{"gene":"IFNAR1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2013,"finding":"IFN-β can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner; the crystal structure of the IFNAR1–IFN-β complex was solved, and this binary complex transduces signals modulating a distinct set of genes independently of canonical Jak-STAT pathways.","method":"Crystal structure determination, surface plasmon resonance, cell signaling assays, Ifnar2−/− mouse model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus functional validation in cells and in vivo mouse model, multiple orthogonal methods in one study","pmids":["23872679"],"is_preprint":false},{"year":2003,"finding":"Tyk2 is essential for stable cell surface expression of IFNAR1; in the absence of Tyk2, mature IFNAR1 is retained in a perinuclear endosomal compartment overlapping with recycling transferrin receptors and EEA1-positive vesicles, and Tyk2 slows IFNAR1 degradation by inhibiting its endocytosis.","method":"Immunofluorescence localization, cell surface expression assays, co-expression experiments in Tyk2-deficient cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, live imaging, endocytosis assay) with functional consequence, replicated across conditions","pmids":["12554654"],"is_preprint":false},{"year":2004,"finding":"Ubiquitination and lysosomal degradation of IFNAR1 are mediated by the SCF-β-TrCP E3 ubiquitin ligase in a phosphorylation-dependent manner; Ser535 and Ser539 in the cytoplasmic degron are essential for β-TrCP recruitment, and Lys501, Lys525, and Lys526 are the critical ubiquitin acceptor sites. Tyk2 stabilizes IFNAR1 independently of β-TrCP binding or ubiquitination.","method":"Site-directed mutagenesis, phospho-specific antibody, ubiquitination assays, degradation assays in cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with phospho-specific antibody and in-cell degradation assays, multiple orthogonal approaches in one rigorous study","pmids":["15337770"],"is_preprint":false},{"year":1997,"finding":"The protein-arginine methyltransferase PRMT1 (IR1B4) binds directly to the intracytoplasmic domain of IFNAR1; S-adenosylmethionine-dependent methyltransferase activity co-precipitates with IFNAR1 from untreated human cells, and antisense knockdown of PRMT1 increases resistance to IFN-mediated growth inhibition.","method":"Yeast two-hybrid screen, GST pulldown with bacterially expressed IFNAR1-IC, co-immunoprecipitation from human cells, antisense knockdown functional assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — two-hybrid discovery confirmed by in vitro pulldown and co-IP from cells, plus functional antisense experiment","pmids":["9029147"],"is_preprint":false},{"year":1994,"finding":"IFNAR1 undergoes ligand-dependent tyrosine phosphorylation within 5 min of IFN-α or IFN-β treatment; Tyk2 (but not Jak1) and STAT2 (but not STAT1) are constitutively associated with IFNAR1. IFN-β uniquely induces the tyrosine phosphorylation of an associated ~95 kDa surface protein (β-PTyr) bound to IFNAR1.","method":"Immunoprecipitation, anti-phosphotyrosine Western blot, extracellular biotin tagging, cross-linking","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with phospho-specific detection plus cross-linking and surface biotinylation in multiple experiments","pmids":["7813427"],"is_preprint":false},{"year":1996,"finding":"STAT3 directly associates with the tyrosine-phosphorylated IFNAR1 chain via the STAT3 SH2 domain in an IFN-α-dependent manner; STAT3 bound to IFNAR1 undergoes secondary serine phosphorylation that is blocked by the PKC inhibitor H-7.","method":"Co-immunoprecipitation, IFN-α stimulation, pharmacological inhibition of PKC, SH2 domain binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with mechanistic inhibitor follow-up, single lab","pmids":["8626489"],"is_preprint":false},{"year":1996,"finding":"A domain comprising JH7–JH6 of Tyk2 (amino acids 22–221) is the minimal IFNAR1-binding region; additional JH5-4-3 regions are required in vivo for stable IFNAR1 protein levels and IFN-α signaling. The Tyk2 kinase-like and kinase domains are not specific for IFN-α/β receptor signaling.","method":"In vitro binding assay with deletion mutants, co-immunoprecipitation, complementation in Tyk2-deficient cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding domain mapping confirmed by co-IP and functional complementation assays","pmids":["8628273"],"is_preprint":false},{"year":1998,"finding":"The JH7-JH6 region of Tyk2 is the major IFNAR1 interaction surface, but this region alone is insufficient to stabilize IFNAR1 protein levels; additional JH regions (JH5-4-3) contribute specifically to in vivo assembly with IFNAR1 and to IFN-α signaling.","method":"In vitro binding assay, co-immunoprecipitation, functional complementation in Tyk2-negative cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay corroborated by co-IP and functional assay, single lab","pmids":["9733772"],"is_preprint":false},{"year":2011,"finding":"SOCS1 inhibits type I IFN signaling not by direct interaction with IFNAR1 but through its SH2 domain interacting with phosphotyrosines Y1054/Y1055 of Tyk2; the KIR domain of SOCS1 is also required. SOCS1 inhibition of Tyk2 reduces IFNAR1 surface expression (which is stabilized by Tyk2), and SOCS1 inhibits Lys63-polyubiquitination of Tyk2.","method":"Co-immunoprecipitation, mutagenesis, ubiquitination assays, surface expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis of interaction residues and ubiquitination assay, multiple orthogonal methods","pmids":["21757742"],"is_preprint":false},{"year":2009,"finding":"Casein kinase 1α (CK1α) is the major kinase that phosphorylates the IFNAR1 degron (Ser535) basally and upon ER stress/viral infection, triggering ubiquitination and lysosomal degradation. ER stress (via PERK) first phosphorylates a proximal priming site Ser532, which then promotes CK1α-dependent Ser535 phosphorylation. Leishmania major CK1 ortholog can also phosphorylate IFNAR1 in mammalian cells, attenuating IFN signaling.","method":"Biochemical purification of kinase activity, in vitro phosphorylation assay, mutagenesis, siRNA knockdown, overexpression in cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — kinase purified to homogeneity, in vitro reconstitution, mutagenesis, and cell-based validation across multiple conditions","pmids":["19805514"],"is_preprint":false},{"year":2009,"finding":"ER stress (UPR) induces ligand-independent IFNAR1 phosphorylation via PERK-dependent phosphorylation of a priming site Ser532, which promotes subsequent CK1α-mediated phosphorylation of Ser535 in the degron, leading to β-TrCP recruitment, ubiquitination, and lysosomal degradation.","method":"Mutagenesis, phospho-specific antibody, UPR induction, co-IP with β-TrCP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic mutagenesis with phospho-specific antibody and E3 recruitment assay, multiple methods in one study","pmids":["19948722"],"is_preprint":false},{"year":2006,"finding":"Catalytic activity of Tyk2 is required for ligand-induced IFNAR1 serine phosphorylation (Ser535), ubiquitination, and efficient lysosomal proteolysis, but is not required for IFNAR1 internalization per se.","method":"Catalytically inactive Tyk2 mutant complementation in Tyk2-null cells, serine phosphorylation assay, ubiquitination assay, proteolysis assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — kinase-dead mutant complementation with multiple downstream readouts, rigorous mechanistic dissection","pmids":["16551269"],"is_preprint":false},{"year":2013,"finding":"The deubiquitinating complex BRISC (containing BRCC36) is recruited to IFNAR1 via its newly identified component SHMT2, which directs BRISC activity toward K63-linked ubiquitin chains on IFNAR1. BRISC-SHMT2 deubiquitinates actively engaged IFNAR1, limiting its K63-Ub-mediated internalization and lysosomal degradation.","method":"Mass spectrometry interactome, co-immunoprecipitation, DUB activity assay, BRISC-deficient cells and mice, endocytosis assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS identification confirmed by co-IP, biochemical DUB assay, and genetic knockout with phenotypic rescue, multiple orthogonal methods","pmids":["24075985"],"is_preprint":false},{"year":2014,"finding":"Inflammatory stimuli trigger IFNAR1 ubiquitination and downregulation, which protects tissues from inflammatory injury. Knock-in mice (Ifnar1SA) unable to undergo IFNAR1 ubiquitination are highly susceptible to pancreatitis and hepatitis, displaying persistent immune infiltration and defective tissue regeneration.","method":"Knock-in mouse model (serine-to-alanine mutation in degron), inflammatory disease models, pharmacological stimulation of IFNAR1 ubiquitination","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-controlled knock-in genetic model with multiple disease readouts and pharmacological validation","pmids":["24480543"],"is_preprint":false},{"year":2012,"finding":"PTP1B binds and dephosphorylates IFNAR1 at Y466, enabling AP2 recruitment to the Y466-based endocytic motif and thereby regulating IFN1-stimulated IFNAR1 endocytosis. RNAi screen identified PTP1B as a specific regulator; genetic or pharmacological modulation of PTP1B activity controls IFN1 signaling in a Y466-dependent manner.","method":"RNAi screen, co-IP/pulldown, endocytosis assay, site-directed mutagenesis of Y466, pharmacological PTP1B inhibitors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — RNAi screen validated by direct binding/dephosphorylation assay, mutagenesis, and pharmacological experiments across multiple cell types","pmids":["23129613"],"is_preprint":false},{"year":2009,"finding":"Palmitoylation of IFNAR1 at Cys463 (the more proximal cytoplasmic cysteine) is required for efficient Stat2 activation and subsequent Stat1 activation and nuclear translocation, but is not required for IFNAR1 endocytosis, intracellular distribution, or cell-surface stability.","method":"Cysteine-to-alanine mutagenesis, metabolic palmitoylation labeling, pharmacological palmitoylation inhibition, microscopy, STAT activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct mutagenesis of palmitoylation site combined with metabolic labeling and multiple functional readouts","pmids":["19561067"],"is_preprint":false},{"year":2008,"finding":"Ligand binding induces a conformational change in the membrane-distal domains of the IFNAR1 ectodomain that is propagated to its membrane-proximal domain (not involved in ligand recognition but essential for signaling), as demonstrated by intramolecular FRET, single-particle electron microscopy of ternary complexes, and stopped-flow fluorescence.","method":"Intramolecular FRET, single-particle electron microscopy, photo-induced electron-transfer fluorescence quenching, stopped-flow fluorescence","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods including EM of ternary complexes and FRET in a single rigorous study","pmids":["18294654"],"is_preprint":false},{"year":2015,"finding":"Prolidase (PEPD) is required for IFNAR1 maturation and accumulation at the cell surface. Flavivirus NS5 binds prolidase, reducing IFNAR1 surface expression. Human fibroblasts from prolidase-deficient patients exhibit decreased IFNAR1 surface expression and reduced IFN-β-stimulated signaling.","method":"Co-immunoprecipitation of NS5 with PEPD, siRNA knockdown, patient-derived fibroblasts, surface expression assay, viral challenge","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — viral protein–host protein interaction confirmed by Co-IP, validated by patient-derived cells and siRNA knockdown with functional readouts","pmids":["26159719"],"is_preprint":false},{"year":1999,"finding":"Catalytically active TYK2 is required for IFN-β-induced tyrosine phosphorylation of STAT3 and IFNAR1, but not for STAT1 or STAT2 activation; PI3K associates with IFNAR1 in a ligand-independent manner and its activation by IFN-β does not require catalytically active TYK2.","method":"TYK2-null cells complemented with kinase-negative or wild-type TYK2, phosphorylation assays, co-IP of PI3K with IFNAR1","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase-dead complementation in null cells with multiple STAT readouts and co-IP, single lab","pmids":["10542297"],"is_preprint":false},{"year":2021,"finding":"For IFNAR1, only the TYK2 binding site in its intracellular domain is required for signaling. Tyrosine residues in the IFNAR1 ICD are not required for signaling. In contrast, the IFNAR2 ICD tyrosines drive STAT dissociation to maintain signaling flux.","method":"Receptor mutants in knockout cells, STAT phosphorylation and reporter assays, antiviral activity assays","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cell complementation with multiple receptor truncation/mutation variants, single lab","pmids":["34813358"],"is_preprint":false},{"year":2004,"finding":"Residues 62FSSLKLNVY70 in the S5-S6 loop and Trp129 in the second subdomain of IFNAR1 are critical for IFN-α binding and signaling. Residues 278LRV in the third subdomain are critical for IFN-α-induced biological activity but not ligand binding. A model predicts receptor complex closure upon IFN binding with the N-terminal IFNAR1 domain acting as a lid.","method":"Site-directed mutagenesis of extracellular domain residues, binding assays, antiviral and antiproliferative activity assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — systematic mutagenesis with both binding and functional readouts, single lab","pmids":["15449939"],"is_preprint":false},{"year":2017,"finding":"A proline deletion in the hinge region of the membrane-proximal domain of IFNAR1 (corresponding to the P335del variant) decreases IFN-β binding affinity of IFNAR1, impairing type I IFN signaling. This variant is associated with decreased tuberculosis susceptibility in humans.","method":"Receptor mutagenesis, surface plasmon resonance binding assay, cell signaling assay, genetic association study","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — SPR binding + cell signaling with mutagenesis, genetic validation in human cohorts","pmids":["29311663"],"is_preprint":false},{"year":2017,"finding":"A hot spot on IFNAR1 subdomain-3, centered on Tyr240 and Tyr274, mediates interaction with the B and C helix termini of IFN-β (residues Phe63, Leu64, Glu77, Thr78, Val81, Arg82). This interface is differentially used by IFN-β versus IFN-α and is required for IFNAR1–IFN-β affinity, STAT1 activation, ISG expression, and antiviral/antiproliferative activity.","method":"Crystal structure-guided mutagenesis, surface plasmon resonance, cell-based STAT1 phosphorylation, antiviral assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided mutagenesis validated by SPR and multiple functional assays in one study","pmids":["28289093"],"is_preprint":false},{"year":2001,"finding":"Five aromatic residues of bovine IFNAR-1 are critical hotspots for ligand (human IFN-α2) binding; IFNAR-1 subdomains 2 and 3 together harbor the primary determinants for moderate-affinity binding, with subdomains 1 and 4 providing additional contributions.","method":"Bovine/human IFNAR-1 chimeras, site-directed mutagenesis of aromatic residues, binding assays on COS cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — systematic chimera and mutagenesis approach with direct binding readout, single lab","pmids":["11278538"],"is_preprint":false},{"year":2016,"finding":"S1PR1 activation accelerates IFNAR1 turnover/degradation (pertussis toxin-resistant, blocked by S1PR1 C-terminal Tat-peptide preventing internalization), suppresses STAT1 phosphorylation, and selectively inhibits the type I IFN autoamplification loop in plasmacytoid dendritic cells.","method":"S1PR1 agonist treatment, pharmacological inhibition, Tat-fusion peptide blockade, STAT1 phosphorylation assay, IFNAR1 protein turnover assay, in vivo CpG-A challenge","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic peptide blockade plus pharmacological/genetic manipulation with multiple readouts, single lab","pmids":["26787880"],"is_preprint":false},{"year":2004,"finding":"IFNAR1 contains a functional nuclear localization sequence (NLS) at residues 382RKIIEKKT in the extracellular domain; following IFN-β stimulation IFNAR1 translocates to the nucleus in an energy-dependent, importin-dependent manner that is inhibited by the SV40 large T-antigen NLS competitor.","method":"NLS identification, nuclear fractionation, energy/importin inhibition assays, competition with SV40 NLS","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NLS characterization with biochemical inhibition controls, single lab","pmids":["15589821"],"is_preprint":false},{"year":2021,"finding":"A truncated IFNAR1 protein (from a genomic deletion of the last exon coding sequence and 3'-UTR) is expressed on the cell surface but cannot interact with TYK2, abolishing STAT1/STAT2/STAT3 phosphorylation and genome-wide ISG induction in response to IFN-α2b or IFN-β, rendering patient fibroblasts susceptible to HSV-1.","method":"Patient-derived fibroblasts and EBV-B cells, STAT phosphorylation assay, ISG expression profiling, viral challenge, TYK2 binding assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — natural human loss-of-function experiment with multiple orthogonal functional readouts (phosphorylation, ISG induction, viral susceptibility), confirmed in two cell types","pmids":["32960813"],"is_preprint":false},{"year":2015,"finding":"Chaperone-mediated autophagy (CMA) targets IFNAR1 (but not IFNLR1) for lysosomal degradation in free fatty acid-treated HCV cell culture; IFNAR1 interacts with the CMA components HSC70 and LAMP2A, as shown by co-immunoprecipitation and colocalization, and siRNA knockdown of these components prevents IFNAR1 degradation.","method":"Co-immunoprecipitation, colocalization microscopy, siRNA knockdown, pharmacological lysosomal inhibitors (ammonium chloride, bafilomycin), CMA activators","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with CMA machinery components, siRNA validation, pharmacological confirmation, single lab","pmids":["25961570"],"is_preprint":false},{"year":2021,"finding":"RNA-binding protein RBM47 binds the 3'-UTR of IFNAR1 mRNA, increases IFNAR1 mRNA stability, and retards IFNAR1 degradation, thereby enhancing downstream IFN signaling and antiviral activity. RBM47 itself is induced by viral infection or interferon stimulation.","method":"RNA immunoprecipitation (RIP) of RBM47 with IFNAR1 3'-UTR, mRNA stability assay, RBM47 knockdown/overexpression, ISG expression, viral challenge models","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP confirmed mRNA binding, mRNA stability assay functional consequence, multiple virus models, single lab","pmids":["34160127"],"is_preprint":false},{"year":2023,"finding":"Secreted LRPAP1 (upregulated by viral proteases 3CLpro and 2Apro) binds the extracellular domain of IFNAR1, triggering receptor ubiquitination and lysosomal degradation, thereby suppressing IFN signaling and promoting viral infection. A small peptide from LRPAP1 N-terminus is sufficient to cause IFNAR1 degradation.","method":"Co-immunoprecipitation (LRPAP1 with IFNAR1 extracellular domain), ubiquitination assay, IFNAR1 surface expression assay, in vitro/ex vivo/in vivo viral infection models","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding Co-IP with functional ubiquitination and degradation assays validated in multiple viral infection models, single lab","pmids":["37743411"],"is_preprint":false},{"year":1998,"finding":"Deletion of the conserved membrane-distal IRTAM (16 aa) sequence from the IFNAR1 intracellular domain increases IFN-α antiviral sensitivity, accelerates and prolongs STAT DNA-binding complex formation, and blocks IFN-dependent downregulation of IFNAR1, indicating that IRTAM negatively regulates signaling by controlling receptor downregulation.","method":"Truncation mutants in stably transfected L929 cells, antiviral assay, EMSA for STAT complexes, receptor downregulation assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mutagenesis with multiple functional readouts, single lab","pmids":["9501047"],"is_preprint":false},{"year":1995,"finding":"The mature IFNAR1 chain is a heavily glycosylated protein (65 kDa precursor → 130 kDa mature form); glycosylation is predominantly N-linked and accounts for approximately half the apparent molecular mass; the receptor undergoes ligand-dependent tyrosine phosphorylation and downregulation; IFN-β uniquely induces phosphorylation of an associated 105 kDa protein in two lymphoblastoid cell lines.","method":"Metabolic labeling, immunoprecipitation, deglycosylation, 125I-IFN cross-linking, IFNIR structure analysis across cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with cross-linking, metabolic labeling, and cross-cell-line validation","pmids":["7479825"],"is_preprint":false},{"year":2023,"finding":"A LINE-1 element (L1M2a) located within the first intron of IFNAR1 functions as a B cell-specific, interferon-inducible enhancer of IFNAR1 transcription. CRISPR deletion of this element in B lymphoblastoid cells reduces both steady-state and interferon-stimulated IFNAR1 expression, creating a positive feedback loop.","method":"CRISPR deletion of intronic LINE-1 element, epigenomic profiling (H3K27ac, H3K9me3), luciferase reporter, IFNAR1 expression measurement","journal":"Mobile DNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional deletion with epigenomic characterization and expression readout, single lab","pmids":["38037122"],"is_preprint":false}],"current_model":"IFNAR1 is the signal-transducing subunit of the heterodimeric type I IFN receptor that constitutively associates with TYK2 (via a JH7-JH6 binding domain), which stabilizes IFNAR1 at the plasma membrane by inhibiting endocytosis; ligand binding induces conformational changes in IFNAR1 that propagate to its membrane-proximal domain, triggering TYK2-dependent tyrosine phosphorylation of IFNAR1 and recruitment of STAT2 and STAT3 through their SH2 domains, while PRMT1 also binds the IFNAR1 intracellular domain to mediate arginine methylation as a complementary signaling mechanism; receptor downregulation is controlled by a two-step phosphorylation cascade (PERK-dependent Ser532 priming followed by CK1α-mediated Ser535 phosphorylation) that recruits the SCF-β-TrCP E3 ligase, ubiquitinates Lys501/525/526, and drives lysosomal degradation, with palmitoylation of Cys463 and deubiquitination by the BRISC-SHMT2 complex providing additional regulatory layers; uniquely, IFN-β can also signal through IFNAR1 alone in an IFNAR2-independent manner, using a Tyr240/Tyr274 hot spot on subdomain 3 to activate a distinct JAK-STAT-independent gene set."},"narrative":{"mechanistic_narrative":"IFNAR1 is the signal-transducing chain of the type I interferon receptor, coupling extracellular IFN-α/IFN-β binding to intracellular JAK-STAT activation and to tightly controlled receptor turnover [PMID:7813427, PMID:32960813]. Ligand binding induces a conformational change in the membrane-distal ectodomain that propagates to a non-ligand-binding membrane-proximal domain essential for signaling [PMID:18294654], with binding determinants mapping to aromatic residues and subdomains 2/3 of the ectodomain and a hinge region in the membrane-proximal domain [PMID:15449939, PMID:28289093, PMID:11278538, PMID:29311663]. IFNAR1 constitutively associates with TYK2 through a JH7-JH6 interaction surface, and this binding is the principal requirement for downstream signaling; a natural human truncation that abolishes TYK2 binding eliminates STAT1/STAT2/STAT3 phosphorylation and ISG induction and confers susceptibility to HSV-1 [PMID:8628273, PMID:34813358, PMID:32960813]. TYK2 also stabilizes IFNAR1 at the cell surface by inhibiting its endocytosis, and its catalytic activity drives ligand-induced tyrosine phosphorylation of IFNAR1 and recruitment of STAT2 and STAT3 via their SH2 domains [PMID:12554654, PMID:7813427, PMID:8626489, PMID:16551269]. Receptor abundance is governed by a phosphodegron in which PERK-dependent Ser532 priming followed by CK1α-mediated Ser535 phosphorylation recruits SCF-β-TrCP, which ubiquitinates Lys501/525/526 to drive lysosomal degradation; this degradation limits inflammatory injury in vivo [PMID:15337770, PMID:19805514, PMID:19948722, PMID:24480543]. Additional regulatory layers include PTP1B-mediated dephosphorylation at Y466 controlling AP2-dependent endocytosis, palmitoylation of Cys463 required for STAT activation, BRISC-SHMT2 deubiquitination of K63 chains, and PRMT1 binding to the intracellular domain [PMID:23129613, PMID:19561067, PMID:24075985, PMID:9029147]. Uniquely, IFN-β can ligate IFNAR1 in an IFNAR2-independent manner through a Tyr240/Tyr274 hot spot to engage a distinct, Jak-STAT-independent gene program [PMID:23872679, PMID:28289093]. Loss-of-function IFNAR1 alleles in humans cause susceptibility to viral disease [PMID:32960813], and surface levels are further tuned by maturation factors and pathogen-driven degradation pathways.","teleology":[{"year":1994,"claim":"Establishing that IFNAR1 is a signaling receptor required defining which kinases and transcription factors it physically couples to and how ligand triggers them.","evidence":"Immunoprecipitation, anti-phosphotyrosine blotting, surface biotinylation and cross-linking in IFN-stimulated cells","pmids":["7813427"],"confidence":"High","gaps":["Did not map the TYK2 or STAT2 binding sites on IFNAR1","Identity of the IFN-β-specific ~95 kDa associated protein left unresolved"]},{"year":1996,"claim":"The molecular basis of constitutive IFNAR1-TYK2 association was mapped, and STAT3 was shown to dock directly on phosphorylated IFNAR1.","evidence":"TYK2 deletion-mutant binding assays with functional complementation, and SH2-domain co-IP of STAT3 with PKC-inhibitor follow-up","pmids":["8628273","8626489"],"confidence":"High","gaps":["JH7-JH6 binding alone insufficient for IFNAR1 stabilization","Kinase that mediates STAT3 secondary serine phosphorylation not definitively identified"]},{"year":1998,"claim":"Functional dissection separated TYK2 binding from its stabilizing role and identified a negative-regulatory cytoplasmic element controlling receptor downregulation.","evidence":"TYK2 JH-region complementation and IFNAR1 IRTAM truncation mutants in cells with antiviral, EMSA and downregulation readouts","pmids":["9733772","9501047"],"confidence":"Medium","gaps":["Mechanism by which JH5-4-3 stabilizes IFNAR1 unclear","IRTAM-dependent downregulation machinery not yet identified"]},{"year":1995,"claim":"Biochemical characterization defined IFNAR1 as a heavily N-glycosylated chain that is tyrosine-phosphorylated and downregulated upon ligand binding.","evidence":"Metabolic labeling, deglycosylation, and 125I-IFN cross-linking across lymphoblastoid lines","pmids":["7479825"],"confidence":"Medium","gaps":["Functional role of glycosylation not tested","Identity of associated 105 kDa IFN-β-induced phosphoprotein unresolved"]},{"year":1997,"claim":"A non-JAK enzymatic partner of IFNAR1 was identified, linking the receptor to arginine methylation as a parallel signaling input.","evidence":"Yeast two-hybrid, GST pulldown, co-IP of methyltransferase activity, and antisense knockdown growth-inhibition assay","pmids":["9029147"],"confidence":"High","gaps":["Methylation substrate(s) downstream of PRMT1 on the IFNAR1 axis not defined","Relationship to JAK-STAT signaling not resolved"]},{"year":2001,"claim":"The ectodomain ligand-binding architecture was mapped, localizing the high-affinity determinants to specific subdomains and aromatic residues.","evidence":"Bovine/human chimeras and aromatic-residue mutagenesis with binding assays","pmids":["11278538"],"confidence":"Medium","gaps":["Did not address conformational signal propagation","Cross-species chimera framework may not fully reflect human affinity"]},{"year":2004,"claim":"The phosphodegron and ubiquitin acceptor sites controlling IFNAR1 degradation were defined, and additional ectodomain residues that uncouple binding from activity were mapped, alongside a functional NLS.","evidence":"Site-directed mutagenesis with phospho-specific antibodies, ubiquitination/degradation assays, and nuclear fractionation with importin inhibition","pmids":["15337770","15449939","15589821"],"confidence":"High","gaps":["Kinase responsible for degron phosphorylation not yet identified at this stage","Functional consequence of nuclear IFNAR1 translocation unclear"]},{"year":2006,"claim":"TYK2 catalytic activity was shown to drive the serine phosphorylation, ubiquitination and proteolysis arm of IFNAR1 regulation, distinct from internalization.","evidence":"Kinase-dead TYK2 complementation in TYK2-null cells with phosphorylation, ubiquitination and proteolysis readouts","pmids":["16551269"],"confidence":"High","gaps":["Direct vs indirect role of TYK2 kinase in degron phosphorylation not separated","Did not identify the Ser535 kinase"]},{"year":2008,"claim":"A mechanistic model for receptor activation was established by showing ligand induces a propagated conformational change from distal to membrane-proximal ectodomain.","evidence":"Intramolecular FRET, single-particle EM of ternary complexes, and stopped-flow fluorescence","pmids":["18294654"],"confidence":"High","gaps":["How the ectodomain change couples to intracellular TYK2 activation not resolved","Structural state at membrane not directly visualized"]},{"year":2009,"claim":"The kinase cascade and ligand-independent stress signal that drive degron phosphorylation were defined, plus a palmitoylation requirement for productive STAT activation.","evidence":"Kinase purification and in vitro phosphorylation (CK1α), PERK/UPR induction with phospho-specific antibodies, and Cys463 palmitoylation mutagenesis with STAT readouts","pmids":["19805514","19948722","19561067"],"confidence":"High","gaps":["How palmitoylation mechanistically promotes STAT2 recruitment not defined","Crosstalk between UPR-driven and ligand-driven degradation incompletely mapped"]},{"year":2011,"claim":"Negative feedback by SOCS1 was shown to act through TYK2 rather than IFNAR1 directly, linking kinase suppression to reduced receptor surface levels.","evidence":"Co-IP, interaction-residue mutagenesis, and ubiquitination/surface-expression assays","pmids":["21757742"],"confidence":"High","gaps":["Does not establish direct IFNAR1 contact by SOCS1","In vivo relevance of TYK2 K63-ubiquitin regulation not addressed"]},{"year":2012,"claim":"An endocytic control point was identified whereby PTP1B dephosphorylates Y466 to enable AP2-dependent IFNAR1 internalization.","evidence":"RNAi screen with direct binding/dephosphorylation assays, Y466 mutagenesis, and pharmacological PTP1B inhibition","pmids":["23129613"],"confidence":"High","gaps":["Spatiotemporal coordination with degron phosphorylation unclear","Structural basis of PTP1B-IFNAR1 recognition not defined"]},{"year":2013,"claim":"IFN-β-specific signaling through IFNAR1 alone was structurally and functionally demonstrated, and a deubiquitination brake on receptor turnover was identified.","evidence":"Crystal structure of IFNAR1-IFN-β with SPR and Ifnar2-/- mouse signaling, and MS interactome plus DUB assays with BRISC knockout phenotyping for BRISC-SHMT2","pmids":["23872679","24075985"],"confidence":"High","gaps":["The Jak-STAT-independent gene set and its transducer remain undefined","How SHMT2 targets BRISC selectively to IFNAR1 K63 chains not fully resolved"]},{"year":2014,"claim":"The physiological purpose of IFNAR1 degradation was established as protection against inflammatory tissue injury.","evidence":"Ifnar1SA degron knock-in mice in pancreatitis/hepatitis models with pharmacological induction of ubiquitination","pmids":["24480543"],"confidence":"High","gaps":["Cell-type-specific contributions to tissue protection not dissected","Link to human inflammatory disease not established here"]},{"year":2015,"claim":"Additional surface-control mechanisms were uncovered: prolidase-dependent maturation (exploited by flavivirus NS5) and CMA-mediated lysosomal degradation under metabolic stress.","evidence":"PEPD/NS5 co-IP with patient fibroblasts and viral challenge; HSC70/LAMP2A co-IP with siRNA and lysosomal inhibitors in HCV cell culture","pmids":["26159719","25961570"],"confidence":"Medium","gaps":["Mechanism of prolidase action on IFNAR1 maturation unclear","CMA targeting motif on IFNAR1 not mapped"]},{"year":2016,"claim":"A receptor-driven negative regulator was found whereby S1PR1 accelerates IFNAR1 turnover to dampen the type I IFN autoamplification loop in pDCs.","evidence":"S1PR1 agonist/peptide-blockade with STAT1 and IFNAR1 turnover assays and in vivo CpG-A challenge","pmids":["26787880"],"confidence":"Medium","gaps":["Direct vs indirect coupling of S1PR1 to the IFNAR1 degradation machinery unclear","Single-lab finding"]},{"year":2017,"claim":"The IFN-β-specific binding interface and a clinically relevant hinge variant were defined, connecting receptor biophysics to human disease susceptibility.","evidence":"Structure-guided mutagenesis with SPR and STAT1/antiviral assays (Tyr240/Tyr274 hot spot), and P335del variant SPR/signaling with genetic association","pmids":["28289093","29311663"],"confidence":"High","gaps":["Mechanism linking reduced affinity to tuberculosis protection not fully resolved","Whether the IFN-β hot spot drives the Jak-STAT-independent program not tested"]},{"year":2021,"claim":"Genetic dissection clarified that TYK2 binding, not IFNAR1 ICD tyrosines, is the essential signaling requirement, and an mRNA-stabilizing input was identified.","evidence":"Receptor mutant complementation in knockout cells with STAT/reporter/antiviral readouts; RBM47 RIP and mRNA stability assays with viral challenge","pmids":["34813358","34160127"],"confidence":"Medium","gaps":["Reconciliation with earlier tyrosine-phosphorylation findings incomplete","How RBM47 selectively stabilizes IFNAR1 mRNA not mechanistically resolved"]},{"year":2021,"claim":"A natural human loss-of-function IFNAR1 allele confirmed that TYK2-dependent signaling is essential for antiviral ISG induction in vivo.","evidence":"Patient-derived fibroblasts and EBV-B cells with STAT phosphorylation, ISG profiling, TYK2 binding and HSV-1 challenge","pmids":["32960813"],"confidence":"High","gaps":["Spectrum of viral susceptibility in patients not fully characterized","Residual Jak-STAT-independent signaling in the truncant not assessed"]},{"year":2023,"claim":"Transcriptional and pathogen-driven control of IFNAR1 abundance was extended by a B-cell enhancer and a secreted viral-induced degradation factor.","evidence":"CRISPR deletion of an intronic LINE-1 enhancer with epigenomic/reporter readouts; LRPAP1 co-IP, ubiquitination and surface-expression assays in viral infection models","pmids":["38037122","37743411"],"confidence":"Medium","gaps":["Generality of the LINE-1 enhancer beyond B cells unknown","How extracellular LRPAP1 binding triggers IFNAR1 ubiquitination mechanistically unclear"]},{"year":null,"claim":"The identity of the transducer and complete gene program engaged by the IFNAR2-independent, Jak-STAT-independent IFN-β signaling through IFNAR1 remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No transducer identified for the IFNAR1-only IFN-β signal","Physiological contexts where IFNAR1-alone signaling dominates not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,26]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,22,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,26]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,14]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,9,27]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,9,12]}],"complexes":["type I interferon receptor (IFNAR1-IFNAR2)"],"partners":["TYK2","STAT2","STAT3","PRMT1","PTP1B","BTRC","SHMT2","PEPD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17181","full_name":"Interferon alpha/beta receptor 1","aliases":["Cytokine receptor class-II member 1","Cytokine receptor family 2 member 1","CRF2-1","Type I interferon receptor 1"],"length_aa":557,"mass_kda":63.5,"function":"Together with IFNAR2, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa) (PubMed:10049744, PubMed:14532120, PubMed:15337770, PubMed:2153461, PubMed:21854986, PubMed:24075985, PubMed:31270247, PubMed:33252644, PubMed:35442418, PubMed:7813427). 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:21854986, PubMed:7665574). 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:21854986, PubMed:32972995, PubMed:7665574, PubMed:7813427). The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors (PubMed:21854986, PubMed:32972995, PubMed:7526154, PubMed:7665574, PubMed:7813427). STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes (PubMed:19561067, PubMed:21854986, PubMed:32972995, PubMed:7665574, PubMed:7813427, PubMed:9121453). Can also act independently of IFNAR2: form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway (By similarity)","subcellular_location":"Cell membrane; Late endosome; Lysosome","url":"https://www.uniprot.org/uniprotkb/P17181/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFNAR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IFNAR1","total_profiled":1310},"omim":[{"mim_id":"619935","title":"IMMUNODEFICIENCY 106, SUSCEPTIBILITY TO VIRAL INFECTIONS; IMD106","url":"https://www.omim.org/entry/619935"},{"mim_id":"619396","title":"ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED (HERPES-SPECIFIC), SUSCEPTIBILITY TO, 10; IIAE10","url":"https://www.omim.org/entry/619396"},{"mim_id":"619378","title":"SMALL NUCLEOLAR RNA, H/ACA BOX, 31; SNORA31","url":"https://www.omim.org/entry/619378"},{"mim_id":"617040","title":"MICRO RNA 1231; MIR1231","url":"https://www.omim.org/entry/617040"},{"mim_id":"615326","title":"INTERFERON, KAPPA; IFNK","url":"https://www.omim.org/entry/615326"}],"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/IFNAR1"},"hgnc":{"alias_symbol":["IFRC"],"prev_symbol":["IFNAR"]},"alphafold":{"accession":"P17181","domains":[{"cath_id":"2.60.40.10","chopping":"35-126","consensus_level":"high","plddt":89.1117,"start":35,"end":126},{"cath_id":"2.60.40.10","chopping":"133-223","consensus_level":"high","plddt":92.8169,"start":133,"end":223},{"cath_id":"2.60.40.10","chopping":"234-330","consensus_level":"high","plddt":90.1806,"start":234,"end":330},{"cath_id":"2.60.40.10","chopping":"337-430","consensus_level":"high","plddt":80.5578,"start":337,"end":430},{"cath_id":"1.20.5","chopping":"437-461","consensus_level":"medium","plddt":88.4964,"start":437,"end":461}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17181","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17181-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17181-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFNAR1","jax_strain_url":"https://www.jax.org/strain/search?query=IFNAR1"},"sequence":{"accession":"P17181","fasta_url":"https://rest.uniprot.org/uniprotkb/P17181.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17181/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17181"}},"corpus_meta":[{"pmid":"18424188","id":"PMC_18424188","title":"Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system.","date":"2008","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18424188","citation_count":330,"is_preprint":false},{"pmid":"17115899","id":"PMC_17115899","title":"Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection.","date":"2006","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/17115899","citation_count":233,"is_preprint":false},{"pmid":"23872679","id":"PMC_23872679","title":"Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1.","date":"2013","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23872679","citation_count":215,"is_preprint":false},{"pmid":"12554654","id":"PMC_12554654","title":"The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12554654","citation_count":181,"is_preprint":false},{"pmid":"9029147","id":"PMC_9029147","title":"A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9029147","citation_count":157,"is_preprint":false},{"pmid":"18250407","id":"PMC_18250407","title":"Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18250407","citation_count":140,"is_preprint":false},{"pmid":"7813427","id":"PMC_7813427","title":"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.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7813427","citation_count":135,"is_preprint":false},{"pmid":"21757742","id":"PMC_21757742","title":"Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21757742","citation_count":135,"is_preprint":false},{"pmid":"15337770","id":"PMC_15337770","title":"Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15337770","citation_count":126,"is_preprint":false},{"pmid":"8626489","id":"PMC_8626489","title":"Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626489","citation_count":118,"is_preprint":false},{"pmid":"26159719","id":"PMC_26159719","title":"Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression.","date":"2015","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/26159719","citation_count":111,"is_preprint":false},{"pmid":"32960813","id":"PMC_32960813","title":"Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32960813","citation_count":101,"is_preprint":false},{"pmid":"29558366","id":"PMC_29558366","title":"Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29558366","citation_count":95,"is_preprint":false},{"pmid":"11154225","id":"PMC_11154225","title":"The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11154225","citation_count":87,"is_preprint":false},{"pmid":"8628273","id":"PMC_8628273","title":"Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8628273","citation_count":86,"is_preprint":false},{"pmid":"24075985","id":"PMC_24075985","title":"A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24075985","citation_count":86,"is_preprint":false},{"pmid":"29752314","id":"PMC_29752314","title":"IFNAR1 Controls Autocrine Type I IFN Regulation of PD-L1 Expression in Myeloid-Derived Suppressor Cells.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29752314","citation_count":83,"is_preprint":false},{"pmid":"12761564","id":"PMC_12761564","title":"Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12761564","citation_count":77,"is_preprint":false},{"pmid":"9733772","id":"PMC_9733772","title":"Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9733772","citation_count":76,"is_preprint":false},{"pmid":"25993119","id":"PMC_25993119","title":"Suppression of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, Anifrolumab, in Adult Patients with Systemic Sclerosis.","date":"2015","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25993119","citation_count":73,"is_preprint":false},{"pmid":"34813358","id":"PMC_34813358","title":"IFNAR1 and IFNAR2 play distinct roles in initiating type I interferon-induced JAK-STAT signaling and activating STATs.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/34813358","citation_count":69,"is_preprint":false},{"pmid":"12193393","id":"PMC_12193393","title":"Expression of interferon receptor subunits, IFNAR1 and IFNAR2, in the ovine uterus.","date":"2002","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12193393","citation_count":69,"is_preprint":false},{"pmid":"16551269","id":"PMC_16551269","title":"TYK2 activity promotes ligand-induced IFNAR1 proteolysis.","date":"2006","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/16551269","citation_count":68,"is_preprint":false},{"pmid":"19805514","id":"PMC_19805514","title":"Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19805514","citation_count":67,"is_preprint":false},{"pmid":"28842285","id":"PMC_28842285","title":"miR-93-5p/IFNAR1 axis promotes gastric cancer metastasis through activating the STAT3 signaling pathway.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28842285","citation_count":64,"is_preprint":false},{"pmid":"19857449","id":"PMC_19857449","title":"Heterologous prime boost vaccination with DNA and recombinant modified vaccinia virus Ankara protects IFNAR(-/-) mice against lethal bluetongue infection.","date":"2009","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/19857449","citation_count":63,"is_preprint":false},{"pmid":"10542297","id":"PMC_10542297","title":"Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10542297","citation_count":62,"is_preprint":false},{"pmid":"35442418","id":"PMC_35442418","title":"A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes.","date":"2022","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35442418","citation_count":59,"is_preprint":false},{"pmid":"16624932","id":"PMC_16624932","title":"Differential responsiveness to IFN-alpha and IFN-beta of human mature DC through modulation of IFNAR expression.","date":"2006","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/16624932","citation_count":58,"is_preprint":false},{"pmid":"30555157","id":"PMC_30555157","title":"Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma.","date":"2018","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30555157","citation_count":57,"is_preprint":false},{"pmid":"24480543","id":"PMC_24480543","title":"Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury.","date":"2014","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24480543","citation_count":56,"is_preprint":false},{"pmid":"23467932","id":"PMC_23467932","title":"Exacerbated autoimmunity in the absence of TLR9 in MRL.Fas(lpr) mice depends on Ifnar1.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23467932","citation_count":56,"is_preprint":false},{"pmid":"26787880","id":"PMC_26787880","title":"S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26787880","citation_count":55,"is_preprint":false},{"pmid":"21549790","id":"PMC_21549790","title":"A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR(-/-) mice upon lethal virus challenge.","date":"2011","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/21549790","citation_count":55,"is_preprint":false},{"pmid":"27812214","id":"PMC_27812214","title":"IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection.","date":"2016","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/27812214","citation_count":54,"is_preprint":false},{"pmid":"34817199","id":"PMC_34817199","title":"Nucleoside-Modified mRNA Vaccines Protect IFNAR-/- Mice against Crimean-Congo Hemorrhagic Fever Virus Infection.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34817199","citation_count":53,"is_preprint":false},{"pmid":"29311663","id":"PMC_29311663","title":"A proline deletion in IFNAR1 impairs IFN-signaling and underlies increased resistance to tuberculosis in humans.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29311663","citation_count":52,"is_preprint":false},{"pmid":"7479825","id":"PMC_7479825","title":"Expression and signaling specificity of the IFNAR chain of the type I interferon receptor complex.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7479825","citation_count":50,"is_preprint":false},{"pmid":"34713375","id":"PMC_34713375","title":"A Case of Autosomal Recessive Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency with Severe COVID-19.","date":"2021","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34713375","citation_count":49,"is_preprint":false},{"pmid":"29106381","id":"PMC_29106381","title":"A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations.","date":"2017","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29106381","citation_count":48,"is_preprint":false},{"pmid":"23585679","id":"PMC_23585679","title":"IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23585679","citation_count":45,"is_preprint":false},{"pmid":"9295335","id":"PMC_9295335","title":"Cloning and characterization of soluble and transmembrane isoforms of a novel component of the murine type I interferon receptor, IFNAR 2.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9295335","citation_count":45,"is_preprint":false},{"pmid":"19948722","id":"PMC_19948722","title":"Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19948722","citation_count":43,"is_preprint":false},{"pmid":"23593251","id":"PMC_23593251","title":"Protection of IFNAR (-/-) mice against bluetongue virus serotype 8, by heterologous (DNA/rMVA) and homologous (rMVA/rMVA) vaccination, expressing outer-capsid protein VP2.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23593251","citation_count":43,"is_preprint":false},{"pmid":"32196487","id":"PMC_32196487","title":"Vaccination with single plasmid DNA encoding IL-12 and antigens of severe fever with thrombocytopenia syndrome virus elicits complete protection in IFNAR knockout mice.","date":"2020","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32196487","citation_count":42,"is_preprint":false},{"pmid":"10048764","id":"PMC_10048764","title":"Characterization of antihuman IFNAR-1 monoclonal antibodies: epitope localization and functional analysis.","date":"1999","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/10048764","citation_count":41,"is_preprint":false},{"pmid":"32541772","id":"PMC_32541772","title":"Annexin-A1 promotes RIG-I-dependent signaling and apoptosis via regulation of the IRF3-IFNAR-STAT1-IFIT1 pathway in A549 lung epithelial cells.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32541772","citation_count":41,"is_preprint":false},{"pmid":"19561067","id":"PMC_19561067","title":"Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19561067","citation_count":41,"is_preprint":false},{"pmid":"21835795","id":"PMC_21835795","title":"Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21835795","citation_count":40,"is_preprint":false},{"pmid":"18294654","id":"PMC_18294654","title":"Ligand binding induces a conformational change in ifnar1 that is propagated to its membrane-proximal domain.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18294654","citation_count":39,"is_preprint":false},{"pmid":"35586249","id":"PMC_35586249","title":"Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35586249","citation_count":38,"is_preprint":false},{"pmid":"23129613","id":"PMC_23129613","title":"Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23129613","citation_count":37,"is_preprint":false},{"pmid":"21716316","id":"PMC_21716316","title":"CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer.","date":"2011","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21716316","citation_count":37,"is_preprint":false},{"pmid":"21830897","id":"PMC_21830897","title":"West Nile virus infection induces depletion of IFNAR1 protein levels.","date":"2011","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21830897","citation_count":34,"is_preprint":false},{"pmid":"11278538","id":"PMC_11278538","title":"Identification of critical residues in bovine IFNAR-1 responsible for interferon binding.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278538","citation_count":34,"is_preprint":false},{"pmid":"35288721","id":"PMC_35288721","title":"Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis.","date":"2022","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/35288721","citation_count":33,"is_preprint":false},{"pmid":"15449939","id":"PMC_15449939","title":"Identification of residues of the IFNAR1 chain of the type I human interferon receptor critical for ligand binding and biological activity.","date":"2004","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15449939","citation_count":33,"is_preprint":false},{"pmid":"18937499","id":"PMC_18937499","title":"Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18937499","citation_count":32,"is_preprint":false},{"pmid":"33892139","id":"PMC_33892139","title":"Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.","date":"2021","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/33892139","citation_count":32,"is_preprint":false},{"pmid":"20565290","id":"PMC_20565290","title":"Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection.","date":"2010","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20565290","citation_count":32,"is_preprint":false},{"pmid":"7544230","id":"PMC_7544230","title":"Human type I interferon receptor, IFNAR, is a heavily glycosylated 120-130 kD membrane protein.","date":"1995","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/7544230","citation_count":31,"is_preprint":false},{"pmid":"31790513","id":"PMC_31790513","title":"Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in Ifnar-/- mice.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31790513","citation_count":31,"is_preprint":false},{"pmid":"35311997","id":"PMC_35311997","title":"Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML.","date":"2022","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35311997","citation_count":29,"is_preprint":false},{"pmid":"38620034","id":"PMC_38620034","title":"African swine fever virus pB318L, a trans-geranylgeranyl-diphosphate synthase, negatively regulates cGAS-STING and IFNAR-JAK-STAT signaling pathways.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38620034","citation_count":28,"is_preprint":false},{"pmid":"30171073","id":"PMC_30171073","title":"Human interferon-ϵ and interferon-κ exhibit low potency and low affinity for cell-surface IFNAR and the poxvirus antagonist B18R.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30171073","citation_count":28,"is_preprint":false},{"pmid":"34160127","id":"PMC_34160127","title":"RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/34160127","citation_count":27,"is_preprint":false},{"pmid":"29875250","id":"PMC_29875250","title":"CD8 T Cell Responses to an Immunodominant Epitope within the Nonstructural Protein NS1 Provide Wide Immunoprotection against Bluetongue Virus in IFNAR-/- Mice.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29875250","citation_count":27,"is_preprint":false},{"pmid":"28647375","id":"PMC_28647375","title":"Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke.","date":"2017","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/28647375","citation_count":27,"is_preprint":false},{"pmid":"17027223","id":"PMC_17027223","title":"Exhaustive genotyping of the interferon alpha receptor 1 (IFNAR1) gene and association of an IFNAR1 protein variant with AIDS progression or susceptibility to HIV-1 infection in a French AIDS cohort.","date":"2006","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/17027223","citation_count":26,"is_preprint":false},{"pmid":"24886956","id":"PMC_24886956","title":"Immunisation with bacterial expressed VP2 and VP5 of bluetongue virus (BTV) protect α/β interferon-receptor knock-out (IFNAR(-/-)) mice from homologous lethal challenge.","date":"2014","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/24886956","citation_count":26,"is_preprint":false},{"pmid":"31221625","id":"PMC_31221625","title":"Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/31221625","citation_count":26,"is_preprint":false},{"pmid":"18761606","id":"PMC_18761606","title":"A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection.","date":"2008","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/18761606","citation_count":26,"is_preprint":false},{"pmid":"35048182","id":"PMC_35048182","title":"ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35048182","citation_count":25,"is_preprint":false},{"pmid":"32265337","id":"PMC_32265337","title":"IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis.","date":"2020","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/32265337","citation_count":25,"is_preprint":false},{"pmid":"25961570","id":"PMC_25961570","title":"Chaperone-Mediated Autophagy Targets IFNAR1 for Lysosomal Degradation in Free Fatty Acid Treated HCV Cell Culture.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25961570","citation_count":25,"is_preprint":false},{"pmid":"28289093","id":"PMC_28289093","title":"A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28289093","citation_count":24,"is_preprint":false},{"pmid":"39441221","id":"PMC_39441221","title":"Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies.","date":"2024","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39441221","citation_count":22,"is_preprint":false},{"pmid":"37743411","id":"PMC_37743411","title":"Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37743411","citation_count":22,"is_preprint":false},{"pmid":"38037122","id":"PMC_38037122","title":"An intronic LINE-1 regulates IFNAR1 expression in human immune cells.","date":"2023","source":"Mobile DNA","url":"https://pubmed.ncbi.nlm.nih.gov/38037122","citation_count":22,"is_preprint":false},{"pmid":"22368279","id":"PMC_22368279","title":"ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22368279","citation_count":22,"is_preprint":false},{"pmid":"27994510","id":"PMC_27994510","title":"Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4.","date":"2016","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27994510","citation_count":22,"is_preprint":false},{"pmid":"9501047","id":"PMC_9501047","title":"The antiviral action of interferon is potentiated by removal of the conserved IRTAM domain of the IFNAR1 chain of the interferon alpha/beta receptor: effects on JAK-STAT activation and receptor down-regulation.","date":"1998","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/9501047","citation_count":22,"is_preprint":false},{"pmid":"39189923","id":"PMC_39189923","title":"CAR T Cells Engineered to Secrete IFNκ Induce Tumor Ferroptosis via an IFNAR/STAT1/ACSL4 Axis.","date":"2024","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/39189923","citation_count":21,"is_preprint":false},{"pmid":"15589821","id":"PMC_15589821","title":"The IFNAR1 subunit of the type I IFN receptor complex contains a functional nuclear localization sequence.","date":"2004","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/15589821","citation_count":20,"is_preprint":false},{"pmid":"32455700","id":"PMC_32455700","title":"The Crimean-Congo Hemorrhagic Fever Virus NSm Protein is Dispensable for Growth In Vitro and Disease in Ifnar-/- Mice.","date":"2020","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/32455700","citation_count":20,"is_preprint":false},{"pmid":"11939908","id":"PMC_11939908","title":"Multiple regions within the promoter of the murine Ifnar-2 gene confer basal and inducible expression.","date":"2002","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11939908","citation_count":19,"is_preprint":false},{"pmid":"28235558","id":"PMC_28235558","title":"DNA vaccination regimes against Schmallenberg virus infection in IFNAR-/- mice suggest two targets for immunization.","date":"2017","source":"Antiviral research","url":"https://pubmed.ncbi.nlm.nih.gov/28235558","citation_count":19,"is_preprint":false},{"pmid":"33075108","id":"PMC_33075108","title":"Feline calicivirus strain 2280 p30 antagonizes type I interferon-mediated antiviral innate immunity through directly degrading IFNAR1 mRNA.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/33075108","citation_count":19,"is_preprint":false},{"pmid":"38956653","id":"PMC_38956653","title":"Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling.","date":"2024","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/38956653","citation_count":17,"is_preprint":false},{"pmid":"35133062","id":"PMC_35133062","title":"Impacts of the STING-IFNAR1-STAT1-IRF1 pathway on the cellular immune reaction induced by fractionated irradiation.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35133062","citation_count":17,"is_preprint":false},{"pmid":"25858859","id":"PMC_25858859","title":"An experimental subunit vaccine based on Bluetongue virus 4 VP2 protein fused to an antigen-presenting cells single chain antibody elicits cellular and humoral immune responses in cattle, guinea pigs and IFNAR(-/-) mice.","date":"2015","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/25858859","citation_count":16,"is_preprint":false},{"pmid":"32034180","id":"PMC_32034180","title":"Virological, immunological and pathological findings of transplacentally transmitted bluetongue virus serotype 1 in IFNAR1-blocked mice during early and mid gestation.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32034180","citation_count":16,"is_preprint":false},{"pmid":"26679744","id":"PMC_26679744","title":"A functional polymorphism in IFNAR1 gene is associated with susceptibility and severity of HFMD with EV71 infection.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26679744","citation_count":15,"is_preprint":false},{"pmid":"35833131","id":"PMC_35833131","title":"IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35833131","citation_count":15,"is_preprint":false},{"pmid":"9737881","id":"PMC_9737881","title":"Mapping human interferon-alpha (IFN-alpha 2) binding determinants of the type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9737881","citation_count":15,"is_preprint":false},{"pmid":"33015402","id":"PMC_33015402","title":"Characterization of local SARS-CoV-2 isolates and pathogenicity in IFNAR-/- mice.","date":"2020","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/33015402","citation_count":15,"is_preprint":false},{"pmid":"39680367","id":"PMC_39680367","title":"A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity.","date":"2024","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39680367","citation_count":14,"is_preprint":false},{"pmid":"21949815","id":"PMC_21949815","title":"T cell-intrinsic and -extrinsic contributions of the IFNAR/STAT1-axis to thymocyte survival.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21949815","citation_count":14,"is_preprint":false},{"pmid":"38729159","id":"PMC_38729159","title":"Intratumoral delivery of the chitin-derived C100 adjuvant promotes robust STING, IFNAR, and CD8+ T cell-dependent anti-tumor immunity.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38729159","citation_count":14,"is_preprint":false},{"pmid":"31512106","id":"PMC_31512106","title":"Cellular Caspase-3 Contributes to EV-A71 2Apro-Mediated Down-Regulation of IFNAR1 at the Translation Level.","date":"2019","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/31512106","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53006,"output_tokens":8291,"usd":0.141691,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18011,"output_tokens":6161,"usd":0.12204,"stage2_stop_reason":"end_turn"},"total_usd":0.263731,"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\": 2013,\n      \"finding\": \"IFN-β can uniquely and specifically ligate to IFNAR1 in an IFNAR2-independent manner; the crystal structure of the IFNAR1–IFN-β complex was solved, and this binary complex transduces signals modulating a distinct set of genes independently of canonical Jak-STAT pathways.\",\n      \"method\": \"Crystal structure determination, surface plasmon resonance, cell signaling assays, Ifnar2−/− mouse model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus functional validation in cells and in vivo mouse model, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23872679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tyk2 is essential for stable cell surface expression of IFNAR1; in the absence of Tyk2, mature IFNAR1 is retained in a perinuclear endosomal compartment overlapping with recycling transferrin receptors and EEA1-positive vesicles, and Tyk2 slows IFNAR1 degradation by inhibiting its endocytosis.\",\n      \"method\": \"Immunofluorescence localization, cell surface expression assays, co-expression experiments in Tyk2-deficient cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, live imaging, endocytosis assay) with functional consequence, replicated across conditions\",\n      \"pmids\": [\"12554654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ubiquitination and lysosomal degradation of IFNAR1 are mediated by the SCF-β-TrCP E3 ubiquitin ligase in a phosphorylation-dependent manner; Ser535 and Ser539 in the cytoplasmic degron are essential for β-TrCP recruitment, and Lys501, Lys525, and Lys526 are the critical ubiquitin acceptor sites. Tyk2 stabilizes IFNAR1 independently of β-TrCP binding or ubiquitination.\",\n      \"method\": \"Site-directed mutagenesis, phospho-specific antibody, ubiquitination assays, degradation assays in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with phospho-specific antibody and in-cell degradation assays, multiple orthogonal approaches in one rigorous study\",\n      \"pmids\": [\"15337770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The protein-arginine methyltransferase PRMT1 (IR1B4) binds directly to the intracytoplasmic domain of IFNAR1; S-adenosylmethionine-dependent methyltransferase activity co-precipitates with IFNAR1 from untreated human cells, and antisense knockdown of PRMT1 increases resistance to IFN-mediated growth inhibition.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown with bacterially expressed IFNAR1-IC, co-immunoprecipitation from human cells, antisense knockdown functional assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — two-hybrid discovery confirmed by in vitro pulldown and co-IP from cells, plus functional antisense experiment\",\n      \"pmids\": [\"9029147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"IFNAR1 undergoes ligand-dependent tyrosine phosphorylation within 5 min of IFN-α or IFN-β treatment; Tyk2 (but not Jak1) and STAT2 (but not STAT1) are constitutively associated with IFNAR1. IFN-β uniquely induces the tyrosine phosphorylation of an associated ~95 kDa surface protein (β-PTyr) bound to IFNAR1.\",\n      \"method\": \"Immunoprecipitation, anti-phosphotyrosine Western blot, extracellular biotin tagging, cross-linking\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with phospho-specific detection plus cross-linking and surface biotinylation in multiple experiments\",\n      \"pmids\": [\"7813427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"STAT3 directly associates with the tyrosine-phosphorylated IFNAR1 chain via the STAT3 SH2 domain in an IFN-α-dependent manner; STAT3 bound to IFNAR1 undergoes secondary serine phosphorylation that is blocked by the PKC inhibitor H-7.\",\n      \"method\": \"Co-immunoprecipitation, IFN-α stimulation, pharmacological inhibition of PKC, SH2 domain binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with mechanistic inhibitor follow-up, single lab\",\n      \"pmids\": [\"8626489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A domain comprising JH7–JH6 of Tyk2 (amino acids 22–221) is the minimal IFNAR1-binding region; additional JH5-4-3 regions are required in vivo for stable IFNAR1 protein levels and IFN-α signaling. The Tyk2 kinase-like and kinase domains are not specific for IFN-α/β receptor signaling.\",\n      \"method\": \"In vitro binding assay with deletion mutants, co-immunoprecipitation, complementation in Tyk2-deficient cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding domain mapping confirmed by co-IP and functional complementation assays\",\n      \"pmids\": [\"8628273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The JH7-JH6 region of Tyk2 is the major IFNAR1 interaction surface, but this region alone is insufficient to stabilize IFNAR1 protein levels; additional JH regions (JH5-4-3) contribute specifically to in vivo assembly with IFNAR1 and to IFN-α signaling.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, functional complementation in Tyk2-negative cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay corroborated by co-IP and functional assay, single lab\",\n      \"pmids\": [\"9733772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SOCS1 inhibits type I IFN signaling not by direct interaction with IFNAR1 but through its SH2 domain interacting with phosphotyrosines Y1054/Y1055 of Tyk2; the KIR domain of SOCS1 is also required. SOCS1 inhibition of Tyk2 reduces IFNAR1 surface expression (which is stabilized by Tyk2), and SOCS1 inhibits Lys63-polyubiquitination of Tyk2.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, ubiquitination assays, surface expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis of interaction residues and ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"21757742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Casein kinase 1α (CK1α) is the major kinase that phosphorylates the IFNAR1 degron (Ser535) basally and upon ER stress/viral infection, triggering ubiquitination and lysosomal degradation. ER stress (via PERK) first phosphorylates a proximal priming site Ser532, which then promotes CK1α-dependent Ser535 phosphorylation. Leishmania major CK1 ortholog can also phosphorylate IFNAR1 in mammalian cells, attenuating IFN signaling.\",\n      \"method\": \"Biochemical purification of kinase activity, in vitro phosphorylation assay, mutagenesis, siRNA knockdown, overexpression in cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — kinase purified to homogeneity, in vitro reconstitution, mutagenesis, and cell-based validation across multiple conditions\",\n      \"pmids\": [\"19805514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ER stress (UPR) induces ligand-independent IFNAR1 phosphorylation via PERK-dependent phosphorylation of a priming site Ser532, which promotes subsequent CK1α-mediated phosphorylation of Ser535 in the degron, leading to β-TrCP recruitment, ubiquitination, and lysosomal degradation.\",\n      \"method\": \"Mutagenesis, phospho-specific antibody, UPR induction, co-IP with β-TrCP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic mutagenesis with phospho-specific antibody and E3 recruitment assay, multiple methods in one study\",\n      \"pmids\": [\"19948722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Catalytic activity of Tyk2 is required for ligand-induced IFNAR1 serine phosphorylation (Ser535), ubiquitination, and efficient lysosomal proteolysis, but is not required for IFNAR1 internalization per se.\",\n      \"method\": \"Catalytically inactive Tyk2 mutant complementation in Tyk2-null cells, serine phosphorylation assay, ubiquitination assay, proteolysis assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — kinase-dead mutant complementation with multiple downstream readouts, rigorous mechanistic dissection\",\n      \"pmids\": [\"16551269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The deubiquitinating complex BRISC (containing BRCC36) is recruited to IFNAR1 via its newly identified component SHMT2, which directs BRISC activity toward K63-linked ubiquitin chains on IFNAR1. BRISC-SHMT2 deubiquitinates actively engaged IFNAR1, limiting its K63-Ub-mediated internalization and lysosomal degradation.\",\n      \"method\": \"Mass spectrometry interactome, co-immunoprecipitation, DUB activity assay, BRISC-deficient cells and mice, endocytosis assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS identification confirmed by co-IP, biochemical DUB assay, and genetic knockout with phenotypic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"24075985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Inflammatory stimuli trigger IFNAR1 ubiquitination and downregulation, which protects tissues from inflammatory injury. Knock-in mice (Ifnar1SA) unable to undergo IFNAR1 ubiquitination are highly susceptible to pancreatitis and hepatitis, displaying persistent immune infiltration and defective tissue regeneration.\",\n      \"method\": \"Knock-in mouse model (serine-to-alanine mutation in degron), inflammatory disease models, pharmacological stimulation of IFNAR1 ubiquitination\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-controlled knock-in genetic model with multiple disease readouts and pharmacological validation\",\n      \"pmids\": [\"24480543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTP1B binds and dephosphorylates IFNAR1 at Y466, enabling AP2 recruitment to the Y466-based endocytic motif and thereby regulating IFN1-stimulated IFNAR1 endocytosis. RNAi screen identified PTP1B as a specific regulator; genetic or pharmacological modulation of PTP1B activity controls IFN1 signaling in a Y466-dependent manner.\",\n      \"method\": \"RNAi screen, co-IP/pulldown, endocytosis assay, site-directed mutagenesis of Y466, pharmacological PTP1B inhibitors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — RNAi screen validated by direct binding/dephosphorylation assay, mutagenesis, and pharmacological experiments across multiple cell types\",\n      \"pmids\": [\"23129613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Palmitoylation of IFNAR1 at Cys463 (the more proximal cytoplasmic cysteine) is required for efficient Stat2 activation and subsequent Stat1 activation and nuclear translocation, but is not required for IFNAR1 endocytosis, intracellular distribution, or cell-surface stability.\",\n      \"method\": \"Cysteine-to-alanine mutagenesis, metabolic palmitoylation labeling, pharmacological palmitoylation inhibition, microscopy, STAT activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct mutagenesis of palmitoylation site combined with metabolic labeling and multiple functional readouts\",\n      \"pmids\": [\"19561067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ligand binding induces a conformational change in the membrane-distal domains of the IFNAR1 ectodomain that is propagated to its membrane-proximal domain (not involved in ligand recognition but essential for signaling), as demonstrated by intramolecular FRET, single-particle electron microscopy of ternary complexes, and stopped-flow fluorescence.\",\n      \"method\": \"Intramolecular FRET, single-particle electron microscopy, photo-induced electron-transfer fluorescence quenching, stopped-flow fluorescence\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods including EM of ternary complexes and FRET in a single rigorous study\",\n      \"pmids\": [\"18294654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Prolidase (PEPD) is required for IFNAR1 maturation and accumulation at the cell surface. Flavivirus NS5 binds prolidase, reducing IFNAR1 surface expression. Human fibroblasts from prolidase-deficient patients exhibit decreased IFNAR1 surface expression and reduced IFN-β-stimulated signaling.\",\n      \"method\": \"Co-immunoprecipitation of NS5 with PEPD, siRNA knockdown, patient-derived fibroblasts, surface expression assay, viral challenge\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — viral protein–host protein interaction confirmed by Co-IP, validated by patient-derived cells and siRNA knockdown with functional readouts\",\n      \"pmids\": [\"26159719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Catalytically active TYK2 is required for IFN-β-induced tyrosine phosphorylation of STAT3 and IFNAR1, but not for STAT1 or STAT2 activation; PI3K associates with IFNAR1 in a ligand-independent manner and its activation by IFN-β does not require catalytically active TYK2.\",\n      \"method\": \"TYK2-null cells complemented with kinase-negative or wild-type TYK2, phosphorylation assays, co-IP of PI3K with IFNAR1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase-dead complementation in null cells with multiple STAT readouts and co-IP, single lab\",\n      \"pmids\": [\"10542297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"For IFNAR1, only the TYK2 binding site in its intracellular domain is required for signaling. Tyrosine residues in the IFNAR1 ICD are not required for signaling. In contrast, the IFNAR2 ICD tyrosines drive STAT dissociation to maintain signaling flux.\",\n      \"method\": \"Receptor mutants in knockout cells, STAT phosphorylation and reporter assays, antiviral activity assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cell complementation with multiple receptor truncation/mutation variants, single lab\",\n      \"pmids\": [\"34813358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Residues 62FSSLKLNVY70 in the S5-S6 loop and Trp129 in the second subdomain of IFNAR1 are critical for IFN-α binding and signaling. Residues 278LRV in the third subdomain are critical for IFN-α-induced biological activity but not ligand binding. A model predicts receptor complex closure upon IFN binding with the N-terminal IFNAR1 domain acting as a lid.\",\n      \"method\": \"Site-directed mutagenesis of extracellular domain residues, binding assays, antiviral and antiproliferative activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic mutagenesis with both binding and functional readouts, single lab\",\n      \"pmids\": [\"15449939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A proline deletion in the hinge region of the membrane-proximal domain of IFNAR1 (corresponding to the P335del variant) decreases IFN-β binding affinity of IFNAR1, impairing type I IFN signaling. This variant is associated with decreased tuberculosis susceptibility in humans.\",\n      \"method\": \"Receptor mutagenesis, surface plasmon resonance binding assay, cell signaling assay, genetic association study\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR binding + cell signaling with mutagenesis, genetic validation in human cohorts\",\n      \"pmids\": [\"29311663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A hot spot on IFNAR1 subdomain-3, centered on Tyr240 and Tyr274, mediates interaction with the B and C helix termini of IFN-β (residues Phe63, Leu64, Glu77, Thr78, Val81, Arg82). This interface is differentially used by IFN-β versus IFN-α and is required for IFNAR1–IFN-β affinity, STAT1 activation, ISG expression, and antiviral/antiproliferative activity.\",\n      \"method\": \"Crystal structure-guided mutagenesis, surface plasmon resonance, cell-based STAT1 phosphorylation, antiviral assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided mutagenesis validated by SPR and multiple functional assays in one study\",\n      \"pmids\": [\"28289093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Five aromatic residues of bovine IFNAR-1 are critical hotspots for ligand (human IFN-α2) binding; IFNAR-1 subdomains 2 and 3 together harbor the primary determinants for moderate-affinity binding, with subdomains 1 and 4 providing additional contributions.\",\n      \"method\": \"Bovine/human IFNAR-1 chimeras, site-directed mutagenesis of aromatic residues, binding assays on COS cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic chimera and mutagenesis approach with direct binding readout, single lab\",\n      \"pmids\": [\"11278538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1PR1 activation accelerates IFNAR1 turnover/degradation (pertussis toxin-resistant, blocked by S1PR1 C-terminal Tat-peptide preventing internalization), suppresses STAT1 phosphorylation, and selectively inhibits the type I IFN autoamplification loop in plasmacytoid dendritic cells.\",\n      \"method\": \"S1PR1 agonist treatment, pharmacological inhibition, Tat-fusion peptide blockade, STAT1 phosphorylation assay, IFNAR1 protein turnover assay, in vivo CpG-A challenge\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic peptide blockade plus pharmacological/genetic manipulation with multiple readouts, single lab\",\n      \"pmids\": [\"26787880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFNAR1 contains a functional nuclear localization sequence (NLS) at residues 382RKIIEKKT in the extracellular domain; following IFN-β stimulation IFNAR1 translocates to the nucleus in an energy-dependent, importin-dependent manner that is inhibited by the SV40 large T-antigen NLS competitor.\",\n      \"method\": \"NLS identification, nuclear fractionation, energy/importin inhibition assays, competition with SV40 NLS\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NLS characterization with biochemical inhibition controls, single lab\",\n      \"pmids\": [\"15589821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A truncated IFNAR1 protein (from a genomic deletion of the last exon coding sequence and 3'-UTR) is expressed on the cell surface but cannot interact with TYK2, abolishing STAT1/STAT2/STAT3 phosphorylation and genome-wide ISG induction in response to IFN-α2b or IFN-β, rendering patient fibroblasts susceptible to HSV-1.\",\n      \"method\": \"Patient-derived fibroblasts and EBV-B cells, STAT phosphorylation assay, ISG expression profiling, viral challenge, TYK2 binding assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — natural human loss-of-function experiment with multiple orthogonal functional readouts (phosphorylation, ISG induction, viral susceptibility), confirmed in two cell types\",\n      \"pmids\": [\"32960813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Chaperone-mediated autophagy (CMA) targets IFNAR1 (but not IFNLR1) for lysosomal degradation in free fatty acid-treated HCV cell culture; IFNAR1 interacts with the CMA components HSC70 and LAMP2A, as shown by co-immunoprecipitation and colocalization, and siRNA knockdown of these components prevents IFNAR1 degradation.\",\n      \"method\": \"Co-immunoprecipitation, colocalization microscopy, siRNA knockdown, pharmacological lysosomal inhibitors (ammonium chloride, bafilomycin), CMA activators\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with CMA machinery components, siRNA validation, pharmacological confirmation, single lab\",\n      \"pmids\": [\"25961570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNA-binding protein RBM47 binds the 3'-UTR of IFNAR1 mRNA, increases IFNAR1 mRNA stability, and retards IFNAR1 degradation, thereby enhancing downstream IFN signaling and antiviral activity. RBM47 itself is induced by viral infection or interferon stimulation.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of RBM47 with IFNAR1 3'-UTR, mRNA stability assay, RBM47 knockdown/overexpression, ISG expression, viral challenge models\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP confirmed mRNA binding, mRNA stability assay functional consequence, multiple virus models, single lab\",\n      \"pmids\": [\"34160127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Secreted LRPAP1 (upregulated by viral proteases 3CLpro and 2Apro) binds the extracellular domain of IFNAR1, triggering receptor ubiquitination and lysosomal degradation, thereby suppressing IFN signaling and promoting viral infection. A small peptide from LRPAP1 N-terminus is sufficient to cause IFNAR1 degradation.\",\n      \"method\": \"Co-immunoprecipitation (LRPAP1 with IFNAR1 extracellular domain), ubiquitination assay, IFNAR1 surface expression assay, in vitro/ex vivo/in vivo viral infection models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding Co-IP with functional ubiquitination and degradation assays validated in multiple viral infection models, single lab\",\n      \"pmids\": [\"37743411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Deletion of the conserved membrane-distal IRTAM (16 aa) sequence from the IFNAR1 intracellular domain increases IFN-α antiviral sensitivity, accelerates and prolongs STAT DNA-binding complex formation, and blocks IFN-dependent downregulation of IFNAR1, indicating that IRTAM negatively regulates signaling by controlling receptor downregulation.\",\n      \"method\": \"Truncation mutants in stably transfected L929 cells, antiviral assay, EMSA for STAT complexes, receptor downregulation assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"9501047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The mature IFNAR1 chain is a heavily glycosylated protein (65 kDa precursor → 130 kDa mature form); glycosylation is predominantly N-linked and accounts for approximately half the apparent molecular mass; the receptor undergoes ligand-dependent tyrosine phosphorylation and downregulation; IFN-β uniquely induces phosphorylation of an associated 105 kDa protein in two lymphoblastoid cell lines.\",\n      \"method\": \"Metabolic labeling, immunoprecipitation, deglycosylation, 125I-IFN cross-linking, IFNIR structure analysis across cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with cross-linking, metabolic labeling, and cross-cell-line validation\",\n      \"pmids\": [\"7479825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A LINE-1 element (L1M2a) located within the first intron of IFNAR1 functions as a B cell-specific, interferon-inducible enhancer of IFNAR1 transcription. CRISPR deletion of this element in B lymphoblastoid cells reduces both steady-state and interferon-stimulated IFNAR1 expression, creating a positive feedback loop.\",\n      \"method\": \"CRISPR deletion of intronic LINE-1 element, epigenomic profiling (H3K27ac, H3K9me3), luciferase reporter, IFNAR1 expression measurement\",\n      \"journal\": \"Mobile DNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional deletion with epigenomic characterization and expression readout, single lab\",\n      \"pmids\": [\"38037122\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFNAR1 is the signal-transducing subunit of the heterodimeric type I IFN receptor that constitutively associates with TYK2 (via a JH7-JH6 binding domain), which stabilizes IFNAR1 at the plasma membrane by inhibiting endocytosis; ligand binding induces conformational changes in IFNAR1 that propagate to its membrane-proximal domain, triggering TYK2-dependent tyrosine phosphorylation of IFNAR1 and recruitment of STAT2 and STAT3 through their SH2 domains, while PRMT1 also binds the IFNAR1 intracellular domain to mediate arginine methylation as a complementary signaling mechanism; receptor downregulation is controlled by a two-step phosphorylation cascade (PERK-dependent Ser532 priming followed by CK1α-mediated Ser535 phosphorylation) that recruits the SCF-β-TrCP E3 ligase, ubiquitinates Lys501/525/526, and drives lysosomal degradation, with palmitoylation of Cys463 and deubiquitination by the BRISC-SHMT2 complex providing additional regulatory layers; uniquely, IFN-β can also signal through IFNAR1 alone in an IFNAR2-independent manner, using a Tyr240/Tyr274 hot spot on subdomain 3 to activate a distinct JAK-STAT-independent gene set.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFNAR1 is the signal-transducing chain of the type I interferon receptor, coupling extracellular IFN-α/IFN-β binding to intracellular JAK-STAT activation and to tightly controlled receptor turnover [#4, #26]. Ligand binding induces a conformational change in the membrane-distal ectodomain that propagates to a non-ligand-binding membrane-proximal domain essential for signaling [#16], with binding determinants mapping to aromatic residues and subdomains 2/3 of the ectodomain and a hinge region in the membrane-proximal domain [#20, #22, #23, #21]. IFNAR1 constitutively associates with TYK2 through a JH7-JH6 interaction surface, and this binding is the principal requirement for downstream signaling; a natural human truncation that abolishes TYK2 binding eliminates STAT1/STAT2/STAT3 phosphorylation and ISG induction and confers susceptibility to HSV-1 [#6, #19, #26]. TYK2 also stabilizes IFNAR1 at the cell surface by inhibiting its endocytosis, and its catalytic activity drives ligand-induced tyrosine phosphorylation of IFNAR1 and recruitment of STAT2 and STAT3 via their SH2 domains [#1, #4, #5, #11]. Receptor abundance is governed by a phosphodegron in which PERK-dependent Ser532 priming followed by CK1α-mediated Ser535 phosphorylation recruits SCF-β-TrCP, which ubiquitinates Lys501/525/526 to drive lysosomal degradation; this degradation limits inflammatory injury in vivo [#2, #9, #10, #13]. Additional regulatory layers include PTP1B-mediated dephosphorylation at Y466 controlling AP2-dependent endocytosis, palmitoylation of Cys463 required for STAT activation, BRISC-SHMT2 deubiquitination of K63 chains, and PRMT1 binding to the intracellular domain [#14, #15, #12, #3]. Uniquely, IFN-β can ligate IFNAR1 in an IFNAR2-independent manner through a Tyr240/Tyr274 hot spot to engage a distinct, Jak-STAT-independent gene program [#0, #22]. Loss-of-function IFNAR1 alleles in humans cause susceptibility to viral disease [#26], and surface levels are further tuned by maturation factors and pathogen-driven degradation pathways.\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that IFNAR1 is a signaling receptor required defining which kinases and transcription factors it physically couples to and how ligand triggers them.\",\n      \"evidence\": \"Immunoprecipitation, anti-phosphotyrosine blotting, surface biotinylation and cross-linking in IFN-stimulated cells\",\n      \"pmids\": [\"7813427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the TYK2 or STAT2 binding sites on IFNAR1\", \"Identity of the IFN-β-specific ~95 kDa associated protein left unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The molecular basis of constitutive IFNAR1-TYK2 association was mapped, and STAT3 was shown to dock directly on phosphorylated IFNAR1.\",\n      \"evidence\": \"TYK2 deletion-mutant binding assays with functional complementation, and SH2-domain co-IP of STAT3 with PKC-inhibitor follow-up\",\n      \"pmids\": [\"8628273\", \"8626489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"JH7-JH6 binding alone insufficient for IFNAR1 stabilization\", \"Kinase that mediates STAT3 secondary serine phosphorylation not definitively identified\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Functional dissection separated TYK2 binding from its stabilizing role and identified a negative-regulatory cytoplasmic element controlling receptor downregulation.\",\n      \"evidence\": \"TYK2 JH-region complementation and IFNAR1 IRTAM truncation mutants in cells with antiviral, EMSA and downregulation readouts\",\n      \"pmids\": [\"9733772\", \"9501047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which JH5-4-3 stabilizes IFNAR1 unclear\", \"IRTAM-dependent downregulation machinery not yet identified\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Biochemical characterization defined IFNAR1 as a heavily N-glycosylated chain that is tyrosine-phosphorylated and downregulated upon ligand binding.\",\n      \"evidence\": \"Metabolic labeling, deglycosylation, and 125I-IFN cross-linking across lymphoblastoid lines\",\n      \"pmids\": [\"7479825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of glycosylation not tested\", \"Identity of associated 105 kDa IFN-β-induced phosphoprotein unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"A non-JAK enzymatic partner of IFNAR1 was identified, linking the receptor to arginine methylation as a parallel signaling input.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, co-IP of methyltransferase activity, and antisense knockdown growth-inhibition assay\",\n      \"pmids\": [\"9029147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Methylation substrate(s) downstream of PRMT1 on the IFNAR1 axis not defined\", \"Relationship to JAK-STAT signaling not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The ectodomain ligand-binding architecture was mapped, localizing the high-affinity determinants to specific subdomains and aromatic residues.\",\n      \"evidence\": \"Bovine/human chimeras and aromatic-residue mutagenesis with binding assays\",\n      \"pmids\": [\"11278538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address conformational signal propagation\", \"Cross-species chimera framework may not fully reflect human affinity\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The phosphodegron and ubiquitin acceptor sites controlling IFNAR1 degradation were defined, and additional ectodomain residues that uncouple binding from activity were mapped, alongside a functional NLS.\",\n      \"evidence\": \"Site-directed mutagenesis with phospho-specific antibodies, ubiquitination/degradation assays, and nuclear fractionation with importin inhibition\",\n      \"pmids\": [\"15337770\", \"15449939\", \"15589821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for degron phosphorylation not yet identified at this stage\", \"Functional consequence of nuclear IFNAR1 translocation unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"TYK2 catalytic activity was shown to drive the serine phosphorylation, ubiquitination and proteolysis arm of IFNAR1 regulation, distinct from internalization.\",\n      \"evidence\": \"Kinase-dead TYK2 complementation in TYK2-null cells with phosphorylation, ubiquitination and proteolysis readouts\",\n      \"pmids\": [\"16551269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect role of TYK2 kinase in degron phosphorylation not separated\", \"Did not identify the Ser535 kinase\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A mechanistic model for receptor activation was established by showing ligand induces a propagated conformational change from distal to membrane-proximal ectodomain.\",\n      \"evidence\": \"Intramolecular FRET, single-particle EM of ternary complexes, and stopped-flow fluorescence\",\n      \"pmids\": [\"18294654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the ectodomain change couples to intracellular TYK2 activation not resolved\", \"Structural state at membrane not directly visualized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The kinase cascade and ligand-independent stress signal that drive degron phosphorylation were defined, plus a palmitoylation requirement for productive STAT activation.\",\n      \"evidence\": \"Kinase purification and in vitro phosphorylation (CK1α), PERK/UPR induction with phospho-specific antibodies, and Cys463 palmitoylation mutagenesis with STAT readouts\",\n      \"pmids\": [\"19805514\", \"19948722\", \"19561067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How palmitoylation mechanistically promotes STAT2 recruitment not defined\", \"Crosstalk between UPR-driven and ligand-driven degradation incompletely mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Negative feedback by SOCS1 was shown to act through TYK2 rather than IFNAR1 directly, linking kinase suppression to reduced receptor surface levels.\",\n      \"evidence\": \"Co-IP, interaction-residue mutagenesis, and ubiquitination/surface-expression assays\",\n      \"pmids\": [\"21757742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish direct IFNAR1 contact by SOCS1\", \"In vivo relevance of TYK2 K63-ubiquitin regulation not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"An endocytic control point was identified whereby PTP1B dephosphorylates Y466 to enable AP2-dependent IFNAR1 internalization.\",\n      \"evidence\": \"RNAi screen with direct binding/dephosphorylation assays, Y466 mutagenesis, and pharmacological PTP1B inhibition\",\n      \"pmids\": [\"23129613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal coordination with degron phosphorylation unclear\", \"Structural basis of PTP1B-IFNAR1 recognition not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"IFN-β-specific signaling through IFNAR1 alone was structurally and functionally demonstrated, and a deubiquitination brake on receptor turnover was identified.\",\n      \"evidence\": \"Crystal structure of IFNAR1-IFN-β with SPR and Ifnar2-/- mouse signaling, and MS interactome plus DUB assays with BRISC knockout phenotyping for BRISC-SHMT2\",\n      \"pmids\": [\"23872679\", \"24075985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The Jak-STAT-independent gene set and its transducer remain undefined\", \"How SHMT2 targets BRISC selectively to IFNAR1 K63 chains not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The physiological purpose of IFNAR1 degradation was established as protection against inflammatory tissue injury.\",\n      \"evidence\": \"Ifnar1SA degron knock-in mice in pancreatitis/hepatitis models with pharmacological induction of ubiquitination\",\n      \"pmids\": [\"24480543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions to tissue protection not dissected\", \"Link to human inflammatory disease not established here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Additional surface-control mechanisms were uncovered: prolidase-dependent maturation (exploited by flavivirus NS5) and CMA-mediated lysosomal degradation under metabolic stress.\",\n      \"evidence\": \"PEPD/NS5 co-IP with patient fibroblasts and viral challenge; HSC70/LAMP2A co-IP with siRNA and lysosomal inhibitors in HCV cell culture\",\n      \"pmids\": [\"26159719\", \"25961570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of prolidase action on IFNAR1 maturation unclear\", \"CMA targeting motif on IFNAR1 not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A receptor-driven negative regulator was found whereby S1PR1 accelerates IFNAR1 turnover to dampen the type I IFN autoamplification loop in pDCs.\",\n      \"evidence\": \"S1PR1 agonist/peptide-blockade with STAT1 and IFNAR1 turnover assays and in vivo CpG-A challenge\",\n      \"pmids\": [\"26787880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect coupling of S1PR1 to the IFNAR1 degradation machinery unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The IFN-β-specific binding interface and a clinically relevant hinge variant were defined, connecting receptor biophysics to human disease susceptibility.\",\n      \"evidence\": \"Structure-guided mutagenesis with SPR and STAT1/antiviral assays (Tyr240/Tyr274 hot spot), and P335del variant SPR/signaling with genetic association\",\n      \"pmids\": [\"28289093\", \"29311663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking reduced affinity to tuberculosis protection not fully resolved\", \"Whether the IFN-β hot spot drives the Jak-STAT-independent program not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic dissection clarified that TYK2 binding, not IFNAR1 ICD tyrosines, is the essential signaling requirement, and an mRNA-stabilizing input was identified.\",\n      \"evidence\": \"Receptor mutant complementation in knockout cells with STAT/reporter/antiviral readouts; RBM47 RIP and mRNA stability assays with viral challenge\",\n      \"pmids\": [\"34813358\", \"34160127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier tyrosine-phosphorylation findings incomplete\", \"How RBM47 selectively stabilizes IFNAR1 mRNA not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A natural human loss-of-function IFNAR1 allele confirmed that TYK2-dependent signaling is essential for antiviral ISG induction in vivo.\",\n      \"evidence\": \"Patient-derived fibroblasts and EBV-B cells with STAT phosphorylation, ISG profiling, TYK2 binding and HSV-1 challenge\",\n      \"pmids\": [\"32960813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spectrum of viral susceptibility in patients not fully characterized\", \"Residual Jak-STAT-independent signaling in the truncant not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Transcriptional and pathogen-driven control of IFNAR1 abundance was extended by a B-cell enhancer and a secreted viral-induced degradation factor.\",\n      \"evidence\": \"CRISPR deletion of an intronic LINE-1 enhancer with epigenomic/reporter readouts; LRPAP1 co-IP, ubiquitination and surface-expression assays in viral infection models\",\n      \"pmids\": [\"38037122\", \"37743411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the LINE-1 enhancer beyond B cells unknown\", \"How extracellular LRPAP1 binding triggers IFNAR1 ubiquitination mechanistically unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the transducer and complete gene program engaged by the IFNAR2-independent, Jak-STAT-independent IFN-β signaling through IFNAR1 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No transducer identified for the IFNAR1-only IFN-β signal\", \"Physiological contexts where IFNAR1-alone signaling dominates not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 26]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 22, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 9, 27]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 12]}\n    ],\n    \"complexes\": [\"type I interferon receptor (IFNAR1-IFNAR2)\"],\n    \"partners\": [\"TYK2\", \"STAT2\", \"STAT3\", \"PRMT1\", \"PTP1B\", \"BTRC\", \"SHMT2\", \"PEPD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}