Disease relevance of IFNAR1

• Flag-IR1B4 fusion proteins bind to the isolated IFNAR1 intracytoplasmic domain produced in Escherichia coli, as well as to the intact IFNAR1 chain extracted by detergent from human U266 cell membranes [1].
• IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response [2].
• Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia [3].
• CONCLUSION: This preliminary result suggests that the promoter GT repeat dinucleotide microsatellite polymorphism of the IFNAR1 gene may represent a risk factor for the development of depressive symptoms during IFN-alpha therapy for hepatitis C and other conditions [4].
• Intrahepatic mRNA Levels of Type I Interferon Receptor and Interferon-Stimulated Genes in Genotype 1b Chronic Hepatitis C. Association between IFNAR1 mRNA Level and Sustained Response to Interferon Therapy [5].

Psychiatry related information on IFNAR1

• This finding suggests that in the double TG mouse model mDCs once infected facilitate systemic MV spreading and infection, which depend on mDC MV permissiveness determined by the level of type I IFN generated via IFNAR1 [6].

High impact information on IFNAR1

• STAT3 as an adapter to couple phosphatidylinositol 3-kinase to the IFNAR1 chain of the type I interferon receptor [7].
• Mechanisms underlying down-regulation of the type I interferon receptor consisting of IFNAR1 and IFNAR2 subunits remain largely unknown [8].
• These findings characterize SCF(HOS) as an E3 ubiquitin ligase that is essential for ubiquitination, proteolysis and down-regulation of IFNAR1, and implicate HOS in the regulation of cellular responses to IFNalpha [8].
• HOS expression and activities are required for IFNalpha-stimulated ubiquitination of IFNAR1, endocytosis of the type I interferon receptor, down-regulation of IFNAR1 levels, and IFNAR1 proteolysis via the lysosomal pathway [8].
• The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression [9].

Chemical compound and disease context of IFNAR1

• The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V(1)-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 mug/kg) [10].
• We have previously demonstrated that both all-trans retinoic acid (ATRA) and interferon á (IFNá) can inhibit proliferation of human PNET cells and that ATRA can up-regulate IFNá receptor expression in vitro [11].
• Involvement of anteroventral third ventricular AMPA/kainate receptors in both hyperosmotic and hypovolemic AVP secretion in conscious rats [12].
• Felypressin and AVP induced a pressor effect, and bradycardia was inhibited by IV V1 antagonist [13].

Biological context of IFNAR1

• One subunit, IFNAR1, has low affinity binding for interferon yet is required for signal transduction [14].
• A trend detected with a single nucleotide polymorphism SNP 16469 (A/T) located at the third intron of the IFNAR1 gene, suggesting modest association with relapse-free status, will require confirmation in an independent data set [15].
• IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis [16].
• No alteration of the expression level of IFNAR-1 was observed with respect to the -408 genotypes or to interferon treatment response [2].
• Although the amino acid sequences of various IFN-alpha/beta subtypes differ markedly, they are all considered to share a common three-dimensional structure and to bind the same heterodimeric receptor, composed of the IFNAR-1 and IFNAR-2 subunits [17].

Anatomical context of IFNAR1

• Northern blot analysis revealed that IFNAR1 mRNA was present in days 15-19 conceptuses and day 18-19 allantoic membranes [18].
• Stably transfected mouse L929 cell lines expressing truncation mutants of the intracellular domain of the human IFNAR1 chain were tested for biological responses to human IFN alpha [19].
• Interferon-tau (IFNtau), produced by the trophectoderm of ruminant ungulates, binds to the type I IFN receptor (IFNAR) located at the uterine endometrium in a paracrine manner [18].
• We examined the role of type I IFNs in macrophage responses to LPS using bone marrow-derived macrophages (BMM) from IFNAR1-/- mice, which lack a component of the type I IFN receptor and do not respond to type I IFNs [20].
• In order to investigate the mechanism of interferon-alpha (IFNalpha) action in the treatment of chronic myelogenous leukemia (CML), we examined surface expressions of both type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) subunits on CD34-positive cells in bone marrow (BM) in a total of 57 CML patients [21].

Associations of IFNAR1 with chemical compounds

• Thus, in interferon-alpha,beta receptors (IFNAR1 and 2), the IC region binds protein-tyrosine and -serine/threonine kinases which phosphorylate the receptor and the associated Stat transcription factors [1].
• In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis [16].
• Differential tyrosine phosphorylation of the IFNAR chain of the type I interferon receptor and of an associated surface protein in response to IFN-alpha and IFN-beta [22].
• The beta-PTyr protein is present on the cell surface, like IFNAR, as shown by extracellular biotin tagging [22].
• Previous work showed that a point mutation in the Src homology 2 (SH2) domain prevents STAT2 from binding to phosphotyrosine 466 of the IFNAR1 subunit of the activated receptor [23].

Physical interactions of IFNAR1

• The IFNAR chain interacts with both IFN-alpha 2 and IFN-beta, as demonstrated by cross-linking [22].
• Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1 [24].
• A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor [1].
• Furthermore, tyrosine-phosphorylated STAT3 bound to the IFNAR-1 chain also undergoes a secondary modification involving serine phosphorylation [25].
• Thus, we show that the differential activities of IFN-beta are directly related to the binding affinity for IFNAR1 [26].

Enzymatic interactions of IFNAR1

• Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1 [27].

Co-localisations of IFNAR1

• Ifnabr colocalized with Ifnar to the distal region of q22 [28].

Regulatory relationships of IFNAR1

• Both are IFN dependent and abrogated by a monoclonal antibody which blocks IFNAR action [22].
• TYK2 activity promotes ligand-induced IFNAR1 proteolysis [16].
• Further, IFN-beta treatment stimulated IFNAR-1-associated phosphoinositol kinase activity equally in either U1.wt or U1.KR930 cells [29].

Other interactions of IFNAR1

• The ifnar1 component is well characterized and a putative ifnar2 cDNA has recently been identified [30].
• In both model systems, titration of the Tyk2 kinase away from the Ifnar1 receptor chain accounts for the observed cross-interference [31].
• NF-kappaB activation requires the IFN-dependent association of STAT3 with the IFNAR1 chain of the IFN receptor [32].
• These experiments indicated that IFNAR1 forms a complex containing the MeV-accessory proteins C and V, RACK1, and STAT1 in MeV-infected cells but not in uninfected cells [33].
• After IFN-beta treatment for 5 min, a tyrosine-phosphorylated protein of approximately 95 kDa (beta-PTyr) is found bound to IFNAR, but can be dissociated by denaturation [22].
• The lack of IFNAR1 palmitoylation affects selectively the activation of Stat2, which results in a lack of efficient Stat1 activation and nuclear translocation and IFN-alpha-activated gene transcription [34].

Analytical, diagnostic and therapeutic context of IFNAR1

• The first cloned chain (IFNAR1) of the human interferon-alpha (IFN alpha) receptor acts as a species-specific transducer for type 1 IFN action when transfected into heterologous mouse cells [19].
• Results: As determined by quantitative RT-PCR analysis and immunocytochemistry, H295 and SW13 cells expressed the active type I IFN receptor (IFNAR) mRNA and protein (IFNAR-1 and IFNAR-2c subunits) [35].
• Immunoprecipitation experiments demonstrated that IFNAR2.2 is present in Daudi cells as a cell surface protein of approximately 90-100 kDa, which is tyrosine-phosphorylated and associated with IFNAR1, upon stimulation of cells with IFN-beta [36].
• Gel filtration of a mixture of IFNAR1 and the IFN-beta-1a/IFNAR2 complex indicated that the three proteins formed a stable ternary complex [37].
• Sequence analysis of the porcine IFNAR1 and IFNGR2 genes [38].

References