{"gene":"IFNLR1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2016,"finding":"Crystal structure of the FERM and SH2-like domains of JAK1 bound to a fragment of the intracellular domain of IFNLR1 was determined at 2.1 Å resolution. Both box1 and box2 regions of IFNLR1 bind simultaneously to the FERM and SH2-like domains of JAK1. A glutamate residue adjacent to the box2 region in IFNLR1 mimics phosphotyrosine binding in classical SH2 domains. Deletion of residues within the box1 region of IFNLR1 abolishes stable interaction with JAK1.","method":"X-ray crystallography at 2.1 Å resolution; deletion mutagenesis of box1 region","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation in a single rigorous study","pmids":["27725180"],"is_preprint":false},{"year":2017,"finding":"IFNLR1 expression specifically on intestinal epithelial cells (IECs) is required for IFN-λ antiviral activity against murine norovirus and reovirus in vivo. Lineage-specific conditional knockout of Ifnlr1 in IECs recapitulated the Ifnlr1-null phenotype (higher intestinal tissue viral titers and increased fecal shedding), and IEC IFNLR1 expression is necessary for sterilizing innate immune effects of IFN-λ even in Rag1-deficient mice.","method":"Conditional knockout mice (lineage-specific Ifnlr1 deletion in IECs); viral titer assays; Rag1-deficient mouse model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with clear cellular phenotype, replicated across two viral pathogens and in immunodeficient background","pmids":["28077655"],"is_preprint":false},{"year":2004,"finding":"IFNLR1 (IL28RA) functions as part of a heterodimeric class II cytokine receptor complex to transduce signals for IFN-λ1, -λ2, and -λ3. It belongs to the CRF2 family and combines with another subunit to form a functional receptor heterodimer.","method":"Genomic/sequence analysis and receptor family characterization","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 — receptor family biochemical characterization without direct binding or structural assay in this paper","pmids":["15120645"],"is_preprint":false},{"year":2018,"finding":"A missense mutation c.296G>A (p.Arg99His) in IFNLR1 is associated with autosomal dominant nonsyndromic sensorineural hearing loss. IFNLR1 is expressed in the mouse inner ear. Morpholino knockdown of ifnlr1 in zebrafish causes significant decrease in hair cells and swim bladder non-inflation, reversible by injection of normal ifnlr1 mRNA. Knockdown upregulates IL-10R2, JAK1, TYK2, STAT3, and STAT5b in the JAK1/STAT3 pathway.","method":"Whole exome sequencing; linkage analysis; immunostaining in mouse inner ear; morpholino knockdown in zebrafish with mRNA rescue; qRT-PCR","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockdown with rescue in zebrafish model, multiple orthogonal methods, single lab","pmids":["29453195"],"is_preprint":false},{"year":2023,"finding":"IFNLR1 isoform 1 (full-length) supports canonical IFN-λ signaling and markedly increases IFNL3-dependent expression of antiviral and pro-inflammatory genes. IFNLR1 isoform 2 (predicted signaling-defective) at low expression levels partially induces antiviral genes but not pro-inflammatory genes after IFNL3 treatment, and this is abrogated at high expression levels. IFNLR1 isoform 3 partially augments antiviral gene expression. Overexpression of isoform 1 also reduces cellular sensitivity to type I IFN (IFNA2).","method":"Stable HEK293T clones with doxycycline-inducible FLAG-tagged IFNLR1 isoforms; antiviral and pro-inflammatory gene expression assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization of isoforms with inducible expression system, single lab, moderate orthogonality","pmids":["36992341"],"is_preprint":false},{"year":2025,"finding":"Full-length IFNLR1 (variant 1) in stem cell-derived hepatocytes enables IFNL-induced expression of both antiviral and pro-inflammatory genes and augments inhibition of HBV replication. A noncanonical IFNLR1 variant missing part of the JAK1-binding domain can induce antiviral genes but cannot support pro-inflammatory gene induction or augmented HBV inhibition. A secreted IFNLR1 variant has no identified function in hepatocytes lacking endogenous IFNLR1.","method":"FLAG-tagged IFNLR1 variants expressed in IFNLR1 knockout stem cell-derived hepatocytes (iHeps); gene expression profiling; HBV replication assay; western blotting","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 — functional variant dissection in KO background with multiple orthogonal readouts, single lab","pmids":["39929255"],"is_preprint":false},{"year":2025,"finding":"IFNLR1 variant 1 (full-length) and variant 2 (lacking part of Box1/Box2 JAK1-interacting motifs) both colocalize with IL10RB after IFNL treatment, but variant 1 is more rapidly and extensively internalized than variant 2. Variant 2 enables higher JAK1 and TYK2 phosphorylation than variant 1, yet variant 1 enables greater STAT1 and STAT2 phosphorylation and broader ISG expression. Noncanonical IFNLR1 variants influence the TYK2-dependence of IFNL signaling. These findings indicate IFNLR1 variants differentially utilize JAK/STAT signaling mediators to shape gene expression patterns.","method":"Duolink proximity ligation assay; ImageStream flow cytometry; western blotting of JAK-STAT proteins; JAK1/TYK2-specific inhibitors; gene expression profiling; doxycycline-inducible FLAG-tagged IFNLR1 in HEK293T and iHeps (WT and KO)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal mechanistic methods in KO background, preprint not yet peer-reviewed","pmids":["41256602"],"is_preprint":true},{"year":2019,"finding":"IL28RA overexpression in pancreatic cancer cells (PANC-1 and BXPC-3) inhibits proliferation and invasion, increases apoptosis, reduces phosphorylation of JAK2 and STAT3, increases pro-apoptotic BAX expression, and decreases anti-apoptotic BCL-2 expression, demonstrating that IFNLR1 exerts anti-proliferative effects via inhibition of the JAK-STAT signaling pathway.","method":"IL28RA overexpression in pancreatic cancer cell lines; western blot for JAK2, STAT3 phosphorylation and apoptosis markers; proliferation and invasion assays; flow cytometry","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, overexpression study without endogenous pathway validation or structural confirmation","pmids":["31799654"],"is_preprint":false},{"year":2019,"finding":"IL28RA (IFNLR1) overexpression in HaCaT keratinocytes inhibits proliferation and causes cell cycle arrest at G0/G1 phases via activation of the JAK-STAT signaling pathway. Knockdown of IL28RA accelerates proliferation and increases the proportion of cells in S and G2/M phases. IL28RA overexpression downregulates cyclin B1 and upregulates cyclin E, while knockdown has the opposite effect.","method":"IL28RA knockdown and overexpression in HaCaT cells; flow cytometry cell cycle analysis; western blot for cyclin B1 and cyclin E; proliferation assays","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanistic pathway placement via western blot but no reconstitution or epistasis","pmids":["30632069"],"is_preprint":false},{"year":2024,"finding":"Knockdown of IFNLR1 in the infarcted mouse myocardium via lentiviral injection reduced p-JAK1/JAK1 and p-STAT1/STAT1 ratios and decreased cardiomyocyte apoptosis, indicating that IL28A signals through IFNLR1 to activate the JAK1/STAT1 pathway and promote cardiomyocyte apoptosis post-AMI.","method":"Lentiviral knockdown of IL28RA in mouse myocardium; echocardiography; immunofluorescence and western blot for JAK1/STAT1 phosphorylation; TUNEL staining; BAX/BCL2 ratio","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — in vivo knockdown with pathway readout, single lab, no reconstitution","pmids":["39706854"],"is_preprint":false},{"year":2024,"finding":"Knockout of IFNLR1 in epithelial cells results in a greater proportion of IAV-infected cells and higher viral RNA and protein levels, with a lower ratio of dying to infected cells, suggesting that IFN-λ signaling through IFNLR1 restricts influenza virus spread by promoting rapid death of infected cells, distinct from JAK/STAT-mediated ISG induction.","method":"IFNLR1 knockout cell lines; IAV and RSV infection; flow cytometry for infection and cell death; STAT1/2 phosphorylation; ISG protein levels","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — KO with specific phenotype, orthogonal measurements of JAK-STAT and cell death, preprint","pmids":["bio_10.1101_2024.09.09.612051"],"is_preprint":true}],"current_model":"IFNLR1 forms a heterodimeric receptor complex with IL10RB that, upon binding IFN-λ, recruits JAK1 through box1 and box2 intracellular motifs (as defined by crystal structure) to activate JAK1/TYK2-STAT1/STAT2 signaling; expression of IFNLR1 specifically on intestinal epithelial cells is required in vivo for antiviral protection, and distinct IFNLR1 splice isoforms differentially regulate internalization kinetics, JAK-STAT activation levels, and the balance between antiviral versus pro-inflammatory gene expression programs."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that IFNLR1 (IL28RA) is a CRF2-family receptor subunit that heterodimerizes to transduce signals for all three IFN-λ ligands defined the gene's core identity as the ligand-binding chain of the type III IFN receptor.","evidence":"Genomic and receptor family characterization","pmids":["15120645"],"confidence":"Medium","gaps":["No direct binding data or structural information in this study","Second subunit (IL10RB) requirement not experimentally dissected here"]},{"year":2016,"claim":"Determination of the JAK1–IFNLR1 intracellular domain crystal structure resolved how the receptor recruits its cognate kinase, showing that box1 and box2 motifs bind simultaneously to JAK1 FERM and SH2-like domains through a glutamate-based phosphotyrosine mimicry mechanism.","evidence":"X-ray crystallography at 2.1 Å resolution with deletion mutagenesis validation","pmids":["27725180"],"confidence":"High","gaps":["Structure captures only the JAK1 interaction; TYK2 recruitment mechanism via IL10RB not resolved","No kinetic or thermodynamic binding data reported"]},{"year":2017,"claim":"Conditional knockout of Ifnlr1 specifically in intestinal epithelial cells demonstrated that IFNLR1-restricted epithelial expression is the critical determinant of IFN-λ antiviral protection in the gut, independent of adaptive immunity.","evidence":"Lineage-specific conditional knockout mice; viral titer assays with norovirus and reovirus; Rag1-deficient background","pmids":["28077655"],"confidence":"High","gaps":["Whether IFNLR1 on other epithelial surfaces (e.g., respiratory) is similarly necessary was not tested","Downstream signaling mediators in IECs not dissected"]},{"year":2018,"claim":"Identification of an IFNLR1 missense mutation (p.Arg99His) segregating with autosomal dominant sensorineural hearing loss, combined with zebrafish knockdown/rescue, expanded the receptor's physiological roles beyond antiviral immunity to sensory organ development.","evidence":"Whole-exome sequencing and linkage analysis in a family; morpholino knockdown with mRNA rescue in zebrafish; immunostaining in mouse inner ear","pmids":["29453195"],"confidence":"Medium","gaps":["Mechanism linking IFN-λ signaling to hair cell maintenance is unknown","No knock-in of the human mutation in a mammalian model","Single family reported"]},{"year":2023,"claim":"Functional dissection of IFNLR1 splice isoforms revealed that the full-length isoform uniquely supports both antiviral and pro-inflammatory gene programs, while a signaling-defective isoform selectively induces antiviral genes at low expression, demonstrating that isoform usage tunes the downstream transcriptional output of IFN-λ signaling.","evidence":"Doxycycline-inducible FLAG-tagged isoform expression in HEK293T; antiviral and pro-inflammatory gene expression assays","pmids":["36992341"],"confidence":"Medium","gaps":["Isoform-specific signaling intermediates not fully mapped","Relative isoform expression in primary tissues not quantified","Cross-talk with type I IFN pathway only partially characterized"]},{"year":2024,"claim":"IFNLR1 knockout in epithelial cells showed that IFN-λ signaling restricts influenza virus spread by promoting rapid death of infected cells, suggesting a cell-death-promoting function distinct from classical ISG induction.","evidence":"IFNLR1 KO cell lines infected with IAV; flow cytometry for infection and cell death (preprint)","pmids":["bio_10.1101_2024.09.09.612051"],"confidence":"Medium","gaps":["Cell death mechanism (apoptosis versus other forms) not molecularly defined","Not yet peer-reviewed","Whether this death-promoting function operates in vivo is untested"]},{"year":2025,"claim":"Comparative analysis of IFNLR1 variants in knockout hepatocytes and with proximity ligation/internalization assays established that differences in the box1/box2 region alter receptor internalization rate, the ratio of JAK1/TYK2 to STAT1/STAT2 phosphorylation, and the dependence on TYK2, mechanistically explaining isoform-specific gene expression patterns.","evidence":"IFNLR1 KO iHeps with re-expression of individual variants; Duolink PLA; ImageStream internalization assay; JAK/TYK2 inhibitors; HBV replication assays; western blot and gene expression profiling","pmids":["39929255","41256602"],"confidence":"Medium","gaps":["Preprint component (PMID:41256602) not yet peer-reviewed","Structural basis for differential internalization not determined","How isoform ratios are regulated at the splicing level is unknown"]},{"year":null,"claim":"How IFNLR1 isoform expression is regulated in different tissues, the structural basis of isoform-specific receptor trafficking, and the mechanism linking IFNLR1 to hearing remain major open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural data for full ectodomain–IFN-λ–IL10RB ternary complex","Splicing regulation of IFNLR1 isoforms uncharacterized","Mechanism of IFNLR1 in inner ear hair cell biology unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4,6]}],"pathway":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"complexes":["IFN-λ receptor (IFNLR1–IL10RB heterodimer)"],"partners":["IL10RB","JAK1","TYK2","STAT1","STAT2"],"other_free_text":[]},"mechanistic_narrative":"IFNLR1 is the ligand-specific subunit of the heterodimeric IFN-λ receptor that restricts type III interferon signaling predominantly to epithelial surfaces, coupling cytokine recognition to JAK1/TYK2–STAT1/STAT2 activation and antiviral gene expression. The intracellular domain engages JAK1 through box1 and box2 motifs, with a crystal structure revealing simultaneous binding of both motifs to the JAK1 FERM and SH2-like domains and a glutamate residue that mimics phosphotyrosine recognition [PMID:27725180]. Lineage-specific deletion of Ifnlr1 in intestinal epithelial cells recapitulates the global knockout phenotype of impaired antiviral defense against norovirus and reovirus, establishing that IEC-restricted expression is necessary and sufficient for IFN-λ–mediated mucosal immunity [PMID:28077655]. Distinct IFNLR1 splice isoforms differentially control receptor internalization kinetics, the balance of JAK1/TYK2 versus STAT1/STAT2 phosphorylation, and the selective induction of antiviral versus pro-inflammatory gene programs, with the full-length isoform uniquely supporting both antiviral and pro-inflammatory responses and augmented inhibition of HBV replication [PMID:36992341, PMID:39929255]."},"prefetch_data":{"uniprot":{"accession":"Q8IU57","full_name":"Interferon lambda receptor 1","aliases":["Cytokine receptor class-II member 12","Cytokine receptor family 2 member 12","CRF2-12","Interleukin-28 receptor subunit alpha","IL-28 receptor subunit alpha","IL-28R-alpha","IL-28RA","Likely interleukin or cytokine receptor 2","LICR2"],"length_aa":520,"mass_kda":57.7,"function":"The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state. Determines the cell type specificity of the lambda interferon action. Shows a more restricted pattern of expression in the epithelial tissues thereby limiting responses to lambda interferons primarily to epithelial cells of the respiratory, gastrointestinal, and reproductive tracts. Seems not to be essential for early virus-activated host defense in vaginal infection, but plays an important role in Toll-like receptor (TLR)-induced antiviral defense. Plays a significant role in the antiviral immune defense in the intestinal epithelium","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q8IU57/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFNLR1","classification":"Not Classified","n_dependent_lines":50,"n_total_lines":1208,"dependency_fraction":0.041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IFNLR1","total_profiled":1310},"omim":[{"mim_id":"615090","title":"INTERFERON, LAMBDA-4; IFNL4","url":"https://www.omim.org/entry/615090"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"607404","title":"INTERFERON-LAMBDA RECEPTOR 1; IFNLR1","url":"https://www.omim.org/entry/607404"},{"mim_id":"607402","title":"INTERFERON, LAMBDA-3; IFNL3","url":"https://www.omim.org/entry/607402"},{"mim_id":"607401","title":"INTERFERON, LAMBDA-2; IFNL2","url":"https://www.omim.org/entry/607401"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFNLR1"},"hgnc":{"alias_symbol":["CRF2/12","IFNLR","IL-28R1"],"prev_symbol":["IL28RA"]},"alphafold":{"accession":"Q8IU57","domains":[{"cath_id":"2.60.40.10","chopping":"24-122","consensus_level":"high","plddt":93.7448,"start":24,"end":122},{"cath_id":"2.60.40.10","chopping":"130-220","consensus_level":"high","plddt":91.3489,"start":130,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU57","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU57-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IU57-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFNLR1","jax_strain_url":"https://www.jax.org/strain/search?query=IFNLR1"},"sequence":{"accession":"Q8IU57","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IU57.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IU57/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IU57"}},"corpus_meta":[{"pmid":"28077655","id":"PMC_28077655","title":"Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28077655","citation_count":143,"is_preprint":false},{"pmid":"15120645","id":"PMC_15120645","title":"Full house: 12 receptors for 27 cytokines.","date":"2004","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15120645","citation_count":80,"is_preprint":false},{"pmid":"27725180","id":"PMC_27725180","title":"Crystal Structure of a Complex of the Intracellular Domain of Interferon λ Receptor 1 (IFNLR1) and the FERM/SH2 Domains of Human JAK1.","date":"2016","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27725180","citation_count":41,"is_preprint":false},{"pmid":"20372826","id":"PMC_20372826","title":"Integrative genomic analyses on IL28RA, the common receptor of interferon-lambda1, -lambda2 and -lambda3.","date":"2010","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20372826","citation_count":30,"is_preprint":false},{"pmid":"21742059","id":"PMC_21742059","title":"Genetic variation in IL28RA is associated with the outcomes of HCV infection in a high-risk Chinese population.","date":"2011","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21742059","citation_count":22,"is_preprint":false},{"pmid":"29080269","id":"PMC_29080269","title":"Role of Functional IFNL4, IFNLR1, IFNA, IFNAR2 Polymorphisms in Hepatitis B virus-related liver disease in Han Chinese population.","date":"2017","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/29080269","citation_count":20,"is_preprint":false},{"pmid":"16819289","id":"PMC_16819289","title":"Analysis of the variations in IL-28RA gene and their association with allergic rhinitis.","date":"2006","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16819289","citation_count":18,"is_preprint":false},{"pmid":"29453195","id":"PMC_29453195","title":"Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29453195","citation_count":17,"is_preprint":false},{"pmid":"23565619","id":"PMC_23565619","title":"IL28RA polymorphism is associated with early hepatitis C virus (HCV) treatment failure in human immunodeficiency virus-/HCV-coinfected patients.","date":"2012","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/23565619","citation_count":17,"is_preprint":false},{"pmid":"34652043","id":"PMC_34652043","title":"Ammonia induces autophagy via circ-IFNLR1/miR-2188-5p/RNF182 axis in tracheas of chickens.","date":"2021","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34652043","citation_count":16,"is_preprint":false},{"pmid":"31799654","id":"PMC_31799654","title":"Significance of IL28RA in diagnosis of early pancreatic cancer and its regulation to pancreatic cancer cells by JAK/STAT signaling pathway - effects of IL28RA on pancreatic cancer.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31799654","citation_count":11,"is_preprint":false},{"pmid":"36992341","id":"PMC_36992341","title":"Influence of Canonical and Non-Canonical IFNLR1 Isoform Expression on Interferon Lambda Signaling.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/36992341","citation_count":9,"is_preprint":false},{"pmid":"36193089","id":"PMC_36193089","title":"lncRNA260 siRNA Accelerates M2 Macrophage Polarization and Alleviates Oxidative Stress via Inhibiting IL28RA Gene Alternative Splicing.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36193089","citation_count":9,"is_preprint":false},{"pmid":"22386267","id":"PMC_22386267","title":"Analysis of the IL28RA locus as genetic risk factor for multiple sclerosis.","date":"2012","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/22386267","citation_count":9,"is_preprint":false},{"pmid":"16759899","id":"PMC_16759899","title":"Structural and spectroscopic properties of trans-difluoro(1,4,8,12-tetraazacyclopentadecane)chromium(III) perchlorate hydrate.","date":"2006","source":"Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy","url":"https://pubmed.ncbi.nlm.nih.gov/16759899","citation_count":9,"is_preprint":false},{"pmid":"25911176","id":"PMC_25911176","title":"Increased expression of IL-28RA mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.","date":"2015","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/25911176","citation_count":8,"is_preprint":false},{"pmid":"21683644","id":"PMC_21683644","title":"Expression of Bcl2l1, Clcf1, IL-28ra and Pias1 in the mouse heart after single and repeated administration of chlorpromazine.","date":"2011","source":"Legal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/21683644","citation_count":8,"is_preprint":false},{"pmid":"30632069","id":"PMC_30632069","title":"IL28RA inhibits human epidermal keratinocyte proliferation by inhibiting cell cycle progression.","date":"2019","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/30632069","citation_count":7,"is_preprint":false},{"pmid":"24438680","id":"PMC_24438680","title":"IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients.","date":"2013","source":"Journal of viral hepatitis","url":"https://pubmed.ncbi.nlm.nih.gov/24438680","citation_count":7,"is_preprint":false},{"pmid":"33751344","id":"PMC_33751344","title":"Association of TNFRSF1A and IFNLR1 Gene Polymorphisms with the Risk of Developing Breast Cancer and Clinical Pathologic Features.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33751344","citation_count":6,"is_preprint":false},{"pmid":"34056880","id":"PMC_34056880","title":"Role of IFNLR1 gene in PRRSV infection of PAM cells.","date":"2021","source":"Journal of veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/34056880","citation_count":4,"is_preprint":false},{"pmid":"28932550","id":"PMC_28932550","title":"LncRNA260-specific siRNA targeting IL28RA gene inhibit cardiomyocytes hypoxic/reoxygenation injury.","date":"2017","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/28932550","citation_count":4,"is_preprint":false},{"pmid":"28639948","id":"PMC_28639948","title":"Protective effects of IL28RA siRNA on cardiomyocytes in hypoxia/reoxygenation injury.","date":"2017","source":"Anatolian journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28639948","citation_count":4,"is_preprint":false},{"pmid":"33269531","id":"PMC_33269531","title":"Interferon III-related IL28RA variant is associated with rheumatoid arthritis and systemic lupus erythematosus and specific disease sub-phenotypes.","date":"2020","source":"International journal of rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33269531","citation_count":4,"is_preprint":false},{"pmid":"39929255","id":"PMC_39929255","title":"Function of Interferon Lambda Receptor 1 Variants in Stem Cell-Derived Hepatocytes with Abrogated Endogenous IFNLR1.","date":"2025","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/39929255","citation_count":1,"is_preprint":false},{"pmid":"39706854","id":"PMC_39706854","title":"Potential therapeutic effects of IL28RA inhibition on acute myocardial infarction through phosphorylated JAK1/STAT1 signaling pathways.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39706854","citation_count":1,"is_preprint":false},{"pmid":"31366248","id":"PMC_31366248","title":"Genetic Polymorphisms of the IFNLR1 Gene Correlate with HCV Infection and Biochemical Features of Chronic HCV Patients in Yunnan, China.","date":"2019","source":"Immunological investigations","url":"https://pubmed.ncbi.nlm.nih.gov/31366248","citation_count":1,"is_preprint":false},{"pmid":"34195850","id":"PMC_34195850","title":"Downregulated expression of IL‑28RA is involved in the pathogenesis of pancreatic ductal adenocarcinoma.","date":"2021","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34195850","citation_count":1,"is_preprint":false},{"pmid":"34968768","id":"PMC_34968768","title":"Transcriptome analysis of the early stage ifnlr1-mutant zebrafish indicates the immune response to auditory dysfunction.","date":"2021","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/34968768","citation_count":0,"is_preprint":false},{"pmid":"41256602","id":"PMC_41256602","title":"Mechanisms of Differential Signal Transduction by IFNLR1 Variants.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41256602","citation_count":0,"is_preprint":false},{"pmid":"38188994","id":"PMC_38188994","title":"Retracted: lncRNA260 siRNA Accelerates M2 Macrophage Polarization and Alleviates Oxidative Stress via Inhibiting IL28RA Gene Alternative Splicing.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/38188994","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.12.669977","title":"Tissue-Resident Macrophage and Dendritic Cell Cooperation Drives Type I IFN Immunity to Enteroviruses in the Liver","date":"2025-08-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.12.669977","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.09.612051","title":"Type III interferons may suppress viral infections by triggering cell death","date":"2024-09-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.09.612051","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19665,"output_tokens":3211,"usd":0.05358},"stage2":{"model":"claude-opus-4-6","input_tokens":6562,"output_tokens":4306,"usd":0.21069},"total_usd":0.26427,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the FERM and SH2-like domains of JAK1 bound to a fragment of the intracellular domain of IFNLR1 was determined at 2.1 Å resolution. Both box1 and box2 regions of IFNLR1 bind simultaneously to the FERM and SH2-like domains of JAK1. A glutamate residue adjacent to the box2 region in IFNLR1 mimics phosphotyrosine binding in classical SH2 domains. Deletion of residues within the box1 region of IFNLR1 abolishes stable interaction with JAK1.\",\n      \"method\": \"X-ray crystallography at 2.1 Å resolution; deletion mutagenesis of box1 region\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation in a single rigorous study\",\n      \"pmids\": [\"27725180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IFNLR1 expression specifically on intestinal epithelial cells (IECs) is required for IFN-λ antiviral activity against murine norovirus and reovirus in vivo. Lineage-specific conditional knockout of Ifnlr1 in IECs recapitulated the Ifnlr1-null phenotype (higher intestinal tissue viral titers and increased fecal shedding), and IEC IFNLR1 expression is necessary for sterilizing innate immune effects of IFN-λ even in Rag1-deficient mice.\",\n      \"method\": \"Conditional knockout mice (lineage-specific Ifnlr1 deletion in IECs); viral titer assays; Rag1-deficient mouse model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with clear cellular phenotype, replicated across two viral pathogens and in immunodeficient background\",\n      \"pmids\": [\"28077655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFNLR1 (IL28RA) functions as part of a heterodimeric class II cytokine receptor complex to transduce signals for IFN-λ1, -λ2, and -λ3. It belongs to the CRF2 family and combines with another subunit to form a functional receptor heterodimer.\",\n      \"method\": \"Genomic/sequence analysis and receptor family characterization\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — receptor family biochemical characterization without direct binding or structural assay in this paper\",\n      \"pmids\": [\"15120645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A missense mutation c.296G>A (p.Arg99His) in IFNLR1 is associated with autosomal dominant nonsyndromic sensorineural hearing loss. IFNLR1 is expressed in the mouse inner ear. Morpholino knockdown of ifnlr1 in zebrafish causes significant decrease in hair cells and swim bladder non-inflation, reversible by injection of normal ifnlr1 mRNA. Knockdown upregulates IL-10R2, JAK1, TYK2, STAT3, and STAT5b in the JAK1/STAT3 pathway.\",\n      \"method\": \"Whole exome sequencing; linkage analysis; immunostaining in mouse inner ear; morpholino knockdown in zebrafish with mRNA rescue; qRT-PCR\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with rescue in zebrafish model, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"29453195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFNLR1 isoform 1 (full-length) supports canonical IFN-λ signaling and markedly increases IFNL3-dependent expression of antiviral and pro-inflammatory genes. IFNLR1 isoform 2 (predicted signaling-defective) at low expression levels partially induces antiviral genes but not pro-inflammatory genes after IFNL3 treatment, and this is abrogated at high expression levels. IFNLR1 isoform 3 partially augments antiviral gene expression. Overexpression of isoform 1 also reduces cellular sensitivity to type I IFN (IFNA2).\",\n      \"method\": \"Stable HEK293T clones with doxycycline-inducible FLAG-tagged IFNLR1 isoforms; antiviral and pro-inflammatory gene expression assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of isoforms with inducible expression system, single lab, moderate orthogonality\",\n      \"pmids\": [\"36992341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Full-length IFNLR1 (variant 1) in stem cell-derived hepatocytes enables IFNL-induced expression of both antiviral and pro-inflammatory genes and augments inhibition of HBV replication. A noncanonical IFNLR1 variant missing part of the JAK1-binding domain can induce antiviral genes but cannot support pro-inflammatory gene induction or augmented HBV inhibition. A secreted IFNLR1 variant has no identified function in hepatocytes lacking endogenous IFNLR1.\",\n      \"method\": \"FLAG-tagged IFNLR1 variants expressed in IFNLR1 knockout stem cell-derived hepatocytes (iHeps); gene expression profiling; HBV replication assay; western blotting\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional variant dissection in KO background with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"39929255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFNLR1 variant 1 (full-length) and variant 2 (lacking part of Box1/Box2 JAK1-interacting motifs) both colocalize with IL10RB after IFNL treatment, but variant 1 is more rapidly and extensively internalized than variant 2. Variant 2 enables higher JAK1 and TYK2 phosphorylation than variant 1, yet variant 1 enables greater STAT1 and STAT2 phosphorylation and broader ISG expression. Noncanonical IFNLR1 variants influence the TYK2-dependence of IFNL signaling. These findings indicate IFNLR1 variants differentially utilize JAK/STAT signaling mediators to shape gene expression patterns.\",\n      \"method\": \"Duolink proximity ligation assay; ImageStream flow cytometry; western blotting of JAK-STAT proteins; JAK1/TYK2-specific inhibitors; gene expression profiling; doxycycline-inducible FLAG-tagged IFNLR1 in HEK293T and iHeps (WT and KO)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal mechanistic methods in KO background, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41256602\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL28RA overexpression in pancreatic cancer cells (PANC-1 and BXPC-3) inhibits proliferation and invasion, increases apoptosis, reduces phosphorylation of JAK2 and STAT3, increases pro-apoptotic BAX expression, and decreases anti-apoptotic BCL-2 expression, demonstrating that IFNLR1 exerts anti-proliferative effects via inhibition of the JAK-STAT signaling pathway.\",\n      \"method\": \"IL28RA overexpression in pancreatic cancer cell lines; western blot for JAK2, STAT3 phosphorylation and apoptosis markers; proliferation and invasion assays; flow cytometry\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, overexpression study without endogenous pathway validation or structural confirmation\",\n      \"pmids\": [\"31799654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL28RA (IFNLR1) overexpression in HaCaT keratinocytes inhibits proliferation and causes cell cycle arrest at G0/G1 phases via activation of the JAK-STAT signaling pathway. Knockdown of IL28RA accelerates proliferation and increases the proportion of cells in S and G2/M phases. IL28RA overexpression downregulates cyclin B1 and upregulates cyclin E, while knockdown has the opposite effect.\",\n      \"method\": \"IL28RA knockdown and overexpression in HaCaT cells; flow cytometry cell cycle analysis; western blot for cyclin B1 and cyclin E; proliferation assays\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic pathway placement via western blot but no reconstitution or epistasis\",\n      \"pmids\": [\"30632069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of IFNLR1 in the infarcted mouse myocardium via lentiviral injection reduced p-JAK1/JAK1 and p-STAT1/STAT1 ratios and decreased cardiomyocyte apoptosis, indicating that IL28A signals through IFNLR1 to activate the JAK1/STAT1 pathway and promote cardiomyocyte apoptosis post-AMI.\",\n      \"method\": \"Lentiviral knockdown of IL28RA in mouse myocardium; echocardiography; immunofluorescence and western blot for JAK1/STAT1 phosphorylation; TUNEL staining; BAX/BCL2 ratio\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vivo knockdown with pathway readout, single lab, no reconstitution\",\n      \"pmids\": [\"39706854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockout of IFNLR1 in epithelial cells results in a greater proportion of IAV-infected cells and higher viral RNA and protein levels, with a lower ratio of dying to infected cells, suggesting that IFN-λ signaling through IFNLR1 restricts influenza virus spread by promoting rapid death of infected cells, distinct from JAK/STAT-mediated ISG induction.\",\n      \"method\": \"IFNLR1 knockout cell lines; IAV and RSV infection; flow cytometry for infection and cell death; STAT1/2 phosphorylation; ISG protein levels\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with specific phenotype, orthogonal measurements of JAK-STAT and cell death, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.09.09.612051\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IFNLR1 forms a heterodimeric receptor complex with IL10RB that, upon binding IFN-λ, recruits JAK1 through box1 and box2 intracellular motifs (as defined by crystal structure) to activate JAK1/TYK2-STAT1/STAT2 signaling; expression of IFNLR1 specifically on intestinal epithelial cells is required in vivo for antiviral protection, and distinct IFNLR1 splice isoforms differentially regulate internalization kinetics, JAK-STAT activation levels, and the balance between antiviral versus pro-inflammatory gene expression programs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IFNLR1 is the ligand-specific subunit of the heterodimeric IFN-λ receptor that restricts type III interferon signaling predominantly to epithelial surfaces, coupling cytokine recognition to JAK1/TYK2–STAT1/STAT2 activation and antiviral gene expression. The intracellular domain engages JAK1 through box1 and box2 motifs, with a crystal structure revealing simultaneous binding of both motifs to the JAK1 FERM and SH2-like domains and a glutamate residue that mimics phosphotyrosine recognition [PMID:27725180]. Lineage-specific deletion of Ifnlr1 in intestinal epithelial cells recapitulates the global knockout phenotype of impaired antiviral defense against norovirus and reovirus, establishing that IEC-restricted expression is necessary and sufficient for IFN-λ–mediated mucosal immunity [PMID:28077655]. Distinct IFNLR1 splice isoforms differentially control receptor internalization kinetics, the balance of JAK1/TYK2 versus STAT1/STAT2 phosphorylation, and the selective induction of antiviral versus pro-inflammatory gene programs, with the full-length isoform uniquely supporting both antiviral and pro-inflammatory responses and augmented inhibition of HBV replication [PMID:36992341, PMID:39929255].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that IFNLR1 (IL28RA) is a CRF2-family receptor subunit that heterodimerizes to transduce signals for all three IFN-λ ligands defined the gene's core identity as the ligand-binding chain of the type III IFN receptor.\",\n      \"evidence\": \"Genomic and receptor family characterization\",\n      \"pmids\": [\"15120645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding data or structural information in this study\", \"Second subunit (IL10RB) requirement not experimentally dissected here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Determination of the JAK1–IFNLR1 intracellular domain crystal structure resolved how the receptor recruits its cognate kinase, showing that box1 and box2 motifs bind simultaneously to JAK1 FERM and SH2-like domains through a glutamate-based phosphotyrosine mimicry mechanism.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å resolution with deletion mutagenesis validation\",\n      \"pmids\": [\"27725180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captures only the JAK1 interaction; TYK2 recruitment mechanism via IL10RB not resolved\", \"No kinetic or thermodynamic binding data reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout of Ifnlr1 specifically in intestinal epithelial cells demonstrated that IFNLR1-restricted epithelial expression is the critical determinant of IFN-λ antiviral protection in the gut, independent of adaptive immunity.\",\n      \"evidence\": \"Lineage-specific conditional knockout mice; viral titer assays with norovirus and reovirus; Rag1-deficient background\",\n      \"pmids\": [\"28077655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFNLR1 on other epithelial surfaces (e.g., respiratory) is similarly necessary was not tested\", \"Downstream signaling mediators in IECs not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of an IFNLR1 missense mutation (p.Arg99His) segregating with autosomal dominant sensorineural hearing loss, combined with zebrafish knockdown/rescue, expanded the receptor's physiological roles beyond antiviral immunity to sensory organ development.\",\n      \"evidence\": \"Whole-exome sequencing and linkage analysis in a family; morpholino knockdown with mRNA rescue in zebrafish; immunostaining in mouse inner ear\",\n      \"pmids\": [\"29453195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking IFN-λ signaling to hair cell maintenance is unknown\", \"No knock-in of the human mutation in a mammalian model\", \"Single family reported\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional dissection of IFNLR1 splice isoforms revealed that the full-length isoform uniquely supports both antiviral and pro-inflammatory gene programs, while a signaling-defective isoform selectively induces antiviral genes at low expression, demonstrating that isoform usage tunes the downstream transcriptional output of IFN-λ signaling.\",\n      \"evidence\": \"Doxycycline-inducible FLAG-tagged isoform expression in HEK293T; antiviral and pro-inflammatory gene expression assays\",\n      \"pmids\": [\"36992341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific signaling intermediates not fully mapped\", \"Relative isoform expression in primary tissues not quantified\", \"Cross-talk with type I IFN pathway only partially characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IFNLR1 knockout in epithelial cells showed that IFN-λ signaling restricts influenza virus spread by promoting rapid death of infected cells, suggesting a cell-death-promoting function distinct from classical ISG induction.\",\n      \"evidence\": \"IFNLR1 KO cell lines infected with IAV; flow cytometry for infection and cell death (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.09.612051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell death mechanism (apoptosis versus other forms) not molecularly defined\", \"Not yet peer-reviewed\", \"Whether this death-promoting function operates in vivo is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comparative analysis of IFNLR1 variants in knockout hepatocytes and with proximity ligation/internalization assays established that differences in the box1/box2 region alter receptor internalization rate, the ratio of JAK1/TYK2 to STAT1/STAT2 phosphorylation, and the dependence on TYK2, mechanistically explaining isoform-specific gene expression patterns.\",\n      \"evidence\": \"IFNLR1 KO iHeps with re-expression of individual variants; Duolink PLA; ImageStream internalization assay; JAK/TYK2 inhibitors; HBV replication assays; western blot and gene expression profiling\",\n      \"pmids\": [\"39929255\", \"41256602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint component (PMID:41256602) not yet peer-reviewed\", \"Structural basis for differential internalization not determined\", \"How isoform ratios are regulated at the splicing level is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFNLR1 isoform expression is regulated in different tissues, the structural basis of isoform-specific receptor trafficking, and the mechanism linking IFNLR1 to hearing remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data for full ectodomain–IFN-λ–IL10RB ternary complex\", \"Splicing regulation of IFNLR1 isoforms uncharacterized\", \"Mechanism of IFNLR1 in inner ear hair cell biology unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"IFN-λ receptor (IFNLR1–IL10RB heterodimer)\"],\n    \"partners\": [\"IL10RB\", \"JAK1\", \"TYK2\", \"STAT1\", \"STAT2\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to correct the pathway field — I used a GO term instead of a Reactome pathway. Let me fix that.\n\n```json\n{\n  \"mechanistic_narrative\": \"IFNLR1 is the ligand-specific subunit of the heterodimeric IFN-λ receptor that restricts type III interferon signaling predominantly to epithelial surfaces, coupling cytokine recognition to JAK1/TYK2–STAT1/STAT2 activation and antiviral gene expression. The intracellular domain engages JAK1 through box1 and box2 motifs, with a crystal structure revealing simultaneous binding of both motifs to the JAK1 FERM and SH2-like domains and a glutamate residue that mimics phosphotyrosine recognition [PMID:27725180]. Lineage-specific deletion of Ifnlr1 in intestinal epithelial cells recapitulates the global knockout phenotype of impaired antiviral defense against norovirus and reovirus, establishing that IEC-restricted expression is necessary and sufficient for IFN-λ–mediated mucosal immunity [PMID:28077655]. Distinct IFNLR1 splice isoforms differentially control receptor internalization kinetics, the balance of JAK1/TYK2 versus STAT1/STAT2 phosphorylation, and the selective induction of antiviral versus pro-inflammatory gene programs, with the full-length isoform uniquely supporting both antiviral and pro-inflammatory responses and augmented inhibition of HBV replication [PMID:36992341, PMID:39929255].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that IFNLR1 (IL28RA) is a CRF2-family receptor subunit that heterodimerizes to transduce signals for all three IFN-λ ligands defined the gene's core identity as the ligand-binding chain of the type III IFN receptor.\",\n      \"evidence\": \"Genomic and receptor family characterization\",\n      \"pmids\": [\"15120645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding data or structural information in this study\", \"Second subunit (IL10RB) requirement not experimentally dissected here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Determination of the JAK1–IFNLR1 intracellular domain crystal structure resolved how the receptor recruits its cognate kinase, showing that box1 and box2 motifs bind simultaneously to JAK1 FERM and SH2-like domains through a glutamate-based phosphotyrosine mimicry mechanism.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å resolution with deletion mutagenesis validation\",\n      \"pmids\": [\"27725180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captures only the JAK1 interaction; TYK2 recruitment mechanism via IL10RB not resolved\", \"No kinetic or thermodynamic binding data reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout of Ifnlr1 specifically in intestinal epithelial cells demonstrated that IFNLR1-restricted epithelial expression is the critical determinant of IFN-λ antiviral protection in the gut, independent of adaptive immunity.\",\n      \"evidence\": \"Lineage-specific conditional knockout mice; viral titer assays with norovirus and reovirus; Rag1-deficient background\",\n      \"pmids\": [\"28077655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IFNLR1 on other epithelial surfaces (e.g., respiratory) is similarly necessary was not tested\", \"Downstream signaling mediators in IECs not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of an IFNLR1 missense mutation (p.Arg99His) segregating with autosomal dominant sensorineural hearing loss, combined with zebrafish knockdown/rescue, expanded the receptor's physiological roles beyond antiviral immunity to sensory organ development.\",\n      \"evidence\": \"Whole-exome sequencing and linkage analysis in a family; morpholino knockdown with mRNA rescue in zebrafish; immunostaining in mouse inner ear\",\n      \"pmids\": [\"29453195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking IFN-λ signaling to hair cell maintenance is unknown\", \"No knock-in of the human mutation in a mammalian model\", \"Single family reported\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional dissection of IFNLR1 splice isoforms revealed that the full-length isoform uniquely supports both antiviral and pro-inflammatory gene programs, while a signaling-defective isoform selectively induces antiviral genes at low expression, demonstrating that isoform usage tunes the downstream transcriptional output of IFN-λ signaling.\",\n      \"evidence\": \"Doxycycline-inducible FLAG-tagged isoform expression in HEK293T; antiviral and pro-inflammatory gene expression assays\",\n      \"pmids\": [\"36992341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific signaling intermediates not fully mapped\", \"Relative isoform expression in primary tissues not quantified\", \"Cross-talk with type I IFN pathway only partially characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IFNLR1 knockout in epithelial cells showed that IFN-λ signaling restricts influenza virus spread by promoting rapid death of infected cells, suggesting a cell-death-promoting function distinct from classical ISG induction.\",\n      \"evidence\": \"IFNLR1 KO cell lines infected with IAV; flow cytometry for infection and cell death (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.09.612051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell death mechanism (apoptosis versus other forms) not molecularly defined\", \"Not yet peer-reviewed\", \"Whether this death-promoting function operates in vivo is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comparative analysis of IFNLR1 variants in knockout hepatocytes and with proximity ligation/internalization assays established that differences in the box1/box2 region alter receptor internalization rate, the ratio of JAK1/TYK2 to STAT1/STAT2 phosphorylation, and the dependence on TYK2, mechanistically explaining isoform-specific gene expression patterns.\",\n      \"evidence\": \"IFNLR1 KO iHeps with re-expression of individual variants; Duolink PLA; ImageStream internalization assay; JAK/TYK2 inhibitors; HBV replication assays; western blot and gene expression profiling (preprint component)\",\n      \"pmids\": [\"39929255\", \"41256602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint component (PMID:41256602) not yet peer-reviewed\", \"Structural basis for differential internalization not determined\", \"How isoform ratios are regulated at the splicing level is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFNLR1 isoform expression is regulated in different tissues, the structural basis of isoform-specific receptor trafficking, and the mechanism linking IFNLR1 to inner ear function remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data for full ectodomain–IFN-λ–IL10RB ternary complex\", \"Splicing regulation of IFNLR1 isoforms uncharacterized\", \"Mechanism of IFNLR1 in inner ear hair cell biology unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 6]}\n    ],\n    \"complexes\": [\"IFN-λ receptor (IFNLR1–IL10RB heterodimer)\"],\n    \"partners\": [\"IL10RB\", \"JAK1\", \"TYK2\", \"STAT1\", \"STAT2\"],\n    \"other_free_text\": []\n  }\n}\n```"}