Affinage

IFNAR1

Interferon alpha/beta receptor 1 · UniProt P17181

Length
557 aa
Mass
63.5 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1994 High

    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

    PMID:7813427

    Open questions at the time
    • Did not map the TYK2 or STAT2 binding sites on IFNAR1
    • Identity of the IFN-β-specific ~95 kDa associated protein left unresolved
  2. 1996 High

    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

    PMID:8626489 PMID:8628273

    Open questions at the time
    • JH7-JH6 binding alone insufficient for IFNAR1 stabilization
    • Kinase that mediates STAT3 secondary serine phosphorylation not definitively identified
  3. 1998 Medium

    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

    PMID:9501047 PMID:9733772

    Open questions at the time
    • Mechanism by which JH5-4-3 stabilizes IFNAR1 unclear
    • IRTAM-dependent downregulation machinery not yet identified
  4. 1995 Medium

    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

    PMID:7479825

    Open questions at the time
    • Functional role of glycosylation not tested
    • Identity of associated 105 kDa IFN-β-induced phosphoprotein unresolved
  5. 1997 High

    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

    PMID:9029147

    Open questions at the time
    • Methylation substrate(s) downstream of PRMT1 on the IFNAR1 axis not defined
    • Relationship to JAK-STAT signaling not resolved
  6. 2001 Medium

    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

    PMID:11278538

    Open questions at the time
    • Did not address conformational signal propagation
    • Cross-species chimera framework may not fully reflect human affinity
  7. 2004 High

    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

    PMID:15337770 PMID:15449939 PMID:15589821

    Open questions at the time
    • Kinase responsible for degron phosphorylation not yet identified at this stage
    • Functional consequence of nuclear IFNAR1 translocation unclear
  8. 2006 High

    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

    PMID:16551269

    Open questions at the time
    • Direct vs indirect role of TYK2 kinase in degron phosphorylation not separated
    • Did not identify the Ser535 kinase
  9. 2008 High

    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

    PMID:18294654

    Open questions at the time
    • How the ectodomain change couples to intracellular TYK2 activation not resolved
    • Structural state at membrane not directly visualized
  10. 2009 High

    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

    PMID:19561067 PMID:19805514 PMID:19948722

    Open questions at the time
    • How palmitoylation mechanistically promotes STAT2 recruitment not defined
    • Crosstalk between UPR-driven and ligand-driven degradation incompletely mapped
  11. 2011 High

    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

    PMID:21757742

    Open questions at the time
    • Does not establish direct IFNAR1 contact by SOCS1
    • In vivo relevance of TYK2 K63-ubiquitin regulation not addressed
  12. 2012 High

    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

    PMID:23129613

    Open questions at the time
    • Spatiotemporal coordination with degron phosphorylation unclear
    • Structural basis of PTP1B-IFNAR1 recognition not defined
  13. 2013 High

    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

    PMID:23872679 PMID:24075985

    Open questions at the time
    • The Jak-STAT-independent gene set and its transducer remain undefined
    • How SHMT2 targets BRISC selectively to IFNAR1 K63 chains not fully resolved
  14. 2014 High

    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

    PMID:24480543

    Open questions at the time
    • Cell-type-specific contributions to tissue protection not dissected
    • Link to human inflammatory disease not established here
  15. 2015 Medium

    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

    PMID:25961570 PMID:26159719

    Open questions at the time
    • Mechanism of prolidase action on IFNAR1 maturation unclear
    • CMA targeting motif on IFNAR1 not mapped
  16. 2016 Medium

    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

    PMID:26787880

    Open questions at the time
    • Direct vs indirect coupling of S1PR1 to the IFNAR1 degradation machinery unclear
    • Single-lab finding
  17. 2017 High

    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

    PMID:28289093 PMID:29311663

    Open questions at the time
    • Mechanism linking reduced affinity to tuberculosis protection not fully resolved
    • Whether the IFN-β hot spot drives the Jak-STAT-independent program not tested
  18. 2021 Medium

    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

    PMID:34160127 PMID:34813358

    Open questions at the time
    • Reconciliation with earlier tyrosine-phosphorylation findings incomplete
    • How RBM47 selectively stabilizes IFNAR1 mRNA not mechanistically resolved
  19. 2021 High

    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

    PMID:32960813

    Open questions at the time
    • Spectrum of viral susceptibility in patients not fully characterized
    • Residual Jak-STAT-independent signaling in the truncant not assessed
  20. 2023 Medium

    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

    PMID:37743411 PMID:38037122

    Open questions at the time
    • Generality of the LINE-1 enhancer beyond B cells unknown
    • How extracellular LRPAP1 binding triggers IFNAR1 ubiquitination mechanistically unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the transducer and complete gene program engaged by the IFNAR2-independent, Jak-STAT-independent IFN-β signaling through IFNAR1 remains unresolved.
  • No transducer identified for the IFNAR1-only IFN-β signal
  • Physiological contexts where IFNAR1-alone signaling dominates not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 3 GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
BTRCPEPDPRMT1PTP1BSHMT2STAT2STAT3TYK2
Complex memberships
type I interferon receptor (IFNAR1-IFNAR2)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. Crystal structure determination, surface plasmon resonance, cell signaling assays, Ifnar2−/− mouse model Nature immunology High 23872679
2003 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. Immunofluorescence localization, cell surface expression assays, co-expression experiments in Tyk2-deficient cells The EMBO journal High 12554654
2004 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. Site-directed mutagenesis, phospho-specific antibody, ubiquitination assays, degradation assays in cells The Journal of biological chemistry High 15337770
1997 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. Yeast two-hybrid screen, GST pulldown with bacterially expressed IFNAR1-IC, co-immunoprecipitation from human cells, antisense knockdown functional assay The EMBO journal High 9029147
1994 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. Immunoprecipitation, anti-phosphotyrosine Western blot, extracellular biotin tagging, cross-linking The EMBO journal High 7813427
1996 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. Co-immunoprecipitation, IFN-α stimulation, pharmacological inhibition of PKC, SH2 domain binding assays The Journal of biological chemistry Medium 8626489
1996 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. In vitro binding assay with deletion mutants, co-immunoprecipitation, complementation in Tyk2-deficient cells Molecular and cellular biology High 8628273
1998 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. In vitro binding assay, co-immunoprecipitation, functional complementation in Tyk2-negative cells The Journal of biological chemistry Medium 9733772
2011 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. Co-immunoprecipitation, mutagenesis, ubiquitination assays, surface expression analysis The Journal of biological chemistry High 21757742
2009 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. Biochemical purification of kinase activity, in vitro phosphorylation assay, mutagenesis, siRNA knockdown, overexpression in cells Molecular and cellular biology High 19805514
2009 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. Mutagenesis, phospho-specific antibody, UPR induction, co-IP with β-TrCP The Journal of biological chemistry High 19948722
2006 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. Catalytically inactive Tyk2 mutant complementation in Tyk2-null cells, serine phosphorylation assay, ubiquitination assay, proteolysis assay The Biochemical journal High 16551269
2013 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. Mass spectrometry interactome, co-immunoprecipitation, DUB activity assay, BRISC-deficient cells and mice, endocytosis assay Cell reports High 24075985
2014 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. Knock-in mouse model (serine-to-alanine mutation in degron), inflammatory disease models, pharmacological stimulation of IFNAR1 ubiquitination EMBO molecular medicine High 24480543
2012 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. RNAi screen, co-IP/pulldown, endocytosis assay, site-directed mutagenesis of Y466, pharmacological PTP1B inhibitors Proceedings of the National Academy of Sciences of the United States of America High 23129613
2009 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. Cysteine-to-alanine mutagenesis, metabolic palmitoylation labeling, pharmacological palmitoylation inhibition, microscopy, STAT activation assays The Journal of biological chemistry High 19561067
2008 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. Intramolecular FRET, single-particle electron microscopy, photo-induced electron-transfer fluorescence quenching, stopped-flow fluorescence Journal of molecular biology High 18294654
2015 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. Co-immunoprecipitation of NS5 with PEPD, siRNA knockdown, patient-derived fibroblasts, surface expression assay, viral challenge Cell host & microbe High 26159719
1999 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. TYK2-null cells complemented with kinase-negative or wild-type TYK2, phosphorylation assays, co-IP of PI3K with IFNAR1 The Journal of biological chemistry Medium 10542297
2021 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. Receptor mutants in knockout cells, STAT phosphorylation and reporter assays, antiviral activity assays Science signaling Medium 34813358
2004 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. Site-directed mutagenesis of extracellular domain residues, binding assays, antiviral and antiproliferative activity assays Biochemistry Medium 15449939
2017 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. Receptor mutagenesis, surface plasmon resonance binding assay, cell signaling assay, genetic association study Nature communications Medium 29311663
2017 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. Crystal structure-guided mutagenesis, surface plasmon resonance, cell-based STAT1 phosphorylation, antiviral assays The Journal of biological chemistry High 28289093
2001 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. Bovine/human IFNAR-1 chimeras, site-directed mutagenesis of aromatic residues, binding assays on COS cells The Journal of biological chemistry Medium 11278538
2016 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. S1PR1 agonist treatment, pharmacological inhibition, Tat-fusion peptide blockade, STAT1 phosphorylation assay, IFNAR1 protein turnover assay, in vivo CpG-A challenge Proceedings of the National Academy of Sciences of the United States of America Medium 26787880
2004 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. NLS identification, nuclear fractionation, energy/importin inhibition assays, competition with SV40 NLS FEBS letters Medium 15589821
2021 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. Patient-derived fibroblasts and EBV-B cells, STAT phosphorylation assay, ISG expression profiling, viral challenge, TYK2 binding assay The Journal of clinical investigation High 32960813
2015 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. Co-immunoprecipitation, colocalization microscopy, siRNA knockdown, pharmacological lysosomal inhibitors (ammonium chloride, bafilomycin), CMA activators PloS one Medium 25961570
2021 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. RNA immunoprecipitation (RIP) of RBM47 with IFNAR1 3'-UTR, mRNA stability assay, RBM47 knockdown/overexpression, ISG expression, viral challenge models EMBO reports Medium 34160127
2023 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. Co-immunoprecipitation (LRPAP1 with IFNAR1 extracellular domain), ubiquitination assay, IFNAR1 surface expression assay, in vitro/ex vivo/in vivo viral infection models Signal transduction and targeted therapy Medium 37743411
1998 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. Truncation mutants in stably transfected L929 cells, antiviral assay, EMSA for STAT complexes, receptor downregulation assay Virology Medium 9501047
1995 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. Metabolic labeling, immunoprecipitation, deglycosylation, 125I-IFN cross-linking, IFNIR structure analysis across cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 7479825
2023 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. CRISPR deletion of intronic LINE-1 element, epigenomic profiling (H3K27ac, H3K9me3), luciferase reporter, IFNAR1 expression measurement Mobile DNA Medium 38037122

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 330 18424188
2006 Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 233 17115899
2013 Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nature immunology 215 23872679
2003 The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. The EMBO journal 181 12554654
1997 A protein-arginine methyltransferase binds to the intracytoplasmic domain of the IFNAR1 chain in the type I interferon receptor. The EMBO journal 157 9029147
2008 Cutting edge: innate immune response triggered by influenza A virus is negatively regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-dependent pathway. Journal of immunology (Baltimore, Md. : 1950) 140 18250407
2011 Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon alpha receptor (IFNAR1)-associated tyrosine kinase Tyk2. The Journal of biological chemistry 135 21757742
1994 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. The EMBO journal 135 7813427
2004 Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. The Journal of biological chemistry 126 15337770
1996 Direct association of STAT3 with the IFNAR-1 chain of the human type I interferon receptor. The Journal of biological chemistry 118 8626489
2015 Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression. Cell host & microbe 111 26159719
2021 Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency. The Journal of clinical investigation 101 32960813
2018 Blocking IFNAR1 inhibits multiple myeloma-driven Treg expansion and immunosuppression. The Journal of clinical investigation 95 29558366
2001 The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties. Blood 87 11154225
2013 A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell reports 86 24075985
1996 Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction. Molecular and cellular biology 86 8628273
2018 IFNAR1 Controls Autocrine Type I IFN Regulation of PD-L1 Expression in Myeloid-Derived Suppressor Cells. Journal of immunology (Baltimore, Md. : 1950) 83 29752314
2003 Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia. Genes and immunity 77 12761564
1998 Specific contribution of Tyk2 JH regions to the binding and the expression of the interferon alpha/beta receptor component IFNAR1. The Journal of biological chemistry 76 9733772
2015 Suppression of T Cell Activation and Collagen Accumulation by an Anti-IFNAR1 mAb, Anifrolumab, in Adult Patients with Systemic Sclerosis. The Journal of investigative dermatology 73 25993119
2021 IFNAR1 and IFNAR2 play distinct roles in initiating type I interferon-induced JAK-STAT signaling and activating STATs. Science signaling 69 34813358
2002 Expression of interferon receptor subunits, IFNAR1 and IFNAR2, in the ovine uterus. Biology of reproduction 69 12193393
2006 TYK2 activity promotes ligand-induced IFNAR1 proteolysis. The Biochemical journal 68 16551269
2009 Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. Molecular and cellular biology 67 19805514
2017 miR-93-5p/IFNAR1 axis promotes gastric cancer metastasis through activating the STAT3 signaling pathway. Cancer letters 64 28842285
2009 Heterologous prime boost vaccination with DNA and recombinant modified vaccinia virus Ankara protects IFNAR(-/-) mice against lethal bluetongue infection. Vaccine 63 19857449
1999 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. The Journal of biological chemistry 62 10542297
2022 A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes. The Journal of experimental medicine 59 35442418
2006 Differential responsiveness to IFN-alpha and IFN-beta of human mature DC through modulation of IFNAR expression. Journal of leukocyte biology 58 16624932
2018 Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma. British journal of cancer 57 30555157
2014 Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury. EMBO molecular medicine 56 24480543
2013 Exacerbated autoimmunity in the absence of TLR9 in MRL.Fas(lpr) mice depends on Ifnar1. Journal of immunology (Baltimore, Md. : 1950) 56 23467932
2016 S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proceedings of the National Academy of Sciences of the United States of America 55 26787880
2011 A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR(-/-) mice upon lethal virus challenge. Vaccine 55 21549790
2016 IFNAR1-Signalling Obstructs ICOS-mediated Humoral Immunity during Non-lethal Blood-Stage Plasmodium Infection. PLoS pathogens 54 27812214
2021 Nucleoside-Modified mRNA Vaccines Protect IFNAR-/- Mice against Crimean-Congo Hemorrhagic Fever Virus Infection. Journal of virology 53 34817199
2018 A proline deletion in IFNAR1 impairs IFN-signaling and underlies increased resistance to tuberculosis in humans. Nature communications 52 29311663
1995 Expression and signaling specificity of the IFNAR chain of the type I interferon receptor complex. Proceedings of the National Academy of Sciences of the United States of America 50 7479825
2021 A Case of Autosomal Recessive Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency with Severe COVID-19. Journal of clinical immunology 49 34713375
2017 A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations. The Journal of clinical investigation 48 29106381
2013 IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice. Journal of immunology (Baltimore, Md. : 1950) 45 23585679
1997 Cloning and characterization of soluble and transmembrane isoforms of a novel component of the murine type I interferon receptor, IFNAR 2. The Journal of biological chemistry 45 9295335
2013 Protection of IFNAR (-/-) mice against bluetongue virus serotype 8, by heterologous (DNA/rMVA) and homologous (rMVA/rMVA) vaccination, expressing outer-capsid protein VP2. PloS one 43 23593251
2009 Inducible priming phosphorylation promotes ligand-independent degradation of the IFNAR1 chain of type I interferon receptor. The Journal of biological chemistry 43 19948722
2020 Vaccination with single plasmid DNA encoding IL-12 and antigens of severe fever with thrombocytopenia syndrome virus elicits complete protection in IFNAR knockout mice. PLoS neglected tropical diseases 42 32196487
2020 Annexin-A1 promotes RIG-I-dependent signaling and apoptosis via regulation of the IRF3-IFNAR-STAT1-IFIT1 pathway in A549 lung epithelial cells. Cell death & disease 41 32541772
2009 Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha. The Journal of biological chemistry 41 19561067
1999 Characterization of antihuman IFNAR-1 monoclonal antibodies: epitope localization and functional analysis. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 41 10048764
2011 Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway. Journal of virology 40 21835795
2008 Ligand binding induces a conformational change in ifnar1 that is propagated to its membrane-proximal domain. Journal of molecular biology 39 18294654
2022 Mycobacterium tuberculosis Induces Irg1 in Murine Macrophages by a Pathway Involving Both TLR-2 and STING/IFNAR Signaling and Requiring Bacterial Phagocytosis. Frontiers in cellular and infection microbiology 38 35586249
2012 Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for antiviral therapies. Proceedings of the National Academy of Sciences of the United States of America 37 23129613
2011 CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer. Genes and immunity 37 21716316
2011 West Nile virus infection induces depletion of IFNAR1 protein levels. Viral immunology 34 21830897
2001 Identification of critical residues in bovine IFNAR-1 responsible for interferon binding. The Journal of biological chemistry 34 11278538
2022 Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis. Nature metabolism 33 35288721
2004 Identification of residues of the IFNAR1 chain of the type I human interferon receptor critical for ligand binding and biological activity. Biochemistry 33 15449939
2021 Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age. Brain, behavior, and immunity 32 33892139
2010 Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection. Viral immunology 32 20565290
2008 Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. Biochemistry 32 18937499
2019 Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in Ifnar-/- mice. PLoS pathogens 31 31790513
1995 Human type I interferon receptor, IFNAR, is a heavily glycosylated 120-130 kD membrane protein. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 31 7544230
2022 Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML. Cancer discovery 29 35311997
2024 African swine fever virus pB318L, a trans-geranylgeranyl-diphosphate synthase, negatively regulates cGAS-STING and IFNAR-JAK-STAT signaling pathways. PLoS pathogens 28 38620034
2018 Human interferon-ϵ and interferon-κ exhibit low potency and low affinity for cell-surface IFNAR and the poxvirus antagonist B18R. The Journal of biological chemistry 28 30171073
2021 RNA-binding protein RBM47 stabilizes IFNAR1 mRNA to potentiate host antiviral activity. EMBO reports 27 34160127
2018 CD8 T Cell Responses to an Immunodominant Epitope within the Nonstructural Protein NS1 Provide Wide Immunoprotection against Bluetongue Virus in IFNAR-/- Mice. Journal of virology 27 29875250
2017 Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke. Neurochemistry international 27 28647375
2019 Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice. Life science alliance 26 31221625
2014 Immunisation with bacterial expressed VP2 and VP5 of bluetongue virus (BTV) protect α/β interferon-receptor knock-out (IFNAR(-/-)) mice from homologous lethal challenge. Vaccine 26 24886956
2008 A non-synonymous single nucleotide polymorphism in IFNAR1 affects susceptibility to chronic hepatitis B virus infection. Journal of viral hepatitis 26 18761606
2006 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. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 17027223
2022 ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis. Cellular and molecular life sciences : CMLS 25 35048182
2020 IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis. Science signaling 25 32265337
2015 Chaperone-Mediated Autophagy Targets IFNAR1 for Lysosomal Degradation in Free Fatty Acid Treated HCV Cell Culture. PloS one 25 25961570
2017 A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling. The Journal of biological chemistry 24 28289093
2024 Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies. Journal of clinical immunology 22 39441221
2023 Secreted LRPAP1 binds and triggers IFNAR1 degradation to facilitate virus evasion from cellular innate immunity. Signal transduction and targeted therapy 22 37743411
2023 An intronic LINE-1 regulates IFNAR1 expression in human immune cells. Mobile DNA 22 38037122
2016 Pathological Characterization Of IFNAR(-/-) Mice Infected With Bluetongue Virus Serotype 4. International journal of biological sciences 22 27994510
2012 ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes. Journal of immunology (Baltimore, Md. : 1950) 22 22368279
1998 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. Virology 22 9501047
2024 CAR T Cells Engineered to Secrete IFNκ Induce Tumor Ferroptosis via an IFNAR/STAT1/ACSL4 Axis. Cancer immunology research 21 39189923
2020 The Crimean-Congo Hemorrhagic Fever Virus NSm Protein is Dispensable for Growth In Vitro and Disease in Ifnar-/- Mice. Microorganisms 20 32455700
2004 The IFNAR1 subunit of the type I IFN receptor complex contains a functional nuclear localization sequence. FEBS letters 20 15589821
2020 Feline calicivirus strain 2280 p30 antagonizes type I interferon-mediated antiviral innate immunity through directly degrading IFNAR1 mRNA. PLoS pathogens 19 33075108
2017 DNA vaccination regimes against Schmallenberg virus infection in IFNAR-/- mice suggest two targets for immunization. Antiviral research 19 28235558
2002 Multiple regions within the promoter of the murine Ifnar-2 gene confer basal and inducible expression. The Biochemical journal 19 11939908
2024 Intermittent hypoxia exacerbates anxiety in high-fat diet-induced diabetic mice by inhibiting TREM2-regulated IFNAR1 signaling. Journal of neuroinflammation 17 38956653
2022 Impacts of the STING-IFNAR1-STAT1-IRF1 pathway on the cellular immune reaction induced by fractionated irradiation. Cancer science 17 35133062
2020 Virological, immunological and pathological findings of transplacentally transmitted bluetongue virus serotype 1 in IFNAR1-blocked mice during early and mid gestation. Scientific reports 16 32034180
2015 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. Vaccine 16 25858859
2022 IFNAR1 Deficiency Impairs Immunostimulatory Properties of Neutrophils in Tumor-Draining Lymph Nodes. Frontiers in immunology 15 35833131
2020 Characterization of local SARS-CoV-2 isolates and pathogenicity in IFNAR-/- mice. Heliyon 15 33015402
2015 A functional polymorphism in IFNAR1 gene is associated with susceptibility and severity of HFMD with EV71 infection. Scientific reports 15 26679744
1998 Mapping human interferon-alpha (IFN-alpha 2) binding determinants of the type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras. Biochemistry 15 9737881
2024 Intratumoral delivery of the chitin-derived C100 adjuvant promotes robust STING, IFNAR, and CD8+ T cell-dependent anti-tumor immunity. Cell reports. Medicine 14 38729159
2024 A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity. The Journal of experimental medicine 14 39680367
2019 Cellular Caspase-3 Contributes to EV-A71 2Apro-Mediated Down-Regulation of IFNAR1 at the Translation Level. Virologica Sinica 14 31512106
2011 T cell-intrinsic and -extrinsic contributions of the IFNAR/STAT1-axis to thymocyte survival. PloS one 14 21949815

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