{"gene":"IFNLR1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2016,"finding":"Crystal structure of the FERM and SH2-like domains of JAK1 bound to a fragment of the IFNLR1 intracellular domain was solved at 2.1 Å resolution. Both the box1 and box2 regions of IFNLR1 simultaneously bind FERM and SH2-like domains of JAK1; a glutamate residue adjacent to box2 mimics phosphotyrosine binding in classical SH2 domains. Deletion of residues within box1 abolishes stable interaction with JAK1.","method":"X-ray crystallography (2.1 Å resolution) with deletion mutagenesis confirming box1 requirement for JAK1 binding","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure combined with mutagenesis validating a key interaction interface","pmids":["27725180"],"is_preprint":false},{"year":2017,"finding":"IEC-specific conditional knockout of Ifnlr1 largely recapitulated the phenotype of global Ifnlr1-null mice (higher intestinal tissue viral titers and increased fecal viral shedding) upon murine norovirus (MNoV) and reovirus infection, demonstrating that IFNLR1 expression on intestinal epithelial cells (IECs) is necessary and sufficient for IFN-λ-mediated antiviral activity in the gut, including sterilizing innate immunity in Rag1-deficient mice.","method":"Lineage-specific conditional knockout mice (Cre-lox), viral challenge with MNoV and reovirus, tissue titer and fecal shedding quantification","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with clean conditional KO, two distinct viral pathogens, confirmed in immunodeficient background","pmids":["28077655"],"is_preprint":false},{"year":2004,"finding":"IFNLR1 (CRF2-12) is a member of the class II cytokine receptor family and forms a heterodimer with IL-10RB to transduce signals for IFN-λ1, -λ2, and -λ3. The intracellular domains of CRF2 family members, including IFNLR1, are structurally dissimilar despite extracellular homology, consistent with cytokine-specific signaling outputs.","method":"Genomic and structural analysis of the complete CRF2 receptor family; functional characterization of receptor combinations","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — family-level structural and functional characterization; receptor heterodimerization assignment based on binding and signaling data, single lab review","pmids":["15120645"],"is_preprint":false},{"year":2018,"finding":"A heterozygous missense mutation (c.296G>A, p.Arg99His) in IFNLR1 co-segregated with autosomal dominant nonsyndromic sensorineural hearing loss in a large Chinese family. Morpholino knockdown of ifnlr1 in zebrafish caused a significant decrease in hair cells and non-inflation of the swim bladder; these defects were rescued by injection of wild-type zebrafish ifnlr1 mRNA. Knockdown also caused upregulation of IL-10R2, JAK1, TYK2, STAT3, and STAT5b mRNA in the JAK1/STAT3 pathway.","method":"Whole-exome sequencing, linkage analysis, immunostaining, zebrafish morpholino knockdown with mRNA rescue, qRT-PCR pathway analysis","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with mRNA rescue in zebrafish plus human genetic co-segregation; single lab, orthogonal methods","pmids":["29453195"],"is_preprint":false},{"year":2023,"finding":"IFNLR1 isoform 1 (full-length) markedly increased IFNL3-dependent antiviral and pro-inflammatory gene expression in HEK293T cells. IFNLR1 isoform 2 at low expression levels partially induced antiviral but not pro-inflammatory genes after IFNL3 treatment, an effect largely abrogated at higher expression levels. IFNLR1 isoform 3 partially augmented antiviral gene expression. Additionally, overexpression of IFNLR1 isoform 1 significantly reduced cellular sensitivity to type-I IFN (IFNA2), revealing cross-pathway regulation.","method":"Stable HEK293T clones with doxycycline-inducible FLAG-tagged IFNLR1 isoforms, IFNL3 stimulation, gene expression profiling","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible isoform expression system with multiple isoforms tested and gene expression profiling; single lab","pmids":["36992341"],"is_preprint":false},{"year":2025,"finding":"Full-length IFNLR1 (variant 1) expressed in IFNLR1 knockout stem cell-derived hepatocytes (iHeps) enabled IFNL-induced expression of both antiviral and proinflammatory genes and augmented inhibition of HBV replication. A noncanonical IFNLR1 variant missing part of the JAK1-binding domain (Box1/Box2) enabled induction of antiviral genes but could not support proinflammatory gene induction or augmented HBV inhibition. A secreted IFNLR1 variant had no detectable function in iHeps lacking endogenous IFNLR1.","method":"FLAG-tagged IFNLR1 variants expressed in CRISPR KO iHeps, antiviral gene expression profiling, HBV replication assay","journal":"Journal of interferon & cytokine research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO iHeps with variant complementation and multiple functional readouts; single lab, orthogonal methods","pmids":["39929255"],"is_preprint":false},{"year":2025,"finding":"Both IFNLR1 variant 1 (full-length) and variant 2 (truncated, missing part of Box1/Box2 JAK1-interacting motifs) colocalized with IL10RB after IFNL3 treatment, but variant 1 underwent more rapid and extensive receptor internalization. In WT iHeps, variant 1 supported greater STAT1 and STAT2 phosphorylation and broader ISG induction than variant 2 despite variant 2 enabling higher JAK1 and TYK2 phosphorylation. In KO-iHeps, variant 2 supported less JAK1/TYK2 phosphorylation and ISG induction than variant 1. Endogenous noncanonical variants influence TYK2-dependence of IFNL signaling, as WT-iHeps expressing variant 1 were more resistant to TYK2 inhibition of antiviral ISGs but more susceptible to TYK2 inhibition of proinflammatory ISGs than KO-iHeps.","method":"Proximity ligation assay, ImageStream flow cytometry, western blotting of JAK-STAT pathway phosphoproteins, JAK1/TYK2-specific inhibitors, gene expression profiling in WT and KO iHeps","journal":"Journal of innate immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (PLA, flow cytometry, WB, inhibitors, gene expression) in both WT and KO iHeps; single lab","pmids":["42213608"],"is_preprint":false},{"year":2025,"finding":"IFNLR1 knockout in epithelial cells resulted in a greater proportion of influenza A virus (IAV)-infected cells and higher viral RNA and protein levels compared to wild-type cells, despite only slightly lower STAT1/2 phosphorylation during infection. The ratio of dying to infected cells was lower in IFNLR1-deficient cells, indicating that IFN-λ promotes rapid death of IAV-infected cells via IFNLR1 to limit viral spread. This death-promoting mechanism was not observed for RSV infection.","method":"IFNLR1 knockout cell lines, IAV and RSV infection assays, STAT1/2 phosphorylation (western blot), cell death quantification, viral RNA/protein measurement","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — mechanistically novel finding (IFNLR1 promotes infected-cell death) but preprint, single lab, no independent replication","pmids":["bio_10.1101_2024.09.09.612051"],"is_preprint":true},{"year":2019,"finding":"IL28RA overexpression in pancreatic cancer cell lines (PANC-1, BXPC-3) inhibited proliferation and invasion, increased apoptosis, and significantly inhibited phosphorylation of JAK2 and STAT3, demonstrating that IL28RA (IFNLR1) exerts anti-proliferative effects via suppression of JAK-STAT pathway activation in these cancer cells.","method":"IL28RA overexpression in PANC-1 and BXPC-3 cells, MTS proliferation assay, flow cytometry (apoptosis), western blot for JAK2/STAT3 phosphorylation","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell line overexpression without mutagenesis or pathway rescue, limited mechanistic depth","pmids":["31799654"],"is_preprint":false},{"year":2021,"finding":"IL28RA (IFNLR1) overexpression in pancreatic ductal adenocarcinoma PANC-1 cells activated the IFNLR1 signaling pathway, reduced cell viability, decreased the G2/M cell cycle fraction by reducing cyclin B1 expression, and inhibited cell migration. IL28RA knockdown had opposing effects. In vivo xenograft experiments confirmed smaller tumors with IL28RA overexpression and larger tumors with knockdown. Effects were mediated via regulation of STAT1 and AKT phosphorylation.","method":"Stable transfection (overexpression and shRNA KD) in PANC-1 cells, MTS assay, wound healing, flow cytometry (cell cycle), western blot (cyclin B1, p-STAT1, p-AKT), nude mouse xenograft","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell line and xenograft model, mechanistic pathway assignment based on phosphorylation western blots without direct rescue experiments","pmids":["34195850"],"is_preprint":false},{"year":2019,"finding":"IL28RA (IFNLR1) overexpression in HaCaT keratinocytes in the presence of IL-29 inhibited cell proliferation and caused G0/G1 arrest; knockdown accelerated proliferation with increased S and G2/M fractions. IL28RA overexpression downregulated cyclinB1 and upregulated cyclinE; knockdown had opposite effects. The anti-proliferative effect was associated with JAK-STAT pathway activation.","method":"IL28RA overexpression and siRNA knockdown in HaCaT cells, BrdU proliferation assay, flow cytometry (cell cycle), western blot (cyclinB1, cyclinE, JAK-STAT proteins)","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immortalized cell line system, pathway placement by correlation of phosphorylation state without direct inhibitor rescue","pmids":["30632069"],"is_preprint":false},{"year":2021,"finding":"IFNLR1 overexpression in porcine alveolar macrophages (PAMs) suppressed PRRSV replication and inhibited PAM proliferation via G0/G1 arrest with upregulation of p-STAT1, while IFNLR1 knockdown promoted PAM proliferation. After JAK/STAT pathway inhibition, IFNLR1-overexpressing cells shifted toward G2/M arrest, confirming signaling through JAK/STAT.","method":"IFNLR1 overexpression and siRNA knockdown in PAMs, PRRSV infection, qRT-PCR, western blot (p-STAT1), flow cytometry (cell cycle), JAK/STAT inhibitor treatment","journal":"Journal of veterinary science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, porcine ortholog context, pathway rescue by inhibitor adds mechanistic detail but moderate method rigor","pmids":["34056880"],"is_preprint":false},{"year":2024,"finding":"In a mouse AMI model, IL28RA knockdown (lentiviral intramyocardial injection) reduced IL28A-induced JAK1 and STAT1 phosphorylation, improved cardiac function, reduced infarct area, and decreased cardiomyocyte apoptosis (TUNEL, BAX/Bcl2 ratio), demonstrating that IL28A signals through IL28RA via the JAK1/STAT1 pathway to promote cardiomyocyte apoptosis post-infarction.","method":"Lentiviral IL28RA knockdown in mouse AMI model, echocardiography, immunofluorescence and western blot (p-JAK1, p-STAT1), TUNEL staining, BAX/Bcl2 ratio","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — in vivo KD with multiple functional readouts but single lab; mechanistic assignment is correlational (pathway phosphorylation without direct rescue)","pmids":["39706854"],"is_preprint":false}],"current_model":"IFNLR1 (IL28RA) is the ligand-binding subunit of the type III interferon receptor; it forms a heterodimer with IL10RB, recruits JAK1 through direct contacts between its cytoplasmic box1 and box2 motifs and the FERM/SH2-like domains of JAK1 (structurally defined at 2.1 Å), and activates JAK-STAT signaling to induce antiviral ISGs—a function required in intestinal epithelial cells for IFN-λ-mediated control of enteric viruses in vivo. Distinct splice isoforms of IFNLR1 differentially tune receptor internalization, JAK/STAT phosphorylation dynamics, and the balance between antiviral and proinflammatory gene programs, with the full-length isoform supporting broader ISG induction and a truncated isoform lacking part of the JAK1-binding domain supporting attenuated proinflammatory but residual antiviral responses. Beyond classical JAK-STAT signaling, IFN-λ acting through IFNLR1 also promotes rapid death of infected epithelial cells to limit viral spread."},"narrative":{"mechanistic_narrative":"IFNLR1 (IL28RA/CRF2-12) is the ligand-binding subunit of the type III interferon receptor, a class II cytokine receptor that pairs with IL10RB to transduce signals from IFN-λ1/λ2/λ3 and drive JAK-STAT activation [PMID:15120645]. The cytoplasmic box1 and box2 motifs of IFNLR1 simultaneously engage the FERM and SH2-like domains of JAK1, with a glutamate adjacent to box2 mimicking the phosphotyrosine normally read by SH2 domains; deletion within box1 abolishes stable JAK1 binding [PMID:27725180]. Through this receptor, IFN-λ signaling is required in intestinal epithelial cells for control of enteric viruses in vivo, where IEC-specific loss of Ifnlr1 recapitulates the global-null phenotype of elevated tissue titers and fecal shedding [PMID:28077655]. Distinct IFNLR1 isoforms differentially tune the response: the full-length receptor supports broad ISG induction together with proinflammatory gene programs and undergoes rapid receptor internalization, whereas a noncanonical variant lacking part of the box1/box2 JAK1-binding domain retains antiviral ISG induction but fails to drive proinflammatory genes, and these isoforms also reset the TYK2-dependence of downstream signaling [PMID:36992341, PMID:39929255, PMID:42213608]. A heterozygous IFNLR1 missense mutation (p.Arg99His) co-segregates with autosomal dominant nonsyndromic sensorineural hearing loss, and ifnlr1 knockdown in zebrafish reduces hair cells in a manner rescued by wild-type mRNA [PMID:29453195].","teleology":[{"year":2004,"claim":"Established the receptor architecture: which subunits and ligands define the type III interferon receptor, framing IFNLR1 as the ligand-specific chain.","evidence":"Genomic and functional characterization of the CRF2 receptor family identifying IFNLR1 (CRF2-12)/IL10RB heterodimerization for IFN-λ1/λ2/λ3","pmids":["15120645"],"confidence":"Medium","gaps":["Does not define the cytoplasmic signaling contacts","Subunit assignment from binding/signaling data in a single review-level study"]},{"year":2016,"claim":"Resolved how IFNLR1 physically couples to the JAK machinery at atomic resolution, defining the box1/box2 motifs as the JAK1-binding interface.","evidence":"2.1 Å crystal structure of JAK1 FERM/SH2-like domains bound to the IFNLR1 intracellular fragment plus box1 deletion mutagenesis","pmids":["27725180"],"confidence":"High","gaps":["Structure of a complete receptor-JAK signaling complex not resolved","Does not address how isoform differences alter this interface in cells"]},{"year":2017,"claim":"Pinpointed the cell type where IFNLR1 function matters in vivo, showing intestinal epithelial receptor expression is sufficient for IFN-λ antiviral protection.","evidence":"IEC-specific conditional Ifnlr1 knockout mice challenged with MNoV and reovirus, including Rag1-deficient background","pmids":["28077655"],"confidence":"High","gaps":["Downstream effector ISGs mediating protection not dissected","Restricted to enteric viruses in gut epithelium"]},{"year":2018,"claim":"Linked IFNLR1 to a Mendelian phenotype and a developmental role beyond antiviral immunity, implicating it in inner-ear hair cell biology.","evidence":"Human family co-segregation of p.Arg99His with hearing loss; zebrafish ifnlr1 morpholino knockdown with wild-type mRNA rescue and JAK/STAT pathway qRT-PCR","pmids":["29453195"],"confidence":"Medium","gaps":["Mechanism connecting IFNLR1 to hair cell development unknown","Morpholino-based, single family and single lab"]},{"year":2023,"claim":"Revealed that IFNLR1 isoforms are not equivalent, separating antiviral from proinflammatory output and uncovering cross-pathway regulation of type-I IFN.","evidence":"Doxycycline-inducible FLAG-tagged IFNLR1 isoforms in HEK293T with IFNL3 stimulation and gene expression profiling","pmids":["36992341"],"confidence":"Medium","gaps":["Mechanism by which truncated isoforms restrict proinflammatory genes not defined","Overexpression in a non-physiological cell line"]},{"year":2025,"claim":"Mapped the isoform functional split to the JAK1-binding domain in a disease-relevant cell type, showing the box1/box2 region gates proinflammatory and HBV-control responses.","evidence":"FLAG-tagged IFNLR1 variant complementation in CRISPR KO stem cell-derived hepatocytes with antiviral/proinflammatory gene profiling and HBV replication assay","pmids":["39929255"],"confidence":"Medium","gaps":["Whether secreted variant has decoy function elsewhere untested","Single lab"]},{"year":2025,"claim":"Connected isoform differences to receptor trafficking and STAT phosphorylation dynamics, showing full-length IFNLR1 internalizes faster and reshapes TYK2-dependence.","evidence":"Proximity ligation assay, ImageStream flow cytometry, JAK-STAT western blotting, and JAK1/TYK2 inhibitors in WT and KO iHeps","pmids":["42213608"],"confidence":"Medium","gaps":["Causal link between internalization rate and gene-program selectivity not established","Single lab"]},{"year":2025,"claim":"Proposed a JAK-STAT-independent arm in which IFN-λ through IFNLR1 promotes death of infected cells to limit spread.","evidence":"IFNLR1 knockout epithelial cells with IAV and RSV infection, cell death quantification, STAT1/2 phosphorylation, viral RNA/protein measurement (preprint)","pmids":["bio_10.1101_2024.09.09.612051"],"confidence":"Low","gaps":["Preprint, single lab, no independent replication","Death pathway and its mechanistic link to IFNLR1 undefined","Virus-specific (IAV not RSV) and unexplained"]},{"year":null,"claim":"How IFNLR1 receptor internalization, isoform composition, and the TYK2/JAK1 balance are mechanistically wired to select between antiviral, proinflammatory, and cell-death programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a full receptor-JAK complex showing isoform-dependent assembly","Effector mechanism of infected-cell death not defined","Mechanism of IFNLR1 in hair cell development unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,0]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4]}],"complexes":["IFN-λ receptor (IFNLR1–IL10RB heterodimer)"],"partners":["IL10RB","JAK1","TYK2"],"other_free_text":[]}},"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":145,"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":42,"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 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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":"42213608","id":"PMC_42213608","title":"Mechanisms of Differential Signal Transduction by IFNLR1 Variants.","date":"2026","source":"Journal of innate immunity","url":"https://pubmed.ncbi.nlm.nih.gov/42213608","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":21061,"output_tokens":4182,"usd":0.062956,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11963,"output_tokens":2981,"usd":0.06717,"stage2_stop_reason":"end_turn"},"total_usd":0.130126,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the FERM and SH2-like domains of JAK1 bound to a fragment of the IFNLR1 intracellular domain was solved at 2.1 Å resolution. Both the box1 and box2 regions of IFNLR1 simultaneously bind FERM and SH2-like domains of JAK1; a glutamate residue adjacent to box2 mimics phosphotyrosine binding in classical SH2 domains. Deletion of residues within box1 abolishes stable interaction with JAK1.\",\n      \"method\": \"X-ray crystallography (2.1 Å resolution) with deletion mutagenesis confirming box1 requirement for JAK1 binding\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure combined with mutagenesis validating a key interaction interface\",\n      \"pmids\": [\"27725180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IEC-specific conditional knockout of Ifnlr1 largely recapitulated the phenotype of global Ifnlr1-null mice (higher intestinal tissue viral titers and increased fecal viral shedding) upon murine norovirus (MNoV) and reovirus infection, demonstrating that IFNLR1 expression on intestinal epithelial cells (IECs) is necessary and sufficient for IFN-λ-mediated antiviral activity in the gut, including sterilizing innate immunity in Rag1-deficient mice.\",\n      \"method\": \"Lineage-specific conditional knockout mice (Cre-lox), viral challenge with MNoV and reovirus, tissue titer and fecal shedding quantification\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with clean conditional KO, two distinct viral pathogens, confirmed in immunodeficient background\",\n      \"pmids\": [\"28077655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IFNLR1 (CRF2-12) is a member of the class II cytokine receptor family and forms a heterodimer with IL-10RB to transduce signals for IFN-λ1, -λ2, and -λ3. The intracellular domains of CRF2 family members, including IFNLR1, are structurally dissimilar despite extracellular homology, consistent with cytokine-specific signaling outputs.\",\n      \"method\": \"Genomic and structural analysis of the complete CRF2 receptor family; functional characterization of receptor combinations\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — family-level structural and functional characterization; receptor heterodimerization assignment based on binding and signaling data, single lab review\",\n      \"pmids\": [\"15120645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A heterozygous missense mutation (c.296G>A, p.Arg99His) in IFNLR1 co-segregated with autosomal dominant nonsyndromic sensorineural hearing loss in a large Chinese family. Morpholino knockdown of ifnlr1 in zebrafish caused a significant decrease in hair cells and non-inflation of the swim bladder; these defects were rescued by injection of wild-type zebrafish ifnlr1 mRNA. Knockdown also caused upregulation of IL-10R2, JAK1, TYK2, STAT3, and STAT5b mRNA in the JAK1/STAT3 pathway.\",\n      \"method\": \"Whole-exome sequencing, linkage analysis, immunostaining, zebrafish morpholino knockdown with mRNA rescue, qRT-PCR pathway analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with mRNA rescue in zebrafish plus human genetic co-segregation; single lab, orthogonal methods\",\n      \"pmids\": [\"29453195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFNLR1 isoform 1 (full-length) markedly increased IFNL3-dependent antiviral and pro-inflammatory gene expression in HEK293T cells. IFNLR1 isoform 2 at low expression levels partially induced antiviral but not pro-inflammatory genes after IFNL3 treatment, an effect largely abrogated at higher expression levels. IFNLR1 isoform 3 partially augmented antiviral gene expression. Additionally, overexpression of IFNLR1 isoform 1 significantly reduced cellular sensitivity to type-I IFN (IFNA2), revealing cross-pathway regulation.\",\n      \"method\": \"Stable HEK293T clones with doxycycline-inducible FLAG-tagged IFNLR1 isoforms, IFNL3 stimulation, gene expression profiling\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible isoform expression system with multiple isoforms tested and gene expression profiling; single lab\",\n      \"pmids\": [\"36992341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Full-length IFNLR1 (variant 1) expressed in IFNLR1 knockout stem cell-derived hepatocytes (iHeps) enabled IFNL-induced expression of both antiviral and proinflammatory genes and augmented inhibition of HBV replication. A noncanonical IFNLR1 variant missing part of the JAK1-binding domain (Box1/Box2) enabled induction of antiviral genes but could not support proinflammatory gene induction or augmented HBV inhibition. A secreted IFNLR1 variant had no detectable function in iHeps lacking endogenous IFNLR1.\",\n      \"method\": \"FLAG-tagged IFNLR1 variants expressed in CRISPR KO iHeps, antiviral gene expression profiling, HBV replication assay\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO iHeps with variant complementation and multiple functional readouts; single lab, orthogonal methods\",\n      \"pmids\": [\"39929255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Both IFNLR1 variant 1 (full-length) and variant 2 (truncated, missing part of Box1/Box2 JAK1-interacting motifs) colocalized with IL10RB after IFNL3 treatment, but variant 1 underwent more rapid and extensive receptor internalization. In WT iHeps, variant 1 supported greater STAT1 and STAT2 phosphorylation and broader ISG induction than variant 2 despite variant 2 enabling higher JAK1 and TYK2 phosphorylation. In KO-iHeps, variant 2 supported less JAK1/TYK2 phosphorylation and ISG induction than variant 1. Endogenous noncanonical variants influence TYK2-dependence of IFNL signaling, as WT-iHeps expressing variant 1 were more resistant to TYK2 inhibition of antiviral ISGs but more susceptible to TYK2 inhibition of proinflammatory ISGs than KO-iHeps.\",\n      \"method\": \"Proximity ligation assay, ImageStream flow cytometry, western blotting of JAK-STAT pathway phosphoproteins, JAK1/TYK2-specific inhibitors, gene expression profiling in WT and KO iHeps\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (PLA, flow cytometry, WB, inhibitors, gene expression) in both WT and KO iHeps; single lab\",\n      \"pmids\": [\"42213608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFNLR1 knockout in epithelial cells resulted in a greater proportion of influenza A virus (IAV)-infected cells and higher viral RNA and protein levels compared to wild-type cells, despite only slightly lower STAT1/2 phosphorylation during infection. The ratio of dying to infected cells was lower in IFNLR1-deficient cells, indicating that IFN-λ promotes rapid death of IAV-infected cells via IFNLR1 to limit viral spread. This death-promoting mechanism was not observed for RSV infection.\",\n      \"method\": \"IFNLR1 knockout cell lines, IAV and RSV infection assays, STAT1/2 phosphorylation (western blot), cell death quantification, viral RNA/protein measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistically novel finding (IFNLR1 promotes infected-cell death) but preprint, single lab, no independent replication\",\n      \"pmids\": [\"bio_10.1101_2024.09.09.612051\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL28RA overexpression in pancreatic cancer cell lines (PANC-1, BXPC-3) inhibited proliferation and invasion, increased apoptosis, and significantly inhibited phosphorylation of JAK2 and STAT3, demonstrating that IL28RA (IFNLR1) exerts anti-proliferative effects via suppression of JAK-STAT pathway activation in these cancer cells.\",\n      \"method\": \"IL28RA overexpression in PANC-1 and BXPC-3 cells, MTS proliferation assay, flow cytometry (apoptosis), western blot for JAK2/STAT3 phosphorylation\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell line overexpression without mutagenesis or pathway rescue, limited mechanistic depth\",\n      \"pmids\": [\"31799654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL28RA (IFNLR1) overexpression in pancreatic ductal adenocarcinoma PANC-1 cells activated the IFNLR1 signaling pathway, reduced cell viability, decreased the G2/M cell cycle fraction by reducing cyclin B1 expression, and inhibited cell migration. IL28RA knockdown had opposing effects. In vivo xenograft experiments confirmed smaller tumors with IL28RA overexpression and larger tumors with knockdown. Effects were mediated via regulation of STAT1 and AKT phosphorylation.\",\n      \"method\": \"Stable transfection (overexpression and shRNA KD) in PANC-1 cells, MTS assay, wound healing, flow cytometry (cell cycle), western blot (cyclin B1, p-STAT1, p-AKT), nude mouse xenograft\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell line and xenograft model, mechanistic pathway assignment based on phosphorylation western blots without direct rescue experiments\",\n      \"pmids\": [\"34195850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL28RA (IFNLR1) overexpression in HaCaT keratinocytes in the presence of IL-29 inhibited cell proliferation and caused G0/G1 arrest; knockdown accelerated proliferation with increased S and G2/M fractions. IL28RA overexpression downregulated cyclinB1 and upregulated cyclinE; knockdown had opposite effects. The anti-proliferative effect was associated with JAK-STAT pathway activation.\",\n      \"method\": \"IL28RA overexpression and siRNA knockdown in HaCaT cells, BrdU proliferation assay, flow cytometry (cell cycle), western blot (cyclinB1, cyclinE, JAK-STAT proteins)\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immortalized cell line system, pathway placement by correlation of phosphorylation state without direct inhibitor rescue\",\n      \"pmids\": [\"30632069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IFNLR1 overexpression in porcine alveolar macrophages (PAMs) suppressed PRRSV replication and inhibited PAM proliferation via G0/G1 arrest with upregulation of p-STAT1, while IFNLR1 knockdown promoted PAM proliferation. After JAK/STAT pathway inhibition, IFNLR1-overexpressing cells shifted toward G2/M arrest, confirming signaling through JAK/STAT.\",\n      \"method\": \"IFNLR1 overexpression and siRNA knockdown in PAMs, PRRSV infection, qRT-PCR, western blot (p-STAT1), flow cytometry (cell cycle), JAK/STAT inhibitor treatment\",\n      \"journal\": \"Journal of veterinary science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, porcine ortholog context, pathway rescue by inhibitor adds mechanistic detail but moderate method rigor\",\n      \"pmids\": [\"34056880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a mouse AMI model, IL28RA knockdown (lentiviral intramyocardial injection) reduced IL28A-induced JAK1 and STAT1 phosphorylation, improved cardiac function, reduced infarct area, and decreased cardiomyocyte apoptosis (TUNEL, BAX/Bcl2 ratio), demonstrating that IL28A signals through IL28RA via the JAK1/STAT1 pathway to promote cardiomyocyte apoptosis post-infarction.\",\n      \"method\": \"Lentiviral IL28RA knockdown in mouse AMI model, echocardiography, immunofluorescence and western blot (p-JAK1, p-STAT1), TUNEL staining, BAX/Bcl2 ratio\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo KD with multiple functional readouts but single lab; mechanistic assignment is correlational (pathway phosphorylation without direct rescue)\",\n      \"pmids\": [\"39706854\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFNLR1 (IL28RA) is the ligand-binding subunit of the type III interferon receptor; it forms a heterodimer with IL10RB, recruits JAK1 through direct contacts between its cytoplasmic box1 and box2 motifs and the FERM/SH2-like domains of JAK1 (structurally defined at 2.1 Å), and activates JAK-STAT signaling to induce antiviral ISGs—a function required in intestinal epithelial cells for IFN-λ-mediated control of enteric viruses in vivo. Distinct splice isoforms of IFNLR1 differentially tune receptor internalization, JAK/STAT phosphorylation dynamics, and the balance between antiviral and proinflammatory gene programs, with the full-length isoform supporting broader ISG induction and a truncated isoform lacking part of the JAK1-binding domain supporting attenuated proinflammatory but residual antiviral responses. Beyond classical JAK-STAT signaling, IFN-λ acting through IFNLR1 also promotes rapid death of infected epithelial cells to limit viral spread.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFNLR1 (IL28RA/CRF2-12) is the ligand-binding subunit of the type III interferon receptor, a class II cytokine receptor that pairs with IL10RB to transduce signals from IFN-\\u03bb1/\\u03bb2/\\u03bb3 and drive JAK-STAT activation [#2]. The cytoplasmic box1 and box2 motifs of IFNLR1 simultaneously engage the FERM and SH2-like domains of JAK1, with a glutamate adjacent to box2 mimicking the phosphotyrosine normally read by SH2 domains; deletion within box1 abolishes stable JAK1 binding [#0]. Through this receptor, IFN-\\u03bb signaling is required in intestinal epithelial cells for control of enteric viruses in vivo, where IEC-specific loss of Ifnlr1 recapitulates the global-null phenotype of elevated tissue titers and fecal shedding [#1]. Distinct IFNLR1 isoforms differentially tune the response: the full-length receptor supports broad ISG induction together with proinflammatory gene programs and undergoes rapid receptor internalization, whereas a noncanonical variant lacking part of the box1/box2 JAK1-binding domain retains antiviral ISG induction but fails to drive proinflammatory genes, and these isoforms also reset the TYK2-dependence of downstream signaling [#4, #5, #6]. A heterozygous IFNLR1 missense mutation (p.Arg99His) co-segregates with autosomal dominant nonsyndromic sensorineural hearing loss, and ifnlr1 knockdown in zebrafish reduces hair cells in a manner rescued by wild-type mRNA [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the receptor architecture: which subunits and ligands define the type III interferon receptor, framing IFNLR1 as the ligand-specific chain.\",\n      \"evidence\": \"Genomic and functional characterization of the CRF2 receptor family identifying IFNLR1 (CRF2-12)/IL10RB heterodimerization for IFN-\\u03bb1/\\u03bb2/\\u03bb3\",\n      \"pmids\": [\"15120645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the cytoplasmic signaling contacts\", \"Subunit assignment from binding/signaling data in a single review-level study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how IFNLR1 physically couples to the JAK machinery at atomic resolution, defining the box1/box2 motifs as the JAK1-binding interface.\",\n      \"evidence\": \"2.1 \\u00c5 crystal structure of JAK1 FERM/SH2-like domains bound to the IFNLR1 intracellular fragment plus box1 deletion mutagenesis\",\n      \"pmids\": [\"27725180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of a complete receptor-JAK signaling complex not resolved\", \"Does not address how isoform differences alter this interface in cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Pinpointed the cell type where IFNLR1 function matters in vivo, showing intestinal epithelial receptor expression is sufficient for IFN-\\u03bb antiviral protection.\",\n      \"evidence\": \"IEC-specific conditional Ifnlr1 knockout mice challenged with MNoV and reovirus, including Rag1-deficient background\",\n      \"pmids\": [\"28077655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector ISGs mediating protection not dissected\", \"Restricted to enteric viruses in gut epithelium\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked IFNLR1 to a Mendelian phenotype and a developmental role beyond antiviral immunity, implicating it in inner-ear hair cell biology.\",\n      \"evidence\": \"Human family co-segregation of p.Arg99His with hearing loss; zebrafish ifnlr1 morpholino knockdown with wild-type mRNA rescue and JAK/STAT pathway qRT-PCR\",\n      \"pmids\": [\"29453195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting IFNLR1 to hair cell development unknown\", \"Morpholino-based, single family and single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that IFNLR1 isoforms are not equivalent, separating antiviral from proinflammatory output and uncovering cross-pathway regulation of type-I IFN.\",\n      \"evidence\": \"Doxycycline-inducible FLAG-tagged IFNLR1 isoforms in HEK293T with IFNL3 stimulation and gene expression profiling\",\n      \"pmids\": [\"36992341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which truncated isoforms restrict proinflammatory genes not defined\", \"Overexpression in a non-physiological cell line\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the isoform functional split to the JAK1-binding domain in a disease-relevant cell type, showing the box1/box2 region gates proinflammatory and HBV-control responses.\",\n      \"evidence\": \"FLAG-tagged IFNLR1 variant complementation in CRISPR KO stem cell-derived hepatocytes with antiviral/proinflammatory gene profiling and HBV replication assay\",\n      \"pmids\": [\"39929255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether secreted variant has decoy function elsewhere untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected isoform differences to receptor trafficking and STAT phosphorylation dynamics, showing full-length IFNLR1 internalizes faster and reshapes TYK2-dependence.\",\n      \"evidence\": \"Proximity ligation assay, ImageStream flow cytometry, JAK-STAT western blotting, and JAK1/TYK2 inhibitors in WT and KO iHeps\",\n      \"pmids\": [\"42213608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between internalization rate and gene-program selectivity not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a JAK-STAT-independent arm in which IFN-\\u03bb through IFNLR1 promotes death of infected cells to limit spread.\",\n      \"evidence\": \"IFNLR1 knockout epithelial cells with IAV and RSV infection, cell death quantification, STAT1/2 phosphorylation, viral RNA/protein measurement (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.09.09.612051\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab, no independent replication\", \"Death pathway and its mechanistic link to IFNLR1 undefined\", \"Virus-specific (IAV not RSV) and unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFNLR1 receptor internalization, isoform composition, and the TYK2/JAK1 balance are mechanistically wired to select between antiviral, proinflammatory, and cell-death programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a full receptor-JAK complex showing isoform-dependent assembly\", \"Effector mechanism of infected-cell death not defined\", \"Mechanism of IFNLR1 in hair cell development unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"IFN-\\u03bb receptor (IFNLR1\\u2013IL10RB heterodimer)\"],\n    \"partners\": [\"IL10RB\", \"JAK1\", \"TYK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}