{"gene":"ILRUN","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2018,"finding":"C6orf106 (ILRUN) suppresses synthesis of IFN-α/β and TNF-α in response to poly(I:C) and Sendai virus infection. It blocks IRF3 and NF-κB activity without modulating their activation, nuclear translocation, cellular expression, or degradation. Instead, ILRUN interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences while reducing nuclear levels of coactivators p300 and CBP.","method":"Overexpression/knockdown in human cells, reporter assays, co-immunoprecipitation, chromatin immunoprecipitation, poly(I:C) and Sendai virus stimulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, reporter assays, KD/OE) in a single focused mechanistic study, replicated in subsequent papers","pmids":["29802199"],"is_preprint":false},{"year":2020,"finding":"ILRUN contains a UBA-like domain and an NBR1-like domain, both of which are essential for inhibition of type I interferon and TNF-α transcription in human cells. The crystal structure of the NBR1-like domain was solved.","method":"Domain deletion/mutation constructs with cytokine transcription assays; X-ray crystallography of the NBR1-like domain","journal":"Heliyon","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional mutagenesis of both domains in human cells, single lab but two orthogonal methods","pmids":["32518853"],"is_preprint":false},{"year":2023,"finding":"ILRUN inhibits IRF3-mediated transcription of antimicrobial and proinflammatory cytokines by inducing degradation of the transcriptional coactivators CBP and p300. In a knockout mouse model, ILRUN-deficient splenocytes show elevated TNF and IL-6 production following poly(I:C) or LPS stimulation.","method":"ILRUN knockout mouse model; splenocyte stimulation assays; cytokine measurement; immunological characterization of spleen and thymus","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO mouse model with defined cellular phenotype, consistent with prior in vitro mechanistic findings across labs","pmids":["37031606"],"is_preprint":false},{"year":2023,"finding":"ILRUN deficiency in mice results in altered populations of several T cell subsets, including regulatory T cells, mucosal-associated invariant T cells, and natural killer T cells, establishing a role for ILRUN in T cell development.","method":"ILRUN knockout mouse model; flow cytometric analysis of immune cell populations in spleen and thymus","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO with defined phenotypic readout, single lab, single method for the T cell subset finding","pmids":["37031606"],"is_preprint":false},{"year":2020,"finding":"Global Ilrun-deficient mice have significantly lower plasma cholesterol levels resulting from reduced hepatic lipoprotein production. Livers from Ilrun-deficient mice have increased PPARα protein. Human ILRUN binds ubiquitinylated proteins including PPARα, and the UBA-like domain of ILRUN is required for its interaction with PPARα.","method":"Global Ilrun knockout mice; plasma lipid measurements; liver transcriptome analysis; co-immunoprecipitation of ILRUN with ubiquitinylated proteins and PPARα; UBA-like domain deletion mutants","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined metabolic phenotype plus Co-IP binding experiments with domain mutagenesis, two orthogonal methods in single lab","pmids":["32912065"],"is_preprint":false},{"year":2022,"finding":"Loss of Ilrun in hyperlipidemic mouse models (LdlrKO and ApoeKO backgrounds) attenuates atherosclerotic lesion development and reduces necrotic area. Hepatic-specific reconstitution of ILRUN normalized plasma lipids but atherosclerotic lesion area and necrotic area remained reduced, demonstrating lipid-independent mechanisms. Loss of Ilrun increased efferocytosis receptor MerTK expression in macrophages and enhanced in vitro and in situ efferocytosis.","method":"Ilrun global KO on two hyperlipidemic backgrounds; hepatic-specific ILRUN reconstitution; atherosclerosis lesion quantification; macrophage MerTK expression; in vitro and in situ efferocytosis assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with hepatic reconstitution experiment plus multiple mechanistic readouts, single lab with orthogonal methods","pmids":["35861973"],"is_preprint":false},{"year":2021,"finding":"ILRUN knockdown in Caco-2 cells upregulates expression of the SARS-CoV-2 entry receptor ACE2 as well as TMPRSS2 and CTSL coreceptors, and increases SARS-CoV-2 replication. Conversely, overexpression of ILRUN reduces SARS-CoV-2 replication, identifying ILRUN as a negative regulator of the renin-angiotensin-aldosterone system components and a novel antiviral factor.","method":"RNA interference knockdown and overexpression in Caco-2 cells; RNA-seq transcriptome profiling; SARS-CoV-2 infection and replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with transcriptome readout plus direct viral replication assay, two orthogonal methods in single lab","pmids":["33963054"],"is_preprint":false},{"year":2015,"finding":"C6orf106 (ILRUN) knockdown in triple-negative breast cancer cell lines (MDA-MB-231, BT-549) inhibits cell proliferation and invasion, accompanied by decreased cyclin A2, cyclin B1, c-Myc, and N-cadherin and increased E-cadherin expression.","method":"siRNA knockdown in breast cancer cell lines; proliferation assay; invasion assay; Western blot for cell cycle and EMT markers","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with defined proliferation and invasion phenotypes plus molecular markers, single lab but multiple readouts","pmids":["25953261"],"is_preprint":false},{"year":2015,"finding":"C6orf106 (ILRUN) overexpression enhances NSCLC cell invasion and upregulates vimentin while downregulating E-cadherin and P120ctn; knockdown has the opposite effect, establishing a role for ILRUN in EMT-associated invasion.","method":"C6orf106 overexpression and siRNA knockdown in lung cancer cell lines; invasion assay; Western blot and immunofluorescence for EMT markers","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal OE and KD with invasion phenotype and molecular readouts, single lab","pmids":["25736925"],"is_preprint":false},{"year":2018,"finding":"C6orf106 (ILRUN) promotes pancreatic cancer cell invasion and proliferation by activating the ERK-P90RSK signaling pathway, increasing Snail, Cyclin D1, and Cyclin E1, and reducing E-cadherin. Addition of ERK inhibitor PD98059 counteracted these effects, placing ILRUN upstream of ERK.","method":"C6orf106 overexpression and knockdown in pancreatic cancer cells; invasion and proliferation assays; Western blot; pharmacological ERK inhibition (PD98059)","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic manipulation plus pharmacological epistasis with defined molecular readouts, single lab","pmids":["30311108"],"is_preprint":false}],"current_model":"ILRUN (C6orf106) is a multifunctional regulator that inhibits innate immune signaling by binding IRF3 and inducing degradation of transcriptional coactivators CBP and p300, thereby suppressing type I interferon and TNF-α transcription; it also promotes hepatic lipoprotein production and atherogenesis partly by binding ubiquitinylated PPARα via its UBA-like domain and partly through lipid-independent mechanisms including suppression of macrophage efferocytosis; and it regulates SARS-CoV-2 susceptibility by downregulating ACE2, TMPRSS2, and CTSL expression."},"narrative":{"mechanistic_narrative":"ILRUN (C6orf106) is a multifunctional regulator that restrains innate immune transcription and shapes lipid metabolism through its capacity to bind ubiquitinylated proteins and limit transcriptional coactivator availability [PMID:29802199, PMID:32912065]. In antiviral signaling, ILRUN interacts with IRF3 and blocks its recruitment to type I interferon promoters without altering IRF3 activation or nuclear translocation, instead reducing nuclear levels of the coactivators CBP and p300 by inducing their degradation, thereby suppressing IFN-α/β and TNF-α transcription [PMID:29802199, PMID:37031606]. Both a UBA-like domain and an NBR1-like domain are required for this cytokine-suppressive activity, and the UBA-like domain mediates binding to ubiquitinylated substrates including PPARα [PMID:32518853, PMID:32912065]. ILRUN-deficient mice confirm these roles in vivo: loss of ILRUN elevates inflammatory cytokine output from splenocytes and alters T cell subset populations [PMID:37031606], while in the liver ILRUN deficiency raises PPARα protein and lowers hepatic lipoprotein production and plasma cholesterol [PMID:32912065]. ILRUN promotes atherogenesis through both lipid-dependent and lipid-independent routes, the latter including suppression of macrophage MerTK expression and efferocytosis [PMID:35861973]. ILRUN additionally functions as a negative regulator of SARS-CoV-2 entry factors, downregulating ACE2, TMPRSS2, and CTSL to limit viral replication [PMID:33963054], and influences cancer cell invasion and proliferation in part through ERK signaling [PMID:30311108].","teleology":[{"year":2015,"claim":"Before any immune or metabolic role was known, ILRUN was first linked to tumor cell behavior, establishing that it influences proliferation, invasion, and epithelial-mesenchymal transition.","evidence":"siRNA knockdown and overexpression in breast and lung cancer lines with proliferation, invasion, and EMT marker readouts","pmids":["25953261","25736925"],"confidence":"Medium","gaps":["No molecular mechanism connecting ILRUN to EMT markers identified","Cell-line phenotypes not validated in vivo","Direct binding partners not defined"]},{"year":2018,"claim":"The core innate immune function was defined: ILRUN suppresses interferon and TNF-α transcription not by blocking IRF3/NF-κB activation but by impairing IRF3 promoter recruitment and depleting nuclear CBP/p300.","evidence":"Overexpression/knockdown, reporter assays, Co-IP, and ChIP in human cells stimulated with poly(I:C) and Sendai virus","pmids":["29802199"],"confidence":"High","gaps":["Mechanism by which coactivator nuclear levels are reduced not yet defined","Whether IRF3 binding is direct not structurally confirmed"]},{"year":2018,"claim":"A pro-tumorigenic signaling axis was placed upstream of ERK, showing ILRUN can act through a defined kinase pathway in pancreatic cancer.","evidence":"Overexpression/knockdown plus pharmacological ERK inhibition (PD98059) with invasion, proliferation, and Western blot readouts","pmids":["30311108"],"confidence":"Medium","gaps":["How ILRUN engages ERK signaling mechanistically unknown","Relationship to the immune/coactivator function not addressed"]},{"year":2020,"claim":"The structural basis of ILRUN function was established by identifying two essential domains, defining it as a ubiquitin-binding adaptor.","evidence":"Domain deletion/mutation cytokine transcription assays and X-ray crystallography of the NBR1-like domain","pmids":["32518853"],"confidence":"High","gaps":["No full-length structure","Ubiquitin-binding specificity of the UBA-like domain not characterized at this stage"]},{"year":2020,"claim":"A metabolic role was uncovered, linking ILRUN to hepatic lipoprotein production via UBA-domain-dependent binding of ubiquitinylated PPARα.","evidence":"Global Ilrun KO mice with plasma lipid and liver transcriptome analysis plus Co-IP of ILRUN with ubiquitinylated PPARα using UBA-domain mutants","pmids":["32912065"],"confidence":"High","gaps":["Whether ILRUN directs PPARα degradation not shown","Connection between ubiquitin-binding and coactivator regulation not unified"]},{"year":2021,"claim":"ILRUN was identified as an antiviral factor against SARS-CoV-2 by transcriptionally downregulating viral entry machinery.","evidence":"Knockdown/overexpression in Caco-2 cells with RNA-seq and SARS-CoV-2 replication assays","pmids":["33963054"],"confidence":"Medium","gaps":["Mechanism of ACE2/TMPRSS2/CTSL repression not defined","Not validated in vivo or in primary airway cells"]},{"year":2022,"claim":"ILRUN was shown to promote atherosclerosis through both lipid-dependent and lipid-independent mechanisms, the latter via suppression of macrophage efferocytosis.","evidence":"Ilrun KO on hyperlipidemic backgrounds with hepatic-specific reconstitution, lesion quantification, MerTK expression, and efferocytosis assays","pmids":["35861973"],"confidence":"High","gaps":["How ILRUN regulates MerTK expression unknown","Direct molecular link between hepatic and macrophage functions not established"]},{"year":2023,"claim":"In vivo loss-of-function confirmed the immunosuppressive mechanism and extended it to T cell development.","evidence":"ILRUN knockout mouse with splenocyte cytokine assays, CBP/p300 degradation analysis, and flow cytometry of immune subsets","pmids":["37031606"],"confidence":"High","gaps":["Cell-intrinsic versus systemic basis of T cell subset changes not resolved","Mechanism of CBP/p300 degradation still undefined"]},{"year":null,"claim":"The unifying biochemical mechanism linking ILRUN's ubiquitin-binding activity to coactivator degradation, PPARα regulation, and entry-factor repression remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Whether ILRUN is an adaptor for an E3 ligase or degradation machinery is unknown","No structure of ILRUN bound to ubiquitin or substrates","How a single ubiquitin-binding adaptor coordinates immune, metabolic, and viral functions is unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":[],"partners":["IRF3","CREBBP","EP300","PPARA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6K1","full_name":"Protein ILRUN","aliases":["Inflammation and lipid regulator with UBA-like and NBR1-like domains protein"],"length_aa":298,"mass_kda":32.9,"function":"Negative regulator of innate antiviral response. Blocks IRF3-dependent cytokine production such as IFNA, IFNB and TNF (PubMed:29802199). Interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences while also reducing nuclear levels of the coactivators EP300 and CREBBP (PubMed:29802199)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H6K1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ILRUN","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MCOLN1","stoichiometry":0.2},{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ILRUN","total_profiled":1310},"omim":[{"mim_id":"612217","title":"INFLAMMATION AND LIPID REGULATOR WITH UBA-LIKE AND NBR1-LIKE DOMAINS; ILRUN","url":"https://www.omim.org/entry/612217"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":202.1}],"url":"https://www.proteinatlas.org/search/ILRUN"},"hgnc":{"alias_symbol":["FLJ22195","dJ391O22.4"],"prev_symbol":["C6orf106"]},"alphafold":{"accession":"Q9H6K1","domains":[{"cath_id":"2.60.40.10","chopping":"74-181","consensus_level":"high","plddt":96.627,"start":74,"end":181},{"cath_id":"1.10.8","chopping":"11-65","consensus_level":"high","plddt":81.1293,"start":11,"end":65}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6K1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6K1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6K1-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ILRUN","jax_strain_url":"https://www.jax.org/strain/search?query=ILRUN"},"sequence":{"accession":"Q9H6K1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6K1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6K1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6K1"}},"corpus_meta":[{"pmid":"32607230","id":"PMC_32607230","title":"New insights into the associations among feed efficiency, metabolizable efficiency traits and related QTL regions in broiler chickens.","date":"2020","source":"Journal of animal science and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32607230","citation_count":34,"is_preprint":false},{"pmid":"29608557","id":"PMC_29608557","title":"A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29608557","citation_count":32,"is_preprint":false},{"pmid":"36308435","id":"PMC_36308435","title":"Trans-ancestry, Bayesian meta-analysis discovers 20 novel risk loci for inflammatory bowel disease in an African American, East Asian and European cohort.","date":"2023","source":"Human molecular 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It blocks IRF3 and NF-κB activity without modulating their activation, nuclear translocation, cellular expression, or degradation. Instead, ILRUN interacts with IRF3 and inhibits IRF3 recruitment to type I IFN promoter sequences while reducing nuclear levels of coactivators p300 and CBP.\",\n      \"method\": \"Overexpression/knockdown in human cells, reporter assays, co-immunoprecipitation, chromatin immunoprecipitation, poly(I:C) and Sendai virus stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, reporter assays, KD/OE) in a single focused mechanistic study, replicated in subsequent papers\",\n      \"pmids\": [\"29802199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ILRUN contains a UBA-like domain and an NBR1-like domain, both of which are essential for inhibition of type I interferon and TNF-α transcription in human cells. The crystal structure of the NBR1-like domain was solved.\",\n      \"method\": \"Domain deletion/mutation constructs with cytokine transcription assays; X-ray crystallography of the NBR1-like domain\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional mutagenesis of both domains in human cells, single lab but two orthogonal methods\",\n      \"pmids\": [\"32518853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ILRUN inhibits IRF3-mediated transcription of antimicrobial and proinflammatory cytokines by inducing degradation of the transcriptional coactivators CBP and p300. In a knockout mouse model, ILRUN-deficient splenocytes show elevated TNF and IL-6 production following poly(I:C) or LPS stimulation.\",\n      \"method\": \"ILRUN knockout mouse model; splenocyte stimulation assays; cytokine measurement; immunological characterization of spleen and thymus\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO mouse model with defined cellular phenotype, consistent with prior in vitro mechanistic findings across labs\",\n      \"pmids\": [\"37031606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ILRUN deficiency in mice results in altered populations of several T cell subsets, including regulatory T cells, mucosal-associated invariant T cells, and natural killer T cells, establishing a role for ILRUN in T cell development.\",\n      \"method\": \"ILRUN knockout mouse model; flow cytometric analysis of immune cell populations in spleen and thymus\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO with defined phenotypic readout, single lab, single method for the T cell subset finding\",\n      \"pmids\": [\"37031606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Global Ilrun-deficient mice have significantly lower plasma cholesterol levels resulting from reduced hepatic lipoprotein production. Livers from Ilrun-deficient mice have increased PPARα protein. Human ILRUN binds ubiquitinylated proteins including PPARα, and the UBA-like domain of ILRUN is required for its interaction with PPARα.\",\n      \"method\": \"Global Ilrun knockout mice; plasma lipid measurements; liver transcriptome analysis; co-immunoprecipitation of ILRUN with ubiquitinylated proteins and PPARα; UBA-like domain deletion mutants\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined metabolic phenotype plus Co-IP binding experiments with domain mutagenesis, two orthogonal methods in single lab\",\n      \"pmids\": [\"32912065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of Ilrun in hyperlipidemic mouse models (LdlrKO and ApoeKO backgrounds) attenuates atherosclerotic lesion development and reduces necrotic area. Hepatic-specific reconstitution of ILRUN normalized plasma lipids but atherosclerotic lesion area and necrotic area remained reduced, demonstrating lipid-independent mechanisms. Loss of Ilrun increased efferocytosis receptor MerTK expression in macrophages and enhanced in vitro and in situ efferocytosis.\",\n      \"method\": \"Ilrun global KO on two hyperlipidemic backgrounds; hepatic-specific ILRUN reconstitution; atherosclerosis lesion quantification; macrophage MerTK expression; in vitro and in situ efferocytosis assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with hepatic reconstitution experiment plus multiple mechanistic readouts, single lab with orthogonal methods\",\n      \"pmids\": [\"35861973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ILRUN knockdown in Caco-2 cells upregulates expression of the SARS-CoV-2 entry receptor ACE2 as well as TMPRSS2 and CTSL coreceptors, and increases SARS-CoV-2 replication. Conversely, overexpression of ILRUN reduces SARS-CoV-2 replication, identifying ILRUN as a negative regulator of the renin-angiotensin-aldosterone system components and a novel antiviral factor.\",\n      \"method\": \"RNA interference knockdown and overexpression in Caco-2 cells; RNA-seq transcriptome profiling; SARS-CoV-2 infection and replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with transcriptome readout plus direct viral replication assay, two orthogonal methods in single lab\",\n      \"pmids\": [\"33963054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C6orf106 (ILRUN) knockdown in triple-negative breast cancer cell lines (MDA-MB-231, BT-549) inhibits cell proliferation and invasion, accompanied by decreased cyclin A2, cyclin B1, c-Myc, and N-cadherin and increased E-cadherin expression.\",\n      \"method\": \"siRNA knockdown in breast cancer cell lines; proliferation assay; invasion assay; Western blot for cell cycle and EMT markers\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with defined proliferation and invasion phenotypes plus molecular markers, single lab but multiple readouts\",\n      \"pmids\": [\"25953261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C6orf106 (ILRUN) overexpression enhances NSCLC cell invasion and upregulates vimentin while downregulating E-cadherin and P120ctn; knockdown has the opposite effect, establishing a role for ILRUN in EMT-associated invasion.\",\n      \"method\": \"C6orf106 overexpression and siRNA knockdown in lung cancer cell lines; invasion assay; Western blot and immunofluorescence for EMT markers\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal OE and KD with invasion phenotype and molecular readouts, single lab\",\n      \"pmids\": [\"25736925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C6orf106 (ILRUN) promotes pancreatic cancer cell invasion and proliferation by activating the ERK-P90RSK signaling pathway, increasing Snail, Cyclin D1, and Cyclin E1, and reducing E-cadherin. Addition of ERK inhibitor PD98059 counteracted these effects, placing ILRUN upstream of ERK.\",\n      \"method\": \"C6orf106 overexpression and knockdown in pancreatic cancer cells; invasion and proliferation assays; Western blot; pharmacological ERK inhibition (PD98059)\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic manipulation plus pharmacological epistasis with defined molecular readouts, single lab\",\n      \"pmids\": [\"30311108\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ILRUN (C6orf106) is a multifunctional regulator that inhibits innate immune signaling by binding IRF3 and inducing degradation of transcriptional coactivators CBP and p300, thereby suppressing type I interferon and TNF-α transcription; it also promotes hepatic lipoprotein production and atherogenesis partly by binding ubiquitinylated PPARα via its UBA-like domain and partly through lipid-independent mechanisms including suppression of macrophage efferocytosis; and it regulates SARS-CoV-2 susceptibility by downregulating ACE2, TMPRSS2, and CTSL expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ILRUN (C6orf106) is a multifunctional regulator that restrains innate immune transcription and shapes lipid metabolism through its capacity to bind ubiquitinylated proteins and limit transcriptional coactivator availability [#0, #4]. In antiviral signaling, ILRUN interacts with IRF3 and blocks its recruitment to type I interferon promoters without altering IRF3 activation or nuclear translocation, instead reducing nuclear levels of the coactivators CBP and p300 by inducing their degradation, thereby suppressing IFN-\\u03b1/\\u03b2 and TNF-\\u03b1 transcription [#0, #2]. Both a UBA-like domain and an NBR1-like domain are required for this cytokine-suppressive activity, and the UBA-like domain mediates binding to ubiquitinylated substrates including PPAR\\u03b1 [#1, #4]. ILRUN-deficient mice confirm these roles in vivo: loss of ILRUN elevates inflammatory cytokine output from splenocytes and alters T cell subset populations [#2, #3], while in the liver ILRUN deficiency raises PPAR\\u03b1 protein and lowers hepatic lipoprotein production and plasma cholesterol [#4]. ILRUN promotes atherogenesis through both lipid-dependent and lipid-independent routes, the latter including suppression of macrophage MerTK expression and efferocytosis [#5]. ILRUN additionally functions as a negative regulator of SARS-CoV-2 entry factors, downregulating ACE2, TMPRSS2, and CTSL to limit viral replication [#6], and influences cancer cell invasion and proliferation in part through ERK signaling [#9].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Before any immune or metabolic role was known, ILRUN was first linked to tumor cell behavior, establishing that it influences proliferation, invasion, and epithelial-mesenchymal transition.\",\n      \"evidence\": \"siRNA knockdown and overexpression in breast and lung cancer lines with proliferation, invasion, and EMT marker readouts\",\n      \"pmids\": [\"25953261\", \"25736925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism connecting ILRUN to EMT markers identified\", \"Cell-line phenotypes not validated in vivo\", \"Direct binding partners not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The core innate immune function was defined: ILRUN suppresses interferon and TNF-\\u03b1 transcription not by blocking IRF3/NF-\\u03baB activation but by impairing IRF3 promoter recruitment and depleting nuclear CBP/p300.\",\n      \"evidence\": \"Overexpression/knockdown, reporter assays, Co-IP, and ChIP in human cells stimulated with poly(I:C) and Sendai virus\",\n      \"pmids\": [\"29802199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which coactivator nuclear levels are reduced not yet defined\", \"Whether IRF3 binding is direct not structurally confirmed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A pro-tumorigenic signaling axis was placed upstream of ERK, showing ILRUN can act through a defined kinase pathway in pancreatic cancer.\",\n      \"evidence\": \"Overexpression/knockdown plus pharmacological ERK inhibition (PD98059) with invasion, proliferation, and Western blot readouts\",\n      \"pmids\": [\"30311108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ILRUN engages ERK signaling mechanistically unknown\", \"Relationship to the immune/coactivator function not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The structural basis of ILRUN function was established by identifying two essential domains, defining it as a ubiquitin-binding adaptor.\",\n      \"evidence\": \"Domain deletion/mutation cytokine transcription assays and X-ray crystallography of the NBR1-like domain\",\n      \"pmids\": [\"32518853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure\", \"Ubiquitin-binding specificity of the UBA-like domain not characterized at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A metabolic role was uncovered, linking ILRUN to hepatic lipoprotein production via UBA-domain-dependent binding of ubiquitinylated PPAR\\u03b1.\",\n      \"evidence\": \"Global Ilrun KO mice with plasma lipid and liver transcriptome analysis plus Co-IP of ILRUN with ubiquitinylated PPAR\\u03b1 using UBA-domain mutants\",\n      \"pmids\": [\"32912065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ILRUN directs PPAR\\u03b1 degradation not shown\", \"Connection between ubiquitin-binding and coactivator regulation not unified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ILRUN was identified as an antiviral factor against SARS-CoV-2 by transcriptionally downregulating viral entry machinery.\",\n      \"evidence\": \"Knockdown/overexpression in Caco-2 cells with RNA-seq and SARS-CoV-2 replication assays\",\n      \"pmids\": [\"33963054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ACE2/TMPRSS2/CTSL repression not defined\", \"Not validated in vivo or in primary airway cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ILRUN was shown to promote atherosclerosis through both lipid-dependent and lipid-independent mechanisms, the latter via suppression of macrophage efferocytosis.\",\n      \"evidence\": \"Ilrun KO on hyperlipidemic backgrounds with hepatic-specific reconstitution, lesion quantification, MerTK expression, and efferocytosis assays\",\n      \"pmids\": [\"35861973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ILRUN regulates MerTK expression unknown\", \"Direct molecular link between hepatic and macrophage functions not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo loss-of-function confirmed the immunosuppressive mechanism and extended it to T cell development.\",\n      \"evidence\": \"ILRUN knockout mouse with splenocyte cytokine assays, CBP/p300 degradation analysis, and flow cytometry of immune subsets\",\n      \"pmids\": [\"37031606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-intrinsic versus systemic basis of T cell subset changes not resolved\", \"Mechanism of CBP/p300 degradation still undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical mechanism linking ILRUN's ubiquitin-binding activity to coactivator degradation, PPAR\\u03b1 regulation, and entry-factor repression remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ILRUN is an adaptor for an E3 ligase or degradation machinery is unknown\", \"No structure of ILRUN bound to ubiquitin or substrates\", \"How a single ubiquitin-binding adaptor coordinates immune, metabolic, and viral functions is unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRF3\", \"CREBBP\", \"EP300\", \"PPARA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}