{"gene":"IFNAR2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1999,"finding":"The extracellular domain of IFNAR2 (ifnar2-EC) binds IFNalpha2 with 1:1 stoichiometry and ~10 nM affinity, as established by gel filtration, chemical cross-linking, BIAcore, reflectometric interference spectroscopy, and fluorescence de-quenching. The association rate has a significant electrostatic component (salt-dependent), and binding affinity decreases with decreasing pH (pKa ~6.7), indicating protonation of a titratable residue at the binding interface.","method":"Gel filtration, chemical cross-linking, surface plasmon resonance (BIAcore), reflectometric interference spectroscopy, fluorescence de-quenching, recombinant protein reconstitution","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods in a single rigorous in vitro study with purified recombinant proteins","pmids":["10339405"],"is_preprint":false},{"year":1999,"finding":"Mutational analysis defined the functional binding epitope on IFNalpha2 (hot-spots L30 and R33 on the AB loop) and on ifnar2-EC (hot-spots T46, I47, M48, plus ~10 additional residues). Although IFNalpha2 and IFNbeta compete for the same epitope on ifnar2, mutagenesis revealed distinct centers of binding, suggesting different angular orientations that may differentially couple to cytoplasmic signaling. Antiviral potency correlated proportionally with ifnar2 binding affinity, implicating ifnar2 binding as rate-limiting for IFN signaling.","method":"Alanine-scanning mutagenesis, label-free surface plasmon resonance kinetics and thermodynamics, antiviral potency assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and multiple quantitative biophysical readouts in a single rigorous study","pmids":["10556041"],"is_preprint":false},{"year":1997,"finding":"The murine type I IFN receptor requires two subunits: muIFNaR1 and muIFNaR2 (49% identical to human IFNAR2). Co-expression of both subunits with an IFN-responsive luciferase reporter in human cells conferred responsiveness to murine IFN-beta; neither subunit alone was sufficient.","method":"cDNA library screening, co-expression of receptor subunits with luciferase reporter, functional reconstitution in human cells","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional reconstitution experiment with rigorous negative controls (single subunit transfections)","pmids":["9322767"],"is_preprint":false},{"year":2001,"finding":"A soluble isoform of murine Ifnar-2 (muIfnar-2a) is present in serum and biological fluids. At low concentrations it acts as an agonist: it forms a complex with IFN-alpha/beta and cell-surface muIfnar-1, and this complex transmits an antiproliferative signal through the Ifnar-1 chain alone (tested on Ifnar-2-/- primary thymocytes), demonstrating that signal transduction can occur through Ifnar-1 in the absence of the Ifnar-2 cytoplasmic domain. At high concentrations the soluble receptor competitively inhibits IFN activity.","method":"Western blot of serum fractions, competitive inhibition reporter assay (L929 cells), antiproliferative and antiviral assays with primary cells, cell-surface complex formation assay using Ifnar-2-/- thymocytes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments with KO primary cells and multiple orthogonal assays; dual agonist/antagonist finding replicated across assay types","pmids":["11154225"],"is_preprint":false},{"year":1999,"finding":"Dimerization of IFNaR2-2 intracellular/transmembrane domain alone (via EpoR extracellular domain chimera) is sufficient to induce IFN-responsive gene transcription (6-16 promoter) upon ligand stimulation, but is insufficient for full antiviral protection. IFNaR1 is required for sustained mRNA and protein levels of antiviral effectors (PKR, OAS, MxA) at later time points.","method":"Chimeric receptor constructs (EpoR extracellular/IFNaR intracellular domains), transfection into 2fTGH and TYK2-deficient cells, promoter reporter assay, gene expression time course, Western blot, viral challenge assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimeric receptor reconstitution with defined loss-of-function genetic backgrounds and multiple functional readouts","pmids":["10574956"],"is_preprint":false},{"year":2004,"finding":"IFNAR2 (IFNaR2) undergoes regulated proteolytic cleavage in response to PMA, IFN-alpha, EGF, and PKC-delta overexpression, generating a transmembrane stub and releasing the intracellular domain (ICD) in a presenilin-dependent, multi-step process resembling Notch/APP regulated intramembrane proteolysis. The released ICD localizes to the nucleus (GFP fusion) and, when fused to Gal4 DBD, represses transcription of ISRE-linked reporters in a histone deacetylase-dependent manner.","method":"Immunoblotting of membrane fractions, chimeric receptor constructs, pharmacological stimulation, fluorescence microscopy (GFP-ICD), Gal4 reporter transcription assay, HDAC inhibitor treatment","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (biochemical cleavage assay, chimeric receptors, live-cell imaging, reporter assay) in a single study","pmids":["15286706"],"is_preprint":false},{"year":2005,"finding":"The IFNaR2 intracellular domain (ICD) modulates transcription through the C-terminal transactivation domain of STAT2. STAT2 binds constitutively to the ICD in a tyrosine-phosphorylation-independent manner. Complementation of STAT2-deficient cells with wild-type STAT2 (but not a TAD-deleted mutant) restored ICD-mediated transcriptional effects. JAK1 kinase activity is also required for ICD-mediated transcription. Mutation of the STAT2 binding site on the ICD reduced its transcriptional activity.","method":"Gal4 DBD-ICD reporter assay in STAT2-deficient cells, complementation with WT vs. TAD-mutant STAT2, JAK1 inhibition, site-directed mutagenesis of STAT2 binding site","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic complementation with separation-of-function mutants plus mutagenesis of binding site, multiple orthogonal methods","pmids":["15717316"],"is_preprint":false},{"year":2007,"finding":"IFNalpha2 and IFNbeta stimulate comparable immediate JAK/STAT activation, but differ in IFNAR2 trafficking: after IFNalpha2 binding, IFNAR2 is internalized and recycled back to the cell surface, whereas after IFNbeta binding it is routed to degradation. This differential routing is governed by the stability and intracellular lifetime of the ternary ligand-receptor complex.","method":"Quantitative measurement of surface receptor decay by flow cytometry, internalization/recycling assays, JAK/STAT phosphorylation kinetics across multiple cell lines with variable IFNAR1 levels","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple cell lines, quantitative surface decay and recycling assays, JAK/STAT activation comparisons in a single study","pmids":["17627610"],"is_preprint":false},{"year":2008,"finding":"The IFNaR2 ICD, STAT2, and IRF9 form a ternary complex. STAT2 acts as an adaptor bridging the ICD to IRF9. The bipartite nuclear localization signal within IRF9 is the primary determinant driving nuclear transit of the ICD-containing complex (visualized with GFP-ICD). Both STAT2 and IRF9 are required for nuclear transit of the IFNaR2 ICD.","method":"Co-immunoprecipitation, GFP-ICD nuclear localization assay, genetic complementation in STAT2/IRF9-deficient cells, co-localization imaging","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and genetic complementation with imaging, single lab but multiple orthogonal approaches","pmids":["18456457"],"is_preprint":false},{"year":2010,"finding":"NMR mapping of IFNalpha2 bound to the binary IFNalpha2/IFNAR2-EC complex revealed that IFNAR1-EC binding affects a patch on the same face as the IFNAR2 binding site (in addition to two patches on the opposing face), demonstrating allosteric communication between the IFNAR1 and IFNAR2 binding sites on IFNalpha2.","method":"1H-15N TROSY-HSQC NMR spectroscopy at 800 MHz on the 89 kDa ternary complex; chemical shift perturbation mapping","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural mapping of the ternary complex, rigorous in vitro experiment with isotopically labeled protein","pmids":["20047337"],"is_preprint":false},{"year":2021,"finding":"IFNAR2 ICD has a major role in initiating JAK-STAT signaling: successive truncations of the IFNAR2 ICD proportionally decreased constitutive STAT binding, STAT phosphorylation, and target gene activation. Tyrosine residues in the IFNAR1 ICD were not required for signaling, but simultaneous mutation of all IFNAR2 ICD tyrosines reduced STAT phosphorylation and antiviral activity without abolishing constitutive STAT2 binding, suggesting that IFNAR2 ICD tyrosine phosphorylation drives dissociation of phosphorylated STATs to maintain high signaling flux. JAK1 is associated with IFNAR2 and TYK2 with IFNAR1.","method":"Receptor ICD truncation/mutation analysis in IFNAR1/IFNAR2 double-knockout cells reconstituted with defined receptor mutants; STAT phosphorylation assays, gene activation assays, antiviral protection assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis in clean KO background with multiple functional readouts; reconstitution approach","pmids":["34813358"],"is_preprint":false},{"year":2022,"finding":"Using synthetic receptor chimeras (nanobody-based extracellular domains fused to native IFNAR transmembrane/intracellular domains), IFNAR2 homodimers were sufficient to induce STAT1/2 signaling via JAK1 and TYK2, whereas IFNAR1 homodimers were not. Mutagenesis identified Y510 and Y335 in murine IFNAR2 as the unique phosphorylation sites required for STAT1/2 activation; other tyrosines in IFNAR1 and IFNAR2 were not involved.","method":"Synthetic receptor chimeras (nanobody-based), STAT1/2 phosphorylation assays, transcriptome analysis, viral replication inhibition assay, intracellular deletion variants and point mutations","journal":"Frontiers in microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — synthetic biology reconstitution with separation-of-function mutagenesis and multiple orthogonal readouts in a single study","pmids":["36118237"],"is_preprint":false},{"year":2015,"finding":"A homozygous loss-of-function mutation in IFNAR2 rendered patient cells unresponsive to IFN-alpha/beta. Reconstitution of patient cells with wild-type IFNAR2 restored IFN-alpha/beta responsiveness and control of IFN-attenuated viruses, establishing IFNAR2 as essential and non-redundant for IFN-I signaling in human antiviral immunity.","method":"Targeted resequencing, functional assays on patient-derived cells (IFN signaling, viral control), complementation with wild-type IFNAR2 cDNA","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function with genetic complementation rescue; functional antiviral assays in patient cells","pmids":["26424569"],"is_preprint":false},{"year":2022,"finding":"A missense variant p.Ser53Pro in IFNAR2 prevents cell-surface expression of IFNAR2 protein; small amounts persist intracellularly in an aberrantly glycosylated state. Cells exclusively expressing p.Ser53Pro lacked responses to recombinant IFN-I and showed heightened viral vulnerability in vitro—a phenotype rescued by wild-type IFNAR2 complementation.","method":"Patient genetic analysis, cell surface expression assays, glycosylation analysis, IFN-I response assays (ISG induction, STAT phosphorylation), viral challenge in vitro, wild-type IFNAR2 complementation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays in patient cells with complementation rescue; independent cohort replication","pmids":["35442417"],"is_preprint":false},{"year":2020,"finding":"In IFNAR2-deficient patient NK cells stimulated with IFNalpha, the expected increase in degranulation was impaired and the expected inhibition of IFNgamma production was absent, demonstrating that IFNAR2-dependent IFN-I signaling is required for normal NK cell effector function modulation.","method":"Ex vivo NK cell functional assays (degranulation, IFNgamma production) on patient PBMC; STAT1 phosphorylation and ISG induction assays","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional ex vivo assays on patient cells, single case report with limited replication","pmids":["33193576"],"is_preprint":false},{"year":2004,"finding":"Soluble IFNAR2 (sIFNAR-2) forms a specific complex with IFN-beta, extending its serum half-life from minutes to hours in mice when co-administered intravenously, and enhances its antitumor efficacy 9–27-fold in xenograft models. The enhancement depends on slow release of IFN-beta from the complex in vivo.","method":"In vitro antiviral enhancement assay, in vivo mouse pharmacokinetic studies (IV administration), xenograft SCID mouse survival assay","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacokinetic and efficacy studies with mechanistic in vitro dissociation data, single lab","pmids":["14980076"],"is_preprint":false},{"year":2004,"finding":"IFNAR2 interacts with stress-activated protein kinase-interacting protein 1 (Sin1) via the C-terminal 185 amino acids of ovine IFNAR2. The interaction is constitutive (yeast two-hybrid and co-immunoprecipitation). When co-expressed, ovSin1 and ovIFNAR2 co-localize at the plasma membrane and perinuclear structures, suggesting Sin1 links IFN-I signaling to stress-activated pathways.","method":"Yeast two-hybrid screen of ovine endometrial cDNA library, co-immunoprecipitation, co-localization by immunofluorescence microscopy","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus co-IP and co-localization, single lab, novel interaction not independently replicated","pmids":["15345682"],"is_preprint":false},{"year":2014,"finding":"IFN-alpha induces cell cycle arrest in G0/G1 phases leading to apoptosis through an IFNAR2-dependent signaling pathway in HuH7 hepatocellular carcinoma cells. Time-lapse imaging with a Fucci fluorescent cell cycle indicator showed that the IFN-alpha/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for death in G0/G1.","method":"Fucci-based live-cell time-lapse imaging, IFNAR2 loss-of-function, biochemical apoptosis assays, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct live-cell mechanistic imaging with defined receptor loss-of-function, single lab and cell line","pmids":["25012666"],"is_preprint":false},{"year":2020,"finding":"IFNAR2 was identified as a novel HCV entry factor. IFNAR2 binds HCV virions through a direct interaction of its D2 domain with the C-terminal end of apolipoprotein E (apoE) on the viral envelope. Silencing IFNAR2 reduced HCV proliferation. An anti-IFNAR2 D2 domain antibody attenuated the IFNAR2-apoE interaction and impaired HCV infection. Recombinant IFNAR2 protein inhibited multiple HCV genotypes in vitro and in humanized mice.","method":"Chemical probes, IFNAR2 knockdown, direct binding assay (IFNAR2 D2 domain with apoE), antibody blocking, in vitro infection assays across HCV genotypes, humanized transgenic mouse model","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct protein-protein interaction mapped to specific domain, genetic KD, antibody blocking, and in vivo validation; multiple orthogonal methods","pmids":["31972076"],"is_preprint":false},{"year":2025,"finding":"The African swine fever virus protein B125R binds to IFNAR2 and promotes its autophagic degradation, thereby impairing JAK-STAT signal transduction at an early stage, reducing nuclear translocation of the ISGF3 complex and decreasing ISG production.","method":"Ectopic expression in HEK293T and PK-15 cells, co-immunoprecipitation (pB125R–IFNAR2 interaction), IFN-beta-triggered JAK-STAT reporter assays, autophagy inhibition experiments, ISGF3 nuclear translocation assay","journal":"Veterinary research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP interaction plus mechanistic pathway assays, single lab, limited independent replication","pmids":["40270033"],"is_preprint":false},{"year":2022,"finding":"Human IFN-I signaling in THP1 monocytic cells absolutely requires IFNAR2, as shown by complete loss of ISG induction upon CRISPR/Cas9 knockout. A 7-bp deletion IFNAR2 mutant retains partial responsiveness to IFNbeta by upregulating a subset of tonic-like ISGs; this residual signaling still depends on IFNAR2 protein expression (via exon skipping producing a truncated but functional protein).","method":"CRISPR/Cas9 knockout, IFN-beta stimulation, ISG expression profiling, RT-qPCR, Western blot, CRISPR-induced exon-skipping analysis","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined phenotypic readout, single lab, single cell line","pmids":["36346319"],"is_preprint":false},{"year":2002,"finding":"The murine Ifnar-2 gene spans ~33 kb, consists of 9 exons and 8 introns, and generates one transmembrane (Ifnar-2c) and two soluble (Ifnar-2a/2a') isoforms by alternative RNA processing. Promoter analysis defined three regulatory regions: a proximal region conferring high basal expression, a distal region conferring IFN-inducible expression, and a negative regulatory region between them. The two transcript isoforms (2a and 2c) are independently regulated in some cell types.","method":"Genomic cloning, promoter-luciferase reporter assays, IFN treatment of multiple cell lines, RT-PCR isoform analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter dissection by reporter assays across multiple cell lines with deletion constructs; first promoter analysis of a type I IFN receptor","pmids":["11939908"],"is_preprint":false}],"current_model":"IFNAR2 is the high-affinity subunit of the heterodimeric type I interferon receptor that binds IFNalpha/beta with ~10 nM affinity through a defined epitope centered on residues T46/I47/M48 in its extracellular domain; upon ligand-driven dimerization with IFNAR1, its intracellular domain (associated with JAK1) recruits and constitutively binds STAT2, and phosphorylation of key tyrosines (Y335/Y510 in mouse) drives STAT dissociation to maintain signaling flux, while the ICD can also be released by presenilin-dependent regulated proteolysis to form a nuclear STAT2/IRF9 ternary complex that modulates transcription; soluble IFNAR2 isoforms act as both agonists and antagonists of IFN signaling, and IFNAR2 additionally serves as an entry receptor for HCV via direct binding of its D2 domain to apolipoprotein E on viral envelopes."},"narrative":{"mechanistic_narrative":"IFNAR2 is the high-affinity ligand-binding subunit of the heterodimeric type I interferon receptor and is essential and non-redundant for IFN-alpha/beta signaling in human antiviral immunity [PMID:10339405, PMID:26424569]. Its extracellular domain binds IFNalpha2 with 1:1 stoichiometry and ~10 nM affinity through a defined epitope centered on hot-spot residues T46/I47/M48, and antiviral potency scales with this binding affinity, making IFNAR2 engagement rate-limiting for signaling [PMID:10339405, PMID:10556041]; productive responsiveness additionally requires the partner subunit IFNAR1, with which it forms an allosterically coupled ternary complex on the ligand [PMID:9322767, PMID:20047337]. Signaling is driven by the IFNAR2 intracellular domain, which associates with JAK1 and constitutively binds STAT2 in a phosphorylation-independent manner; tyrosine phosphorylation of the IFNAR2 ICD (Y335/Y510 in mouse) drives dissociation of phosphorylated STATs to sustain signaling flux, and IFNAR2 dimerization is itself sufficient to activate STAT1/2 via JAK1 and TYK2 [PMID:15717316, PMID:34813358, PMID:36118237]. The IFNAR2 ICD is also released by presenilin-dependent regulated intramembrane proteolysis and translocates to the nucleus as a ternary complex with STAT2 and IRF9, where it modulates ISRE-linked transcription [PMID:15286706, PMID:18456457]. Soluble IFNAR2 isoforms generated by alternative RNA processing act as agonists at low concentrations and competitive antagonists at high concentrations, and can stabilize circulating IFN-beta [PMID:11154225, PMID:14980076, PMID:11939908]. Human loss-of-function and trafficking-defective IFNAR2 variants abolish IFN-I responses and confer heightened viral vulnerability [PMID:26424569, PMID:35442417]. Independent of its cytokine-receptor role, IFNAR2 serves as an HCV entry factor via direct binding of its D2 domain to viral-envelope apolipoprotein E [PMID:31972076].","teleology":[{"year":1997,"claim":"Established that the functional murine type I IFN receptor requires two distinct subunits rather than one, defining IFNAR2 as one of two obligatory chains.","evidence":"cDNA co-expression of muIFNaR1 and muIFNaR2 with an IFN-responsive luciferase reporter in human cells, with single-subunit negative controls","pmids":["9322767"],"confidence":"High","gaps":["Did not resolve which subunit binds ligand with high affinity","No structural or biophysical characterization of the interaction"]},{"year":1999,"claim":"Defined IFNAR2 as the high-affinity ligand-binding subunit and mapped the binding interface, showing IFNAR2 engagement is rate-limiting for IFN signaling.","evidence":"Multiple orthogonal biophysics (gel filtration, cross-linking, SPR, RIfS) and alanine-scanning mutagenesis with antiviral potency assays on recombinant ifnar2-EC and IFNalpha2","pmids":["10339405","10556041"],"confidence":"High","gaps":["Did not define how IFNAR1 contributes to the ternary complex geometry","Did not connect binding to intracellular signaling output"]},{"year":1999,"claim":"Showed the IFNAR2 intracellular/transmembrane domain alone can initiate ISG transcription upon dimerization but is insufficient for durable antiviral protection, partitioning early signaling from sustained effector output.","evidence":"EpoR-IFNaR chimeric receptors in 2fTGH and TYK2-deficient cells with promoter reporters, antiviral effector time courses, and viral challenge","pmids":["10574956"],"confidence":"High","gaps":["Did not identify the ICD residues required for signaling","Mechanism of IFNAR1 requirement for sustained effector expression unresolved"]},{"year":2001,"claim":"Demonstrated that a soluble IFNAR2 isoform can transmit signal through IFNAR1 alone and acts as a concentration-dependent agonist/antagonist, revealing IFNAR2 can function without its own cytoplasmic domain.","evidence":"Serum fractionation, competitive reporter assays, and antiproliferative/complex-formation assays using Ifnar-2-/- primary thymocytes","pmids":["11154225"],"confidence":"High","gaps":["Physiological concentrations governing agonist vs antagonist switch not defined in humans","Relationship to membrane isoform regulation unclear"]},{"year":2002,"claim":"Characterized the gene architecture and promoter regulation generating transmembrane and soluble IFNAR2 isoforms, explaining how isoform balance is controlled and is itself IFN-inducible.","evidence":"Genomic cloning, promoter-luciferase deletion analysis across cell lines, and RT-PCR isoform profiling of murine Ifnar-2","pmids":["11939908"],"confidence":"Medium","gaps":["Human promoter regulation not directly addressed","Trans-acting factors controlling the negative regulatory region not identified"]},{"year":2004,"claim":"Identified regulated intramembrane proteolysis of IFNAR2 that releases a nuclear-targeting ICD with transcription-modulating activity, uncovering a non-canonical nuclear arm of IFNAR2 function.","evidence":"Membrane-fraction immunoblotting, chimeric receptors, GFP-ICD imaging, and Gal4 reporter assays with presenilin and HDAC dependency in stimulated cells","pmids":["15286706"],"confidence":"High","gaps":["In vivo physiological significance of the released ICD not established","Cleavage protease(s) downstream of presenilin not fully defined"]},{"year":2004,"claim":"Reported IFNAR2 interactions extending beyond canonical signaling, linking it to stress-activated pathways and to pharmacologic stabilization of IFN-beta.","evidence":"Yeast two-hybrid, co-IP, and co-localization for ovine IFNAR2-Sin1; in vivo pharmacokinetics and xenograft efficacy for soluble IFNAR2-IFN-beta complexes","pmids":["15345682","14980076"],"confidence":"Medium","gaps":["Sin1 interaction not independently replicated and functional consequence unclear","Human relevance of the Sin1 link unaddressed"]},{"year":2005,"claim":"Mechanistically defined the nuclear ICD activity as STAT2-dependent, showing constitutive phosphorylation-independent STAT2 binding via its transactivation domain plus a JAK1 requirement.","evidence":"Gal4-ICD reporter assays in STAT2-deficient cells complemented with WT vs TAD-mutant STAT2, JAK1 inhibition, and STAT2-binding-site mutagenesis","pmids":["15717316"],"confidence":"High","gaps":["Target gene set modulated by the ICD-STAT2 axis not defined","Quantitative contribution relative to canonical ISGF3 signaling unknown"]},{"year":2007,"claim":"Showed that ligand identity controls IFNAR2 receptor fate, with IFNalpha2 driving recycling and IFNbeta driving degradation, providing a trafficking basis for differential signaling outcomes.","evidence":"Quantitative flow-cytometry surface decay, internalization/recycling assays, and JAK/STAT kinetics across cell lines with variable IFNAR1","pmids":["17627610"],"confidence":"High","gaps":["Sorting machinery directing recycling vs degradation not identified","Link between trafficking fate and downstream gene programs not fully mapped"]},{"year":2008,"claim":"Resolved the nuclear transport mechanism of the ICD by showing it forms an ICD-STAT2-IRF9 ternary complex where STAT2 bridges and IRF9's NLS drives nuclear entry.","evidence":"Co-IP, GFP-ICD nuclear localization, and complementation in STAT2/IRF9-deficient cells with co-localization imaging","pmids":["18456457"],"confidence":"Medium","gaps":["Single-lab finding without reciprocal in vivo validation","Transcriptional targets of the nuclear ternary complex not enumerated"]},{"year":2010,"claim":"Provided structural evidence for allosteric coupling between IFNAR1 and IFNAR2 binding sites on the shared ligand, explaining how the two subunits cooperate in ternary complex assembly.","evidence":"TROSY-HSQC NMR chemical-shift perturbation mapping of the 89 kDa IFNalpha2/IFNAR2-EC/IFNAR1-EC complex","pmids":["20047337"],"confidence":"High","gaps":["Does not connect allosteric changes to specific signaling output differences","Conformational dynamics in full-length membrane receptors not addressed"]},{"year":2015,"claim":"Established IFNAR2 as essential and non-redundant for human antiviral immunity through a causative loss-of-function mutation rescuable by wild-type cDNA.","evidence":"Patient resequencing, IFN signaling and viral-control assays in patient cells, and complementation with WT IFNAR2","pmids":["26424569"],"confidence":"High","gaps":["Full clinical spectrum of IFNAR2 deficiency not delineated here","Tissue-specific consequences beyond antiviral control not addressed"]},{"year":2014,"claim":"Linked IFNAR2 signaling to a defined cell-fate program, showing the IFNalpha/IFNAR2 axis drives cell-cycle arrest and apoptosis in hepatocellular carcinoma cells.","evidence":"Fucci live-cell imaging, IFNAR2 loss-of-function, and apoptosis/cell-cycle assays in HuH7 cells","pmids":["25012666"],"confidence":"Medium","gaps":["Single cell line; generality across tissues unknown","Downstream effectors coupling IFNAR2 to apoptosis not defined"]},{"year":2020,"claim":"Revealed a cytokine-receptor-independent role of IFNAR2 as an HCV entry factor binding viral apolipoprotein E through its D2 domain.","evidence":"IFNAR2 knockdown, direct D2-apoE binding assays, antibody blocking, multi-genotype infection assays, and humanized mouse validation","pmids":["31972076"],"confidence":"High","gaps":["Structural basis of D2-apoE binding not resolved","Relationship between entry-factor role and signaling role not integrated"]},{"year":2020,"claim":"Connected IFNAR2 deficiency to impaired innate effector function, showing disrupted NK cell degranulation and IFNgamma regulation.","evidence":"Ex vivo NK functional assays on patient PBMC with STAT1 phosphorylation and ISG induction readouts","pmids":["33193576"],"confidence":"Medium","gaps":["Single case report with limited replication","Cell-intrinsic vs systemic contributions to NK phenotype not separated"]},{"year":2021,"claim":"Defined the IFNAR2 ICD as the principal driver of JAK-STAT initiation, with its tyrosines promoting phosphorylated-STAT dissociation to maintain signaling flux while IFNAR1 tyrosines are dispensable.","evidence":"Systematic ICD truncation/tyrosine mutagenesis in IFNAR1/IFNAR2 double-knockout cells with STAT phosphorylation, gene activation, and antiviral assays","pmids":["34813358"],"confidence":"High","gaps":["Identity of phosphatases or release machinery acting on STATs not defined","Quantitative kinetics of STAT cycling not measured"]},{"year":2022,"claim":"Showed IFNAR2 homodimerization is sufficient to activate STAT1/2 via JAK1/TYK2 and pinpointed Y335/Y510 as the unique signaling tyrosines, while a human trafficking-defective variant confirmed surface expression is required for function.","evidence":"Nanobody-based synthetic receptor chimeras with separation-of-function mutagenesis; patient p.Ser53Pro analysis with surface-expression, glycosylation, IFN-response and complementation assays; CRISPR knockout in THP1 monocytes","pmids":["36118237","35442417","36346319"],"confidence":"High","gaps":["Whether IFNAR2 homodimers form physiologically without IFNAR1 unknown","Tonic-like residual ISG program of partial-function alleles incompletely characterized"]},{"year":2025,"claim":"Demonstrated that a viral protein subverts IFNAR2 by driving its autophagic degradation to blunt JAK-STAT signaling, identifying IFNAR2 as a target of immune evasion.","evidence":"Ectopic expression and co-IP of ASFV pB125R with IFNAR2, JAK-STAT reporter assays, autophagy inhibition, and ISGF3 nuclear translocation assays in HEK293T/PK-15 cells","pmids":["40270033"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Degradation machinery and physiological relevance during infection not fully established"]},{"year":null,"claim":"How the canonical surface signaling role, the proteolytically released nuclear ICD arm, and the IFNAR2 trafficking and HCV-entry functions are integrated and balanced within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking surface signaling, RIP-released nuclear ICD, and entry-factor roles","Physiological triggers and quantitative contribution of regulated proteolysis in vivo unknown","Structural basis of full-length ternary signaling complex not solved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,8,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7,13,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,14,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,19]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[17]}],"complexes":["Type I interferon receptor (IFNAR1/IFNAR2 heterodimer)","ICD-STAT2-IRF9 ternary complex"],"partners":["IFNAR1","STAT2","IRF9","JAK1","SIN1","APOLIPOPROTEIN E"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48551","full_name":"Interferon alpha/beta receptor 2","aliases":["Interferon alpha binding protein","Type I interferon receptor 2"],"length_aa":515,"mass_kda":57.8,"function":"Together with IFNAR1, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa) (PubMed:10049744, PubMed:10556041, PubMed:21854986, PubMed:26424569, PubMed:28165510, PubMed:32972995, PubMed:7665574, PubMed:7759950, PubMed:8181059, PubMed:8798579, PubMed:8969169). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response (PubMed:10049744, PubMed:17517919, PubMed:21854986, PubMed:26424569, PubMed:28165510, PubMed:32972995, PubMed:7665574, PubMed:7759950, PubMed:8181059, PubMed:8798579, PubMed:8969169). Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another (PubMed:10556041, PubMed:11682488, PubMed:12105218, PubMed:21854986, PubMed:32972995). The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (STAT1, STAT2 and STAT) (PubMed:11682488, PubMed:12105218, PubMed:21854986, PubMed:32972995). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes (PubMed:12105218, PubMed:28165510, PubMed:9121453) Potent inhibitor of type I IFN receptor activity","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P48551/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFNAR2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFNAR2","total_profiled":1310},"omim":[{"mim_id":"618886","title":"PSEUDO-TORCH SYNDROME 3; PTORCH3","url":"https://www.omim.org/entry/618886"},{"mim_id":"616669","title":"IMMUNODEFICIENCY 45; IMD45","url":"https://www.omim.org/entry/616669"},{"mim_id":"615326","title":"INTERFERON, KAPPA; IFNK","url":"https://www.omim.org/entry/615326"},{"mim_id":"615223","title":"INTERFERON, EPSILON; IFNE","url":"https://www.omim.org/entry/615223"},{"mim_id":"610424","title":"HEPATITIS B VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/610424"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFNAR2"},"hgnc":{"alias_symbol":[],"prev_symbol":["IFNABR"]},"alphafold":{"accession":"P48551","domains":[{"cath_id":"2.60.40.10","chopping":"40-132","consensus_level":"high","plddt":90.8897,"start":40,"end":132},{"cath_id":"2.60.40.10","chopping":"137-235","consensus_level":"high","plddt":87.2187,"start":137,"end":235}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48551","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48551-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48551-F1-predicted_aligned_error_v6.png","plddt_mean":64.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFNAR2","jax_strain_url":"https://www.jax.org/strain/search?query=IFNAR2"},"sequence":{"accession":"P48551","fasta_url":"https://rest.uniprot.org/uniprotkb/P48551.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48551/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48551"}},"corpus_meta":[{"pmid":"26424569","id":"PMC_26424569","title":"Human 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binders","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.628626","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31384,"output_tokens":6277,"usd":0.094154,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14976,"output_tokens":5879,"usd":0.110927,"stage2_stop_reason":"end_turn"},"total_usd":0.205081,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"The extracellular domain of IFNAR2 (ifnar2-EC) binds IFNalpha2 with 1:1 stoichiometry and ~10 nM affinity, as established by gel filtration, chemical cross-linking, BIAcore, reflectometric interference spectroscopy, and fluorescence de-quenching. The association rate has a significant electrostatic component (salt-dependent), and binding affinity decreases with decreasing pH (pKa ~6.7), indicating protonation of a titratable residue at the binding interface.\",\n      \"method\": \"Gel filtration, chemical cross-linking, surface plasmon resonance (BIAcore), reflectometric interference spectroscopy, fluorescence de-quenching, recombinant protein reconstitution\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods in a single rigorous in vitro study with purified recombinant proteins\",\n      \"pmids\": [\"10339405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mutational analysis defined the functional binding epitope on IFNalpha2 (hot-spots L30 and R33 on the AB loop) and on ifnar2-EC (hot-spots T46, I47, M48, plus ~10 additional residues). Although IFNalpha2 and IFNbeta compete for the same epitope on ifnar2, mutagenesis revealed distinct centers of binding, suggesting different angular orientations that may differentially couple to cytoplasmic signaling. Antiviral potency correlated proportionally with ifnar2 binding affinity, implicating ifnar2 binding as rate-limiting for IFN signaling.\",\n      \"method\": \"Alanine-scanning mutagenesis, label-free surface plasmon resonance kinetics and thermodynamics, antiviral potency assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and multiple quantitative biophysical readouts in a single rigorous study\",\n      \"pmids\": [\"10556041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The murine type I IFN receptor requires two subunits: muIFNaR1 and muIFNaR2 (49% identical to human IFNAR2). Co-expression of both subunits with an IFN-responsive luciferase reporter in human cells conferred responsiveness to murine IFN-beta; neither subunit alone was sufficient.\",\n      \"method\": \"cDNA library screening, co-expression of receptor subunits with luciferase reporter, functional reconstitution in human cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional reconstitution experiment with rigorous negative controls (single subunit transfections)\",\n      \"pmids\": [\"9322767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"A soluble isoform of murine Ifnar-2 (muIfnar-2a) is present in serum and biological fluids. At low concentrations it acts as an agonist: it forms a complex with IFN-alpha/beta and cell-surface muIfnar-1, and this complex transmits an antiproliferative signal through the Ifnar-1 chain alone (tested on Ifnar-2-/- primary thymocytes), demonstrating that signal transduction can occur through Ifnar-1 in the absence of the Ifnar-2 cytoplasmic domain. At high concentrations the soluble receptor competitively inhibits IFN activity.\",\n      \"method\": \"Western blot of serum fractions, competitive inhibition reporter assay (L929 cells), antiproliferative and antiviral assays with primary cells, cell-surface complex formation assay using Ifnar-2-/- thymocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments with KO primary cells and multiple orthogonal assays; dual agonist/antagonist finding replicated across assay types\",\n      \"pmids\": [\"11154225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Dimerization of IFNaR2-2 intracellular/transmembrane domain alone (via EpoR extracellular domain chimera) is sufficient to induce IFN-responsive gene transcription (6-16 promoter) upon ligand stimulation, but is insufficient for full antiviral protection. IFNaR1 is required for sustained mRNA and protein levels of antiviral effectors (PKR, OAS, MxA) at later time points.\",\n      \"method\": \"Chimeric receptor constructs (EpoR extracellular/IFNaR intracellular domains), transfection into 2fTGH and TYK2-deficient cells, promoter reporter assay, gene expression time course, Western blot, viral challenge assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric receptor reconstitution with defined loss-of-function genetic backgrounds and multiple functional readouts\",\n      \"pmids\": [\"10574956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFNAR2 (IFNaR2) undergoes regulated proteolytic cleavage in response to PMA, IFN-alpha, EGF, and PKC-delta overexpression, generating a transmembrane stub and releasing the intracellular domain (ICD) in a presenilin-dependent, multi-step process resembling Notch/APP regulated intramembrane proteolysis. The released ICD localizes to the nucleus (GFP fusion) and, when fused to Gal4 DBD, represses transcription of ISRE-linked reporters in a histone deacetylase-dependent manner.\",\n      \"method\": \"Immunoblotting of membrane fractions, chimeric receptor constructs, pharmacological stimulation, fluorescence microscopy (GFP-ICD), Gal4 reporter transcription assay, HDAC inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (biochemical cleavage assay, chimeric receptors, live-cell imaging, reporter assay) in a single study\",\n      \"pmids\": [\"15286706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The IFNaR2 intracellular domain (ICD) modulates transcription through the C-terminal transactivation domain of STAT2. STAT2 binds constitutively to the ICD in a tyrosine-phosphorylation-independent manner. Complementation of STAT2-deficient cells with wild-type STAT2 (but not a TAD-deleted mutant) restored ICD-mediated transcriptional effects. JAK1 kinase activity is also required for ICD-mediated transcription. Mutation of the STAT2 binding site on the ICD reduced its transcriptional activity.\",\n      \"method\": \"Gal4 DBD-ICD reporter assay in STAT2-deficient cells, complementation with WT vs. TAD-mutant STAT2, JAK1 inhibition, site-directed mutagenesis of STAT2 binding site\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic complementation with separation-of-function mutants plus mutagenesis of binding site, multiple orthogonal methods\",\n      \"pmids\": [\"15717316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IFNalpha2 and IFNbeta stimulate comparable immediate JAK/STAT activation, but differ in IFNAR2 trafficking: after IFNalpha2 binding, IFNAR2 is internalized and recycled back to the cell surface, whereas after IFNbeta binding it is routed to degradation. This differential routing is governed by the stability and intracellular lifetime of the ternary ligand-receptor complex.\",\n      \"method\": \"Quantitative measurement of surface receptor decay by flow cytometry, internalization/recycling assays, JAK/STAT phosphorylation kinetics across multiple cell lines with variable IFNAR1 levels\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell lines, quantitative surface decay and recycling assays, JAK/STAT activation comparisons in a single study\",\n      \"pmids\": [\"17627610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The IFNaR2 ICD, STAT2, and IRF9 form a ternary complex. STAT2 acts as an adaptor bridging the ICD to IRF9. The bipartite nuclear localization signal within IRF9 is the primary determinant driving nuclear transit of the ICD-containing complex (visualized with GFP-ICD). Both STAT2 and IRF9 are required for nuclear transit of the IFNaR2 ICD.\",\n      \"method\": \"Co-immunoprecipitation, GFP-ICD nuclear localization assay, genetic complementation in STAT2/IRF9-deficient cells, co-localization imaging\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and genetic complementation with imaging, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"18456457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NMR mapping of IFNalpha2 bound to the binary IFNalpha2/IFNAR2-EC complex revealed that IFNAR1-EC binding affects a patch on the same face as the IFNAR2 binding site (in addition to two patches on the opposing face), demonstrating allosteric communication between the IFNAR1 and IFNAR2 binding sites on IFNalpha2.\",\n      \"method\": \"1H-15N TROSY-HSQC NMR spectroscopy at 800 MHz on the 89 kDa ternary complex; chemical shift perturbation mapping\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural mapping of the ternary complex, rigorous in vitro experiment with isotopically labeled protein\",\n      \"pmids\": [\"20047337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFNAR2 ICD has a major role in initiating JAK-STAT signaling: successive truncations of the IFNAR2 ICD proportionally decreased constitutive STAT binding, STAT phosphorylation, and target gene activation. Tyrosine residues in the IFNAR1 ICD were not required for signaling, but simultaneous mutation of all IFNAR2 ICD tyrosines reduced STAT phosphorylation and antiviral activity without abolishing constitutive STAT2 binding, suggesting that IFNAR2 ICD tyrosine phosphorylation drives dissociation of phosphorylated STATs to maintain high signaling flux. JAK1 is associated with IFNAR2 and TYK2 with IFNAR1.\",\n      \"method\": \"Receptor ICD truncation/mutation analysis in IFNAR1/IFNAR2 double-knockout cells reconstituted with defined receptor mutants; STAT phosphorylation assays, gene activation assays, antiviral protection assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis in clean KO background with multiple functional readouts; reconstitution approach\",\n      \"pmids\": [\"34813358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using synthetic receptor chimeras (nanobody-based extracellular domains fused to native IFNAR transmembrane/intracellular domains), IFNAR2 homodimers were sufficient to induce STAT1/2 signaling via JAK1 and TYK2, whereas IFNAR1 homodimers were not. Mutagenesis identified Y510 and Y335 in murine IFNAR2 as the unique phosphorylation sites required for STAT1/2 activation; other tyrosines in IFNAR1 and IFNAR2 were not involved.\",\n      \"method\": \"Synthetic receptor chimeras (nanobody-based), STAT1/2 phosphorylation assays, transcriptome analysis, viral replication inhibition assay, intracellular deletion variants and point mutations\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — synthetic biology reconstitution with separation-of-function mutagenesis and multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"36118237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous loss-of-function mutation in IFNAR2 rendered patient cells unresponsive to IFN-alpha/beta. Reconstitution of patient cells with wild-type IFNAR2 restored IFN-alpha/beta responsiveness and control of IFN-attenuated viruses, establishing IFNAR2 as essential and non-redundant for IFN-I signaling in human antiviral immunity.\",\n      \"method\": \"Targeted resequencing, functional assays on patient-derived cells (IFN signaling, viral control), complementation with wild-type IFNAR2 cDNA\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function with genetic complementation rescue; functional antiviral assays in patient cells\",\n      \"pmids\": [\"26424569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A missense variant p.Ser53Pro in IFNAR2 prevents cell-surface expression of IFNAR2 protein; small amounts persist intracellularly in an aberrantly glycosylated state. Cells exclusively expressing p.Ser53Pro lacked responses to recombinant IFN-I and showed heightened viral vulnerability in vitro—a phenotype rescued by wild-type IFNAR2 complementation.\",\n      \"method\": \"Patient genetic analysis, cell surface expression assays, glycosylation analysis, IFN-I response assays (ISG induction, STAT phosphorylation), viral challenge in vitro, wild-type IFNAR2 complementation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays in patient cells with complementation rescue; independent cohort replication\",\n      \"pmids\": [\"35442417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In IFNAR2-deficient patient NK cells stimulated with IFNalpha, the expected increase in degranulation was impaired and the expected inhibition of IFNgamma production was absent, demonstrating that IFNAR2-dependent IFN-I signaling is required for normal NK cell effector function modulation.\",\n      \"method\": \"Ex vivo NK cell functional assays (degranulation, IFNgamma production) on patient PBMC; STAT1 phosphorylation and ISG induction assays\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional ex vivo assays on patient cells, single case report with limited replication\",\n      \"pmids\": [\"33193576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Soluble IFNAR2 (sIFNAR-2) forms a specific complex with IFN-beta, extending its serum half-life from minutes to hours in mice when co-administered intravenously, and enhances its antitumor efficacy 9–27-fold in xenograft models. The enhancement depends on slow release of IFN-beta from the complex in vivo.\",\n      \"method\": \"In vitro antiviral enhancement assay, in vivo mouse pharmacokinetic studies (IV administration), xenograft SCID mouse survival assay\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacokinetic and efficacy studies with mechanistic in vitro dissociation data, single lab\",\n      \"pmids\": [\"14980076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFNAR2 interacts with stress-activated protein kinase-interacting protein 1 (Sin1) via the C-terminal 185 amino acids of ovine IFNAR2. The interaction is constitutive (yeast two-hybrid and co-immunoprecipitation). When co-expressed, ovSin1 and ovIFNAR2 co-localize at the plasma membrane and perinuclear structures, suggesting Sin1 links IFN-I signaling to stress-activated pathways.\",\n      \"method\": \"Yeast two-hybrid screen of ovine endometrial cDNA library, co-immunoprecipitation, co-localization by immunofluorescence microscopy\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus co-IP and co-localization, single lab, novel interaction not independently replicated\",\n      \"pmids\": [\"15345682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IFN-alpha induces cell cycle arrest in G0/G1 phases leading to apoptosis through an IFNAR2-dependent signaling pathway in HuH7 hepatocellular carcinoma cells. Time-lapse imaging with a Fucci fluorescent cell cycle indicator showed that the IFN-alpha/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for death in G0/G1.\",\n      \"method\": \"Fucci-based live-cell time-lapse imaging, IFNAR2 loss-of-function, biochemical apoptosis assays, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct live-cell mechanistic imaging with defined receptor loss-of-function, single lab and cell line\",\n      \"pmids\": [\"25012666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IFNAR2 was identified as a novel HCV entry factor. IFNAR2 binds HCV virions through a direct interaction of its D2 domain with the C-terminal end of apolipoprotein E (apoE) on the viral envelope. Silencing IFNAR2 reduced HCV proliferation. An anti-IFNAR2 D2 domain antibody attenuated the IFNAR2-apoE interaction and impaired HCV infection. Recombinant IFNAR2 protein inhibited multiple HCV genotypes in vitro and in humanized mice.\",\n      \"method\": \"Chemical probes, IFNAR2 knockdown, direct binding assay (IFNAR2 D2 domain with apoE), antibody blocking, in vitro infection assays across HCV genotypes, humanized transgenic mouse model\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct protein-protein interaction mapped to specific domain, genetic KD, antibody blocking, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"31972076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The African swine fever virus protein B125R binds to IFNAR2 and promotes its autophagic degradation, thereby impairing JAK-STAT signal transduction at an early stage, reducing nuclear translocation of the ISGF3 complex and decreasing ISG production.\",\n      \"method\": \"Ectopic expression in HEK293T and PK-15 cells, co-immunoprecipitation (pB125R–IFNAR2 interaction), IFN-beta-triggered JAK-STAT reporter assays, autophagy inhibition experiments, ISGF3 nuclear translocation assay\",\n      \"journal\": \"Veterinary research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP interaction plus mechanistic pathway assays, single lab, limited independent replication\",\n      \"pmids\": [\"40270033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human IFN-I signaling in THP1 monocytic cells absolutely requires IFNAR2, as shown by complete loss of ISG induction upon CRISPR/Cas9 knockout. A 7-bp deletion IFNAR2 mutant retains partial responsiveness to IFNbeta by upregulating a subset of tonic-like ISGs; this residual signaling still depends on IFNAR2 protein expression (via exon skipping producing a truncated but functional protein).\",\n      \"method\": \"CRISPR/Cas9 knockout, IFN-beta stimulation, ISG expression profiling, RT-qPCR, Western blot, CRISPR-induced exon-skipping analysis\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined phenotypic readout, single lab, single cell line\",\n      \"pmids\": [\"36346319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The murine Ifnar-2 gene spans ~33 kb, consists of 9 exons and 8 introns, and generates one transmembrane (Ifnar-2c) and two soluble (Ifnar-2a/2a') isoforms by alternative RNA processing. Promoter analysis defined three regulatory regions: a proximal region conferring high basal expression, a distal region conferring IFN-inducible expression, and a negative regulatory region between them. The two transcript isoforms (2a and 2c) are independently regulated in some cell types.\",\n      \"method\": \"Genomic cloning, promoter-luciferase reporter assays, IFN treatment of multiple cell lines, RT-PCR isoform analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter dissection by reporter assays across multiple cell lines with deletion constructs; first promoter analysis of a type I IFN receptor\",\n      \"pmids\": [\"11939908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFNAR2 is the high-affinity subunit of the heterodimeric type I interferon receptor that binds IFNalpha/beta with ~10 nM affinity through a defined epitope centered on residues T46/I47/M48 in its extracellular domain; upon ligand-driven dimerization with IFNAR1, its intracellular domain (associated with JAK1) recruits and constitutively binds STAT2, and phosphorylation of key tyrosines (Y335/Y510 in mouse) drives STAT dissociation to maintain signaling flux, while the ICD can also be released by presenilin-dependent regulated proteolysis to form a nuclear STAT2/IRF9 ternary complex that modulates transcription; soluble IFNAR2 isoforms act as both agonists and antagonists of IFN signaling, and IFNAR2 additionally serves as an entry receptor for HCV via direct binding of its D2 domain to apolipoprotein E on viral envelopes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFNAR2 is the high-affinity ligand-binding subunit of the heterodimeric type I interferon receptor and is essential and non-redundant for IFN-alpha/beta signaling in human antiviral immunity [#0, #12]. Its extracellular domain binds IFNalpha2 with 1:1 stoichiometry and ~10 nM affinity through a defined epitope centered on hot-spot residues T46/I47/M48, and antiviral potency scales with this binding affinity, making IFNAR2 engagement rate-limiting for signaling [#0, #1]; productive responsiveness additionally requires the partner subunit IFNAR1, with which it forms an allosterically coupled ternary complex on the ligand [#2, #9]. Signaling is driven by the IFNAR2 intracellular domain, which associates with JAK1 and constitutively binds STAT2 in a phosphorylation-independent manner; tyrosine phosphorylation of the IFNAR2 ICD (Y335/Y510 in mouse) drives dissociation of phosphorylated STATs to sustain signaling flux, and IFNAR2 dimerization is itself sufficient to activate STAT1/2 via JAK1 and TYK2 [#6, #10, #11]. The IFNAR2 ICD is also released by presenilin-dependent regulated intramembrane proteolysis and translocates to the nucleus as a ternary complex with STAT2 and IRF9, where it modulates ISRE-linked transcription [#5, #8]. Soluble IFNAR2 isoforms generated by alternative RNA processing act as agonists at low concentrations and competitive antagonists at high concentrations, and can stabilize circulating IFN-beta [#3, #15, #21]. Human loss-of-function and trafficking-defective IFNAR2 variants abolish IFN-I responses and confer heightened viral vulnerability [#12, #13]. Independent of its cytokine-receptor role, IFNAR2 serves as an HCV entry factor via direct binding of its D2 domain to viral-envelope apolipoprotein E [#18].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that the functional murine type I IFN receptor requires two distinct subunits rather than one, defining IFNAR2 as one of two obligatory chains.\",\n      \"evidence\": \"cDNA co-expression of muIFNaR1 and muIFNaR2 with an IFN-responsive luciferase reporter in human cells, with single-subunit negative controls\",\n      \"pmids\": [\"9322767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which subunit binds ligand with high affinity\", \"No structural or biophysical characterization of the interaction\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined IFNAR2 as the high-affinity ligand-binding subunit and mapped the binding interface, showing IFNAR2 engagement is rate-limiting for IFN signaling.\",\n      \"evidence\": \"Multiple orthogonal biophysics (gel filtration, cross-linking, SPR, RIfS) and alanine-scanning mutagenesis with antiviral potency assays on recombinant ifnar2-EC and IFNalpha2\",\n      \"pmids\": [\"10339405\", \"10556041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how IFNAR1 contributes to the ternary complex geometry\", \"Did not connect binding to intracellular signaling output\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed the IFNAR2 intracellular/transmembrane domain alone can initiate ISG transcription upon dimerization but is insufficient for durable antiviral protection, partitioning early signaling from sustained effector output.\",\n      \"evidence\": \"EpoR-IFNaR chimeric receptors in 2fTGH and TYK2-deficient cells with promoter reporters, antiviral effector time courses, and viral challenge\",\n      \"pmids\": [\"10574956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the ICD residues required for signaling\", \"Mechanism of IFNAR1 requirement for sustained effector expression unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated that a soluble IFNAR2 isoform can transmit signal through IFNAR1 alone and acts as a concentration-dependent agonist/antagonist, revealing IFNAR2 can function without its own cytoplasmic domain.\",\n      \"evidence\": \"Serum fractionation, competitive reporter assays, and antiproliferative/complex-formation assays using Ifnar-2-/- primary thymocytes\",\n      \"pmids\": [\"11154225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological concentrations governing agonist vs antagonist switch not defined in humans\", \"Relationship to membrane isoform regulation unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterized the gene architecture and promoter regulation generating transmembrane and soluble IFNAR2 isoforms, explaining how isoform balance is controlled and is itself IFN-inducible.\",\n      \"evidence\": \"Genomic cloning, promoter-luciferase deletion analysis across cell lines, and RT-PCR isoform profiling of murine Ifnar-2\",\n      \"pmids\": [\"11939908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human promoter regulation not directly addressed\", \"Trans-acting factors controlling the negative regulatory region not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified regulated intramembrane proteolysis of IFNAR2 that releases a nuclear-targeting ICD with transcription-modulating activity, uncovering a non-canonical nuclear arm of IFNAR2 function.\",\n      \"evidence\": \"Membrane-fraction immunoblotting, chimeric receptors, GFP-ICD imaging, and Gal4 reporter assays with presenilin and HDAC dependency in stimulated cells\",\n      \"pmids\": [\"15286706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological significance of the released ICD not established\", \"Cleavage protease(s) downstream of presenilin not fully defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reported IFNAR2 interactions extending beyond canonical signaling, linking it to stress-activated pathways and to pharmacologic stabilization of IFN-beta.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and co-localization for ovine IFNAR2-Sin1; in vivo pharmacokinetics and xenograft efficacy for soluble IFNAR2-IFN-beta complexes\",\n      \"pmids\": [\"15345682\", \"14980076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sin1 interaction not independently replicated and functional consequence unclear\", \"Human relevance of the Sin1 link unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mechanistically defined the nuclear ICD activity as STAT2-dependent, showing constitutive phosphorylation-independent STAT2 binding via its transactivation domain plus a JAK1 requirement.\",\n      \"evidence\": \"Gal4-ICD reporter assays in STAT2-deficient cells complemented with WT vs TAD-mutant STAT2, JAK1 inhibition, and STAT2-binding-site mutagenesis\",\n      \"pmids\": [\"15717316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target gene set modulated by the ICD-STAT2 axis not defined\", \"Quantitative contribution relative to canonical ISGF3 signaling unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that ligand identity controls IFNAR2 receptor fate, with IFNalpha2 driving recycling and IFNbeta driving degradation, providing a trafficking basis for differential signaling outcomes.\",\n      \"evidence\": \"Quantitative flow-cytometry surface decay, internalization/recycling assays, and JAK/STAT kinetics across cell lines with variable IFNAR1\",\n      \"pmids\": [\"17627610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sorting machinery directing recycling vs degradation not identified\", \"Link between trafficking fate and downstream gene programs not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the nuclear transport mechanism of the ICD by showing it forms an ICD-STAT2-IRF9 ternary complex where STAT2 bridges and IRF9's NLS drives nuclear entry.\",\n      \"evidence\": \"Co-IP, GFP-ICD nuclear localization, and complementation in STAT2/IRF9-deficient cells with co-localization imaging\",\n      \"pmids\": [\"18456457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without reciprocal in vivo validation\", \"Transcriptional targets of the nuclear ternary complex not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided structural evidence for allosteric coupling between IFNAR1 and IFNAR2 binding sites on the shared ligand, explaining how the two subunits cooperate in ternary complex assembly.\",\n      \"evidence\": \"TROSY-HSQC NMR chemical-shift perturbation mapping of the 89 kDa IFNalpha2/IFNAR2-EC/IFNAR1-EC complex\",\n      \"pmids\": [\"20047337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not connect allosteric changes to specific signaling output differences\", \"Conformational dynamics in full-length membrane receptors not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established IFNAR2 as essential and non-redundant for human antiviral immunity through a causative loss-of-function mutation rescuable by wild-type cDNA.\",\n      \"evidence\": \"Patient resequencing, IFN signaling and viral-control assays in patient cells, and complementation with WT IFNAR2\",\n      \"pmids\": [\"26424569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full clinical spectrum of IFNAR2 deficiency not delineated here\", \"Tissue-specific consequences beyond antiviral control not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked IFNAR2 signaling to a defined cell-fate program, showing the IFNalpha/IFNAR2 axis drives cell-cycle arrest and apoptosis in hepatocellular carcinoma cells.\",\n      \"evidence\": \"Fucci live-cell imaging, IFNAR2 loss-of-function, and apoptosis/cell-cycle assays in HuH7 cells\",\n      \"pmids\": [\"25012666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line; generality across tissues unknown\", \"Downstream effectors coupling IFNAR2 to apoptosis not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a cytokine-receptor-independent role of IFNAR2 as an HCV entry factor binding viral apolipoprotein E through its D2 domain.\",\n      \"evidence\": \"IFNAR2 knockdown, direct D2-apoE binding assays, antibody blocking, multi-genotype infection assays, and humanized mouse validation\",\n      \"pmids\": [\"31972076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of D2-apoE binding not resolved\", \"Relationship between entry-factor role and signaling role not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected IFNAR2 deficiency to impaired innate effector function, showing disrupted NK cell degranulation and IFNgamma regulation.\",\n      \"evidence\": \"Ex vivo NK functional assays on patient PBMC with STAT1 phosphorylation and ISG induction readouts\",\n      \"pmids\": [\"33193576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report with limited replication\", \"Cell-intrinsic vs systemic contributions to NK phenotype not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the IFNAR2 ICD as the principal driver of JAK-STAT initiation, with its tyrosines promoting phosphorylated-STAT dissociation to maintain signaling flux while IFNAR1 tyrosines are dispensable.\",\n      \"evidence\": \"Systematic ICD truncation/tyrosine mutagenesis in IFNAR1/IFNAR2 double-knockout cells with STAT phosphorylation, gene activation, and antiviral assays\",\n      \"pmids\": [\"34813358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of phosphatases or release machinery acting on STATs not defined\", \"Quantitative kinetics of STAT cycling not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed IFNAR2 homodimerization is sufficient to activate STAT1/2 via JAK1/TYK2 and pinpointed Y335/Y510 as the unique signaling tyrosines, while a human trafficking-defective variant confirmed surface expression is required for function.\",\n      \"evidence\": \"Nanobody-based synthetic receptor chimeras with separation-of-function mutagenesis; patient p.Ser53Pro analysis with surface-expression, glycosylation, IFN-response and complementation assays; CRISPR knockout in THP1 monocytes\",\n      \"pmids\": [\"36118237\", \"35442417\", \"36346319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFNAR2 homodimers form physiologically without IFNAR1 unknown\", \"Tonic-like residual ISG program of partial-function alleles incompletely characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that a viral protein subverts IFNAR2 by driving its autophagic degradation to blunt JAK-STAT signaling, identifying IFNAR2 as a target of immune evasion.\",\n      \"evidence\": \"Ectopic expression and co-IP of ASFV pB125R with IFNAR2, JAK-STAT reporter assays, autophagy inhibition, and ISGF3 nuclear translocation assays in HEK293T/PK-15 cells\",\n      \"pmids\": [\"40270033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Degradation machinery and physiological relevance during infection not fully established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the canonical surface signaling role, the proteolytically released nuclear ICD arm, and the IFNAR2 trafficking and HCV-entry functions are integrated and balanced within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking surface signaling, RIP-released nuclear ICD, and entry-factor roles\", \"Physiological triggers and quantitative contribution of regulated proteolysis in vivo unknown\", \"Structural basis of full-length ternary signaling complex not solved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7, 13, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 14, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 19]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"Type I interferon receptor (IFNAR1/IFNAR2 heterodimer)\",\n      \"ICD-STAT2-IRF9 ternary complex\"\n    ],\n    \"partners\": [\n      \"IFNAR1\",\n      \"STAT2\",\n      \"IRF9\",\n      \"JAK1\",\n      \"Sin1\",\n      \"apolipoprotein E\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}