IFNAR receptor subunits are associated with Janus activating kinases (JAKs) that phosphorylate receptors and signal transducing molecules [reviewed in (16;17)] (see Background). IFNAR2 is able to recruit JAK1, while IFNAR1 binds to tyrosine kinase 2 (TYK2) (18-21). The human IFNAR2 intracellular domain contains a proline-rich sequence (box 1 motif) close to the transmembrane domain (residues 291-296) that has been shown to recruit and activate tyrosine kinases in other cytokine receptors (2). This motif is not well-conserved in mouse IFNAR2, although this region is still proline-rich. IFNAR2 contains several tyrosine residues that become phosphorylated by activated JAK1, and then are able to recruit signal transduction molecules such as signal transducer and activator of transcription (STAT) 1 (see the records for domino and poison) and STAT2 (18;21;22). Mutational analysis of tyrosine residues in human IFNAR2 suggests that phosphorylated Tyr337 and Tyr512 play redundant roles in the recruitment and activation of STATs (21), while a similar mutational analysis of mouse IFNAR2 suggests that Tyr510 (corresponding to human Tyr512) plays a critical role in recruiting and activating STATs in response to type I IFN binding, while Tyr335 (corresponding to human Tyr337) plays a minor role (18). Some studies suggest that JAK1, STAT1, and STAT2 are preassociated with IFNAR2 and do not require IFNAR2 to be phosphorylated (23;24). STAT2 is recruited by both IFNAR subunits, but the STAT2 binding to IFNAR2 is stronger (25), suggesting IFNAR2 may normally have a more prominent role in STAT2 recruitment and activation. However, STAT2 interaction with IFNAR2 may not be necessary for IFN signaling (24).
In addition to JAK/STATs, IFNAR2 also associates with other factors that are important in signal transduction (see Background). Phosphorylation of human IFNAR2 on Ser364 and Ser384 in two adjacent proline box motifs allows binding to CREB-binding protein (CBP), which then is able to acetylate IFNAR2 on Lys399. Acetylated Lys399 is a docking site for interferon regulatory factor 9 (IRF9), while phosphorylation of the adjacent Ser400 strengthens this interaction leading to the formation of the ISGF3 complex (26). Neither Ser364 nor Ser384 are conserved in mouse IFNAR2, although a number of serine residues as well as Lys399 and its adjacent serine are present. Additionally, amino acids 300-346 of human IFNAR2 associate with receptor for activated C-kinase 1 (RACK1) (27), which plays a role in activating protein kinase C. IFNAR2 also associates with the negative regulator of type I IFN signaling UBP43, which interferes with the interaction of JAK1 with IFNAR2 (28). Furthermore, a region corresponding to amino acids 346-417 of human IFNAR2 was found to negatively regulate type I IFN by associating with an unidentified protein tyrosine phosphatase (29).
In humans, four IFNAR2 transcripts produce three protein isoforms by exon skipping, alternative splicing, and differential usage of polyadenylation sites (3). The human protein isoforms of IFNAR2 include a long, transmembrane form (IFNAR2c) that forms the functional type I IFN receptor, along with IFNAR1. The other two human IFNAR2 isoforms include sIFNAR2a, which lacks the transmembrane domain and is soluble and IFNAR2b, a short, transmembrane isoform (Figure 3). Although the mouse Ifnar2 gene does not encode a short, transmembrane isoform, two Ifnar2 transcripts (sIfnar2a and sIfnar2a’) are generated by alternative splicing and produce two soluble isoforms, in addition to the Ifnar2 transcript producing the complete receptor (5). sIFNAR2a, the most abundant isoform, contains the complete extracellular domain of IFNAR2 and reads through the splice site in exon 7 to produce a transcript encoding 12 unique and mostly hydrophobic C-terminal residues, while sIFnar2a’ is generated from a transcript missing 128 nucleotides after codon 236 of Ifnar2. The transmembrane-encoding exon 8 is skipped, leading to a frameshift, the generation of 11 unique C-terminal amino acids and a premature stop codon. The soluble form of mouse IFNAR2 has been shown to bind type I IFNs and can even form a type I IFN complex with IFNAR1 (30).
The residue mutated in macro-2 mice is the methionine start site. Presumably, mutation of this residue prevents IFNAR2 translation.
Ifnar2 transcripts are expressed in all tissues, organs and most cell lines, but the transmembrane and soluble Ifnar2 mRNAs are differentially expressed and regulated (30;31). Mouse Ifnar2 expression is regulated by three regions that either confer basal expression, inducible expression by interferons, or are involved in negative regulation (31). In general the mRNA for soluble IFNAR2a is more abundant than that encoding the full-length receptor, although the ratio is nearly 1:1 in hemopoietic tissues (30). Ratios of more than 10:1 were observed in the small intestine, liver and fat. Ifnar2 mRNA (for all isoforms) is ubiquitously expressed as early as embryonic day 10. The mRNA ratio of soluble to full-length isoforms is generally much lower than in adults.
Type I IFNs are a critical class of cytokines that have potent antiviral, growth-inhibitory, anti-tumorigenic and immunomodulatory functions [reviewed in (6;33)]. Classically, the production of type I IFNs (notably IFN-α/β) in response to viral infections is considered to be essential for antiviral defense, a role highlighted by the phenotype of Ifnar1 and Ifnar2 knockout mice that lack type I IFN signaling (7;34-36). The production of type I IFNs in response to viral infection leads to inhibition of viral propagation and increases the vulnerability of infected cells to virus-induced apoptosis (37), a mechanism that is suggested to limit viral spread and may also increase the delivery of antigen to professional antigen-presenting cells (APCs) and be important to the onset of adaptive immunity. Type I IFNs activate natural killer (NK) cells, macrophages and dendritic cells (DCs), all of which play an essential role in the innate immune system (38;39). In addition to their antiviral effects, type I IFNs are also produced in response infection with bacterial pathogens and have an important role in the host response to bacterial infection, although type I IFN signaling has been demonstrated to increase susceptibility to certain bacterial infections in mice [reviewed by (40)]. The antiproliferative and apoptotic effects of type I IFNs on macrophages may be the reason why type I IFNs promote susceptibility to certain bacterial infections (41).
All cell types that are susceptible to viral infection are able to release type I IFNs. However, in the immune system, plasmacytoid dendritic cells (pDCs) produce the largest amounts of IFN-α/β in response to nucleic acids derived from pathogenic organisms [reviewed by (42)]. In general, the induction of type I IFN genes is transcriptionally controlled and depends on two members of the IFN regulatory factor (IRF) family, IRF-3 and IRF-7. In response to microbial infections, these factors become phosphorylated, undergo nuclear translocation and induce transcription of genes encoding members of the IFN-α/β family (43). IRF-3 is relatively specific in its induction of the solitary Ifnβ gene; IRF-7 is relatively specific for induction of the Ifnα cluster. Upstream of these events, the recognition of various pathogens leading to type I IFN induction occurs through the toll-like receptors (TLRs) as well as the nucleic-acid cytosolic sensors retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA5) (43;44). The TLRs engage various adaptors including myeloid differentiation (MyD) 88 (see pococurante and lackadaisical), TIRAP for toll-interleukin 1 receptor domain containing adaptor protein (also called MAL for MyD88 adaptor-like) (see torpid), TRIF for Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-β (also known as TICAM-1 for TIR domain-containing adaptor molecule-1) (see Lps2), and TRAM for TRIF related adaptor molecule (also called TICAM-2) (see Tram KO). With the exception of TLR3, which signals solely by activating TRIF, all TLRs recruit MyD88, which triggers signaling pathways leading to nuclear translocation of NF-κB and phosphorylation of IRF-7 (43). Both the MyD88-dependent and TRIF mediated pathways are used by TLR4 (44). The TRIF pathway mediates the phosphorylation of IRF-3 by activating the TANK-binding kinase 1 (TBK1) and IκB kinase (IKK)-i/ε (45). Interestingly, pDCs produce both IFN-α/β, while conventional or myeloid DCs produce only IFN-β. Differences in expression of the receptors that sense viral components play a major role in these differences (42). TLR7 and TLR9 are the critical sensing components in pDCs and result in the activation of the MyD88/IRF-7 pathway in the endosomal compartment, while type I IFN production in cDCs is generally MyD88-independent/IRF-3 dependent and occurs through TLR3, TLR4 and the nucleic-acid cytosolic sensors (17;42).
Type I IFN signaling modulates the expression of hundreds of IFN-stimulated genes (ISGs), accounting for the diverse biological properties of these cytokines and their highly pleiotropic and diverse effects. Some of these antimicrobial gene products include proteins that can bind directly to viral RNA and inactivate it. Other type I IFN-induced proteins affect the intracellular transport of viral particles, regulate transcription and translation and induce apoptosis. ISGs also include MHC class I, which contribute to T cell responses (40). Type I IFNs induce ISGs by activating several signal transduction pathways including the classical JAK/STAT signaling pathway (Figure 4). As discussed above, the IFNAR receptor associates with protein tyrosine kinases including JAK1 in the case of IFNAR2 and TYK2 in the case of IFNAR1. Binding of ligand to the IFNAR complex results in conformational changes that juxtapose these protein tyrosine kinases, resulting in auto and cross-phosphorylation and activation [reviewed by (17;46)]. Phosphorylation of critical tyrosine residues on the IFNAR receptor results in recruitment of signal transducing molecules such as STAT1 and STAT2 to the complex (18-21;23). Phosphorylation of these signal transducing molecules by the IFNAR-associated protein kinases results in formation of STAT1/STAT2 heterodimers and STAT1 homodimers that dissociate from the receptor and translocate into the nucleus to form transcriptional complexes with other factors. STAT1/STAT2 heterodimers, along with IRF-9, forms the IFN-stimulated gene factor 3 (ISGF3) complex that binds to upstream regulatory consensus sequences (IFN-stimulated response elements or ISRE) of type I IFN-inducible genes to initiate transcription. ISGF3 regulates the transcription of IRF-7 (47;48), providing the type I IFN system a positive feedback loop that allows massive amplification of the type I IFN response. STAT1 homodimers stimulate the transcription of genes containing the IFN-γ-activated sequence (GAS) (49).
In addition to the positive feedback loop mediated by ISGF3-induction of IRF-7, constitutively low levels of IFN-α/β have been found to be expressed in several cell types and appear to be a prerequisite for enhanced production of type I IFNs in response to stimuli. These low levels of IFN-α/β do not significantly activate downstream signaling events through IFNAR, but they do maintain tyrosine phosphorylation on IFNAR1, allowing for more efficient recruitment of STAT1 (50). Basal levels of IFN-α/β are also correlated with IRF-7 expression, providing another mechanism for more efficient induction of type I IFN upon infection (17). Constitutive IFN-α/β signaling appears to be required for more efficient type II IFN (IFN-γ) signaling as IFNAR1-deficient cells have a defective IFN-γ response associated with impaired dimerization of STAT1.
Unique among all the cytokines, type I IFNs are able to promote the activation of all seven STAT family members resulting in the formation of a number of homo- and heterodimer combinations and differing gene induction responses. The particular STAT(s) activated, STAT complexes formed, and the biological activities evoked are dependent on a variety of factors including cell type, cytokine milieu and stimulus [reviewed in (33)]. Indeed, some of the particular STATs have opposing activities and may compete with each other for binding to IFNAR and other STATs. For instance, activated STAT1 is known to promote antiproliferative and apoptotic effects (51), while STAT4 promotes survival and proliferation in CD8+ T cells, particularly those with low levels of STAT1 (52-54). In CD4+ T cells, activation of STAT3 and 5 in the presence of low STAT1 levels is necessary for the antiapoptotic and mitogenic effects of type I IFN (51), although STAT3 has also been shown to mediate apoptotic effects in still other cell types (55). Unlike T cells, the activation of STAT1 in NK cells does not promote apoptosis, but is necessary for NK cytotoxicity (56). Through these opposing effects, type I IFNs can mediate both the destruction of virally infected cells, while promoting the function of cells that are critical for mounting an appropriate immune response.
In addition to the classical JAK-STAT pathway, type I IFN signaling through IFNAR is able to induce several other pathways that can act either in conjunction with STATs or independently [reviewed in (16;33))] (Figure 2). For instance, some IRF family members can induce gene transcription independently of STATs in response to type I IFN signaling (ie IRF-1; mutated in Endeka) (57). Additionally, type I IFN signaling activates p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol (PI) 3-kinase (PI3K), and extracellular signal regulated kinase (ERK), kinases that are known to be involved in the activation of a variety of critical factors including the transcription factors NF-κB and activator protein (AP)-1, and the serine/threonine kinases protein kinase B (PKB or Akt) and the mammalian target of rapamycin(MTOR). Indeed, NF-κB is activated by type I IFNs both through the classical NF-κB pathway involving the IκB kinase (IKK) complex as well as an alternative pathway involving NF-κB inducing kinase (NIK) and TNF receptor associated factor (TRAF) 2 (see the record for panr2) (58). All of these pathways have been shown to be critical for many of the biological effects of type I IFNs including growth inhibition and antiviral responses.
The responses to type I IFNs are negatively regulated by several mechanisms. Some of these include the receptor subunits, including dephosphorylation of critical tyrosine residues and receptor internalization and degradation. Other mechanisms include dephosphorylation of JAKs and STATs by several phosphatases. In addition, the association of IFNAR1 with SOCS1 prevents the tyrosine phosphorylation of STATs (36), and the association of IFNAR2 with UBP43 interferes with JAK1 interaction (28). Further downstream, the inhibition of STAT functions in the nucleus by protein inhibitors of activated STATs (PIAS) proteins occurs (59). Many viruses have similarly found a way to prevent host antiviral responses by producing factors that inhibit the production of type I IFNs as well as type I IFN signaling [reviewed in (17)]. For example, poxvirus encodes a soluble protein that binds with high affinity to type I IFNs, thus neutralizing type I IFN signaling (60), while the V proteins of paramyxoviruses prevent the activation of STAT proteins through a variety of mechanisms including proteasomal degradation, inhibition of phosphorylation, sequestration, and blockage of nuclear translocation (17).
Due to their potent antiviral and anti-proliferative effects, type I IFNs are widely used to treat certain viral infections and cancers. In addition, type I IFNs have been found to play important roles in the etiology of some autoimmune diseases [reviewed in (46)]. For instance, type I IFNs are widely used for the treatment of multiple sclerosis (MS), a chronic autoimmune demyelinating disease characterized by the infiltration of inflammatory cells, including macrophages and T cells, into the CNS resulting in the destruction of axonal myelin sheaths (61). In an animal model of MS, animals deficient in IFN-β or IFNAR1 show an increased level of disease (62-64). The mechanisms underlying this involvement are not well understood, but appear to involve TRIF-dependent induction of type I IFN and subsequent inhibition of the development of a certain T cell subtype (Th17 cells) through IFNAR-dependent signaling in macrophages (63). Although another study studying IFNAR1-deficient mice in the same animal model of MS did not find a connection with Th17 cells, the absence of IFNAR1 on myeloid cells specifically led to severe disease and increased lethality (64). Mice with a B or T cell-specific IFNAR1 deficiency did not show increased disease levels. These results suggest that type I IFN signaling through IFNAR in myeloid cells plays a protective role against the development of multiple sclerosis. By contrast, excess type I IFNs and IFN-stimulated gene expression have been linked to the pathogenesis of other autoimmune diseases such as systemic lupus erythematosus (SLE) and insulin-dependent diabetes mellitus (IDDM) [reviewed by (46)]. Furthermore, IFN-α treatment for viral infections and tumors can sometimes induce these diseases as well as other autoimmune symptoms. The mechanisms behind these effects are not well understood, but likely include enhanced DC maturation and function, promotion of T and B cell differentiation, proliferation and survival, and changes in cytokine expression (46).
Polymorphisms in the human IFNAR2 and IFNAR1 genes have been implicated in a number of diseases [reviewed in (7)]. IFNAR2 polymorphisms include susceptibility to multiple sclerosis (65), and hepatitis B and C (64;66). Cells from Down syndrome patients are more sensitive to type I IFN treatment due to trisomy of Chromosome 21, which carries the gene complex containing both IFNAR genes. Accordingly, patients with Down syndrome have an aberrant immune response (67). Increased levels of soluble IFNAR2a have been reported in many chronic viral infections, cancers and other diseases (68-70), and was correlated with a decreased response to IFN therapy in one study (68). Furthermore, in vitro experiments demonstrated that sIFNAR2 was able to inhibit IFN signaling in wild type cells. However, in primary thymocytes from Ifnar2-/- mice sIFNAR2 was able to bind to type I IFNs and generate an antiproliferative signal (30), and another study demonstrated that ovine soluble IFNAR2 was able to mediate antiviral activity (71). Thus, whether soluble IFNAR2 isoforms behave as agonists or antagonists of type I IFN signaling remains uncertain.
Human deficiencies in proteins that are involved in the type I IFN response, including various STATs (see records for domino and poison) and TYK2, result in immunodeficiency (72-74). TYK2 deficiency in humans confirms the essential role TYK2 plays in type I IFN signaling, in contrast to results from mice that suggests that TYK2 plays a minor role in the type I IFN response (75).
As the macro-2 mutant was discovered in an ex vivo macrophage screen, it is not known whether macro-2 mice have a similar phenotype to those of Ifnar2 knockout animals. The permissiveness of homozygous macro-2 macrophages to viral infections suggests that IFNAR function in these cells is severely affected, and that the macro-2 mutation may be equivalent to a severely hypomorphic or null allele. However, the effects of this mutation in NK cells and DCs have not been tested. Macro-2 macrophages also produce lower levels of type I IFN relative to wild type macrophages in response to certain stimuli, perhaps due to the lack of the positive feedback loop through IRF-7 (47;48).
The macro-2 mutation affects the methionine start site of IFNAR2, and likely prevents protein translation. It is possible an alternative start site is used and some functional protein expressed in macro-2 mutants. No alternative in-frame start sites are present upstream of the Ifnar2 ATG start site, but the IFNAR2 protein has another methionine seventy-three amino acids downstream from the first methionine. Thus, minor amounts of IFNAR2 protein missing the first seventy-two amino acids are likely to be produced in homozygous macro-2 mutants. The deleted amino acids include most of the residues that are critical for binding to type I IFNS (12-14). It is likely this altered IFNAR2 would be defective in IFN binding and not responsive to type I IFN stimulation, although dominant negative effects from the intact intracellular domain may be possible.
|Primers||Primers cannot be located by automatic search.|
Macro-2 genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Primers for PCR amplification
Macro-2(F): 5’- TTGATACCACAGCGGAAGGTGAGC -3’
Macro-2(R): 5’- AACCATAGGCGGGACACATTAACTG -3’
1) 94°C 2:00
2) 94°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C 8
Primers for sequencing
Macro2_seq(F): 5’- CCTCTCTGCTTAGAGGACAGATG -3’
Macro2_seq(R): 5’- CAAGGCCGTTTCCTGAATATG -3’
The following sequence of 1002 nucleotides (from Genbank genomic region NC_000082 for linear DNA sequence of Ifnar2) is amplified:
10580 t tgataccaca gcggaaggtg agctaagcaa gtcccaggga
10621 tcaaggaagg actgaaacca gaatttggct actttttaat ttatttttaa agacaggtag
10681 ctcctctagc tggcttcaaa cttgctatgt agccgaggat gaccttgaat gcctgacctt
10741 tcccccacct ctctgcttag aggacagatg tgacacgcac agtaaactca tgcaagttta
10801 accctaatcc taaccaatcc agggctacca cggggccgca tctgcagcta aatctggctc
10861 gttcttactc gtctctcgtt agcgtgtatg tgtctatcat gtaaattaca atataattgg
10921 gtgcttctga gttttgacca actcaatatt gatctctttc aggtgtgaga gcagaaaaac
10981 ggacttaaga gctgagcagg atgcgttcac ggtgcaccgt ctctgccgtc ggtctcctca
11041 gcttgtgtct tgtgggtaag ggctacttct cagcacagcc cttagaggag aaagcctctg
11101 tttctgtcat cacagagagc cctggtgtgg agcagcacac tgatgtccat atctggagaa
11161 cccagatcag cacggccagc atcaggcacc ccacgggggt cttccccttc attttagcta
11221 agccagaata atataggcta cagccatatt caggaaacgg ccttgtttat aattcaaagg
11281 gttgcggctc tgcacaccct gaatctcacg cccggtggcg tttagaaggt ggccatccct
11341 ttatctcttc ccatataaac taacttgaaa aatccatccc tacacattga tttatactct
11401 tcctttcttt ttagccctta tcttttctat atctgtattt cttcacgtcc tttctgttcc
11461 ttcctctgaa ctgtttgaat tccacaatgt catctctccc attcattgtc ctcagcggat
11521 ccaggagtat gacaaatgtc tcagtgtgga catccacagt taatgtgtcc cgcctatggt
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated A is shown in red text.
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|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine|
|Authors||Sungyong Won, Celine Eidenschenk, Owen Siggs, Bruce Beutler|