{"gene":"RNF39","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2001,"finding":"LIRF (RNF39) encodes a novel protein containing RING finger and B30.2 domains in its N- and C-terminal portions, respectively, each encoded by a single exon suggesting exon shuffling. Heterologously expressed LIRF-EGFP fusion protein localizes specifically to the cytoplasm in COS-7 cells. LIRF is expressed as an immediate-early gene in hippocampal granule cells following induction of long-lasting LTP at perforant pathway-dentate gyrus synapses, with expression returning to baseline within 150 min.","method":"EGFP fusion protein live-cell localization in COS-7 cells; in vivo LTP induction with temporal expression profiling; domain analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct subcellular localization experiment and in vivo expression kinetics, single lab, single paper","pmids":["11716498"],"is_preprint":false},{"year":2021,"finding":"RNF39 functions as an E3 ubiquitin ligase that mediates K48-linked ubiquitination of the RNA helicase DDX3X, leading to its proteasomal degradation. This suppresses RIG-I-like receptor (RLR)-dependent antiviral innate immune signaling. Rnf39 deficiency enhances RNA virus-triggered innate immune responses and attenuates viral replication in cells.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), proteasome inhibitor rescue, Rnf39 knockout/knockdown with viral infection readout, innate immune signaling reporter assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, K48-specific ubiquitination assay, proteasomal degradation rescue, and KO phenotype with defined immune signaling readout in single rigorous study","pmids":["33674311"],"is_preprint":false},{"year":2024,"finding":"RNF39 interacts with STING in macrophages and HEK293T cells and promotes K63-linked ubiquitination of STING, facilitating formation of the STING-TBK1 complex and thereby accelerating the cGAS-dependent DNA-sensing innate immune pathway. Rnf39 deficiency inhibits innate immune responses to DNA viral infection and accelerates viral replication. HSV-1 infection induces RNF39 expression in an IFN-I-dependent manner, revealing a positive feedback mechanism.","method":"Co-immunoprecipitation, K63-specific ubiquitination assay, Rnf39 knockdown/knockout with DNA viral infection (HSV-1) readout, IFN-I signaling reporter assays, STING-TBK1 complex formation assay","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, K63-specific ubiquitination assay, KO phenotype with defined innate immune readout, IFN-I feedback validated, single lab with multiple orthogonal methods","pmids":["39255680"],"is_preprint":false},{"year":2026,"finding":"RNF39 directly interacts with RINT1 and catalyzes K48-linked polyubiquitination and proteasomal degradation of RINT1 in colorectal adenocarcinoma cells. This degradation suppresses the unfolded protein response (UPR) and CHOP expression, limiting ER stress-induced apoptosis and promoting tumor progression. The transcription factor MEF2D directly activates RNF39 transcription. RNF39 E3 ligase activity is required for its pro-tumorigenic function, and the anti-tumor phenotypes of RNF39 loss are partially reversed by simultaneous RINT1 knockdown.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linked), shRNA knockdown, CRISPR/Cas9 knockout, overexpression rescue, in vivo xenograft, chromatin immunoprecipitation, luciferase reporter assay","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including ubiquitination assay with linkage specificity, genetic rescue, in vivo xenograft, ChIP, and epistasis via double knockdown in single rigorous study","pmids":["41457280"],"is_preprint":false},{"year":2026,"finding":"SEC14L4 inhibits RNF39-mediated ubiquitination and proteasomal degradation of DDX3X in esophageal squamous cell carcinoma (ESCC) cells. SEC14L4 directly interacts with DDX3X (confirmed by Co-IP and mass spectrometry), and its overexpression stabilizes DDX3X by preventing RNF39-dependent ubiquitination. DDX3X overexpression rescues the oncogenic phenotypes induced by SEC14L4.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, shRNA knockdown, overexpression rescue, in vivo tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with MS confirmation, ubiquitination assay, and genetic rescue, single lab, single paper; mechanistic role of RNF39 inferred from inhibition by SEC14L4 rather than direct RNF39 manipulation","pmids":["41741625"],"is_preprint":false},{"year":2014,"finding":"RNF39 protein knockdown inhibits HIV-1 expression in cell lines, and patients with a specific RNF39 haplotype (ht1-GG/GG) show lower RNF39 expression levels and lower HIV-1 viral loads, indicating RNF39 positively supports HIV-1 replication.","method":"RNF39 knockdown in cell lines with HIV-1 replication readout; genetic association study linking haplotype to RNF39 expression and viral load","journal":"Cell & bioscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment in cell culture without mechanistic pathway detail; haplotype-expression link is correlative","pmids":["25126410"],"is_preprint":false}],"current_model":"RNF39 is a RING finger E3 ubiquitin ligase that negatively regulates antiviral innate immunity by mediating K48-linked ubiquitination and proteasomal degradation of DDX3X (suppressing RLR/RNA virus sensing), while positively regulating the cGAS-STING DNA-sensing pathway by promoting K63-linked ubiquitination of STING to facilitate STING-TBK1 complex formation; it also drives colorectal cancer progression by targeting RINT1 for K48-linked degradation to suppress ER stress-induced apoptosis, and was originally identified as an immediate-early gene product that localizes to the cytoplasm following hippocampal LTP induction."},"narrative":{"mechanistic_narrative":"RNF39 is a RING finger E3 ubiquitin ligase that acts as a substrate-specific regulator of innate antiviral signaling and, in cancer cells, of the ER stress response [PMID:33674311, PMID:39255680, PMID:41457280]. It carries N-terminal RING finger and C-terminal B30.2 domains and was first identified as a cytoplasmically localized immediate-early gene product induced in hippocampal granule cells following long-term potentiation [PMID:11716498]. In RNA-sensing immunity, RNF39 catalyzes K48-linked polyubiquitination and proteasomal degradation of the RNA helicase DDX3X, thereby dampening RIG-I-like receptor antiviral responses; its loss enhances RNA virus-triggered immunity and restricts viral replication [PMID:33674311]. In the DNA-sensing arm, RNF39 conversely promotes K63-linked ubiquitination of STING to facilitate STING-TBK1 complex assembly and accelerate cGAS-dependent type I interferon responses, with HSV-1 inducing RNF39 in an IFN-I-dependent positive feedback loop [PMID:39255680]. In colorectal adenocarcinoma, RNF39 is transcriptionally activated by MEF2D and drives tumor progression by targeting RINT1 for K48-linked degradation, suppressing the unfolded protein response, CHOP expression, and ER stress-induced apoptosis in a manner dependent on its E3 ligase activity [PMID:41457280].","teleology":[{"year":2001,"claim":"Established the molecular identity of RNF39 as a RING/B30.2-domain protein and placed it as an activity-induced immediate-early gene, raising the question of what cytoplasmic function its E3-type architecture serves.","evidence":"EGFP fusion live-cell localization in COS-7 cells and in vivo LTP induction with temporal expression profiling","pmids":["11716498"],"confidence":"Medium","gaps":["No catalytic activity or substrate demonstrated at this stage","Functional role of LTP-induced expression in neurons not defined","Domain composition inferred from sequence, not biochemically validated as an active ligase"]},{"year":2014,"claim":"First functional link of RNF39 to viral biology, indicating RNF39 levels positively influence HIV-1 replication, though without a defined molecular mechanism.","evidence":"RNF39 knockdown in cell lines with HIV-1 replication readout plus correlative haplotype-expression-viral load genetic association","pmids":["25126410"],"confidence":"Low","gaps":["Single knockdown experiment without mechanistic pathway detail; haplotype link is correlative","No substrate or ubiquitination activity identified","Direction of effect not reconciled with later antiviral findings"]},{"year":2021,"claim":"Defined RNF39 as a bona fide E3 ligase and identified its first substrate, showing it negatively regulates RNA-sensing innate immunity by degrading DDX3X.","evidence":"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, proteasome inhibitor rescue, and Rnf39 knockout with viral infection and immune reporter readouts","pmids":["33674311"],"confidence":"High","gaps":["Domain requirements (RING vs B30.2) for DDX3X recognition not dissected","In vivo organismal relevance not tested","Whether DDX3X is the sole RLR-pathway substrate unknown"]},{"year":2024,"claim":"Revealed RNF39 as a bifunctional immune regulator that, in contrast to its RNA-pathway role, positively drives DNA-sensing immunity via non-degradative K63 ubiquitination of STING.","evidence":"Reciprocal Co-IP, K63-specific ubiquitination assay, STING-TBK1 complex formation assay, and Rnf39 knockdown/knockout with HSV-1 infection and IFN-I reporter readouts","pmids":["39255680"],"confidence":"High","gaps":["Structural basis for K48 vs K63 linkage choice between substrates unknown","STING ubiquitination site not mapped","How opposing RNA and DNA pathway roles are coordinated in a single cell unresolved"]},{"year":2026,"claim":"Extended RNF39 beyond immunity to oncogenesis, identifying RINT1 as a degradation substrate and MEF2D as an upstream transcriptional activator that together drive colorectal cancer by limiting ER stress apoptosis.","evidence":"Co-IP, K48-linked ubiquitination assay, shRNA/CRISPR knockout, overexpression and double-knockdown epistasis rescue, in vivo xenograft, ChIP and luciferase reporter assays","pmids":["41457280"],"confidence":"High","gaps":["Whether RINT1 degradation occurs in non-cancer or immune contexts not addressed","Connection between RNF39's immune substrates and its tumor role unexplored","RINT1 recognition determinants on RNF39 not mapped"]},{"year":2026,"claim":"Identified an upstream antagonist of RNF39 activity, showing SEC14L4 stabilizes DDX3X by blocking RNF39-mediated ubiquitination in esophageal squamous cell carcinoma.","evidence":"Co-IP with mass spectrometry, ubiquitination assay, shRNA knockdown and DDX3X-overexpression rescue, in vivo tumor models","pmids":["41741625"],"confidence":"Medium","gaps":["RNF39 role inferred from inhibition by SEC14L4 rather than direct RNF39 manipulation","Mechanism by which SEC14L4 shields DDX3X from RNF39 not defined","Whether SEC14L4 affects RNF39's other substrates unknown"]},{"year":null,"claim":"How RNF39 selects between K48 (degradative) and K63 (non-degradative) ubiquitination across its substrates, and what governs its opposing roles in RNA versus DNA antiviral sensing, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model linking RING/B30.2 domains to substrate or linkage selection","No study integrating its neuronal, antiviral, and oncogenic functions","Regulation of RNF39 abundance/activity outside IFN-I and MEF2D inputs uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["DDX3X","STING1","TBK1","RINT1","MEF2D","SEC14L4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2S5","full_name":"RING finger protein 39","aliases":["Protein HZFw"],"length_aa":420,"mass_kda":45.5,"function":"Plays an inhibitory role in anti-RNA viral innate immunity by targeting the adapter DDX3X and promoting its 'Lys-48'-linked polyubiquitination (PubMed:33674311). Alternatively, enhances the cGAS-STING pathway activation by promoting 'Lys-63'-linked ubiquitination of STING1, facilitating the STING1-TBK1 complex formation and STING1 activation (PubMed:39255680) (Microbial infection) Plays a positive role in human immunodeficiency virus (HIV-1) replication","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H2S5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF39","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1090,"dependency_fraction":0.0027522935779816515},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF39","total_profiled":1310},"omim":[{"mim_id":"607524","title":"RING FINGER PROTEIN 39; RNF39","url":"https://www.omim.org/entry/607524"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Centrosome","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"cervix","ntpm":22.1},{"tissue":"esophagus","ntpm":24.4},{"tissue":"skin 1","ntpm":63.7},{"tissue":"vagina","ntpm":22.7}],"url":"https://www.proteinatlas.org/search/RNF39"},"hgnc":{"alias_symbol":["HZFw1","LIRF","FAP216"],"prev_symbol":[]},"alphafold":{"accession":"Q9H2S5","domains":[{"cath_id":"3.30.40.10","chopping":"78-119_127-162","consensus_level":"high","plddt":81.1335,"start":78,"end":162},{"cath_id":"2.60.120.920","chopping":"227-291_308-415","consensus_level":"high","plddt":88.0073,"start":227,"end":415}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2S5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2S5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2S5-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF39","jax_strain_url":"https://www.jax.org/strain/search?query=RNF39"},"sequence":{"accession":"Q9H2S5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2S5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2S5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2S5"}},"corpus_meta":[{"pmid":"28630453","id":"PMC_28630453","title":"Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder.","date":"2017","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/28630453","citation_count":102,"is_preprint":false},{"pmid":"19050382","id":"PMC_19050382","title":"Association of HLA-C and HCP5 gene regions with the clinical course of HIV-1 infection.","date":"2009","source":"AIDS (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19050382","citation_count":82,"is_preprint":false},{"pmid":"26405558","id":"PMC_26405558","title":"DNA methylation patterns in naïve CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus.","date":"2015","source":"Lupus science & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26405558","citation_count":73,"is_preprint":false},{"pmid":"33356526","id":"PMC_33356526","title":"Prenatal Exposure to Per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study.","date":"2020","source":"Environmental health perspectives","url":"https://pubmed.ncbi.nlm.nih.gov/33356526","citation_count":66,"is_preprint":false},{"pmid":"28729889","id":"PMC_28729889","title":"Differential methylation at MHC in CD4+ T cells is associated with multiple sclerosis independently of HLA-DRB1.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28729889","citation_count":54,"is_preprint":false},{"pmid":"33674311","id":"PMC_33674311","title":"RNF39 mediates K48-linked ubiquitination of DDX3X and inhibits RLR-dependent antiviral immunity.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33674311","citation_count":44,"is_preprint":false},{"pmid":"31672705","id":"PMC_31672705","title":"Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31672705","citation_count":33,"is_preprint":false},{"pmid":"34177938","id":"PMC_34177938","title":"Emerging Roles of MHC Class I Region-Encoded E3 Ubiquitin Ligases in Innate Immunity.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34177938","citation_count":33,"is_preprint":false},{"pmid":"20875797","id":"PMC_20875797","title":"TRIM39 and RNF39 are associated with Behçet's disease independently of HLA-B∗51 and -A∗26.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20875797","citation_count":32,"is_preprint":false},{"pmid":"11716498","id":"PMC_11716498","title":"LIRF, a gene induced during hippocampal long-term potentiation as an immediate-early gene, encodes a novel RING finger protein.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11716498","citation_count":30,"is_preprint":false},{"pmid":"29617171","id":"PMC_29617171","title":"Lenvatinib-induced renal failure: two first-time case reports and review of literature.","date":"2018","source":"Expert opinion on drug metabolism & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/29617171","citation_count":30,"is_preprint":false},{"pmid":"29492303","id":"PMC_29492303","title":"Association between DNA methylation profiles in leukocytes and serum levels of persistent organic pollutants in Dutch men.","date":"2017","source":"Environmental epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29492303","citation_count":29,"is_preprint":false},{"pmid":"31103287","id":"PMC_31103287","title":"Array-based DNA methylation profiling reveals peripheral blood differential methylation in male infertility.","date":"2019","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/31103287","citation_count":27,"is_preprint":false},{"pmid":"35325772","id":"PMC_35325772","title":"Prenatal exposure to phthalates and peripheral blood and buccal epithelial DNA methylation in infants: An epigenome-wide association study.","date":"2022","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/35325772","citation_count":26,"is_preprint":false},{"pmid":"24612962","id":"PMC_24612962","title":"Exploring the molecular causes of hepatitis B virus vaccination response: an approach with epigenomic and transcriptomic data.","date":"2014","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24612962","citation_count":25,"is_preprint":false},{"pmid":"21242233","id":"PMC_21242233","title":"High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis.","date":"2011","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21242233","citation_count":22,"is_preprint":false},{"pmid":"34600028","id":"PMC_34600028","title":"Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959-1961.","date":"2021","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34600028","citation_count":19,"is_preprint":false},{"pmid":"34722520","id":"PMC_34722520","title":"Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34722520","citation_count":17,"is_preprint":false},{"pmid":"26534935","id":"PMC_26534935","title":"Genetic loci associated with nonobstructive coronary artery disease in Caucasian women.","date":"2015","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/26534935","citation_count":16,"is_preprint":false},{"pmid":"33875724","id":"PMC_33875724","title":"Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33875724","citation_count":15,"is_preprint":false},{"pmid":"28149331","id":"PMC_28149331","title":"Combining omics data to identify genes associated with allergic rhinitis.","date":"2017","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28149331","citation_count":14,"is_preprint":false},{"pmid":"32212948","id":"PMC_32212948","title":"Differential methylation of imprinting genes and MHC locus in 22q11.2 deletion syndrome-related schizophrenia spectrum disorders.","date":"2020","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32212948","citation_count":13,"is_preprint":false},{"pmid":"34944912","id":"PMC_34944912","title":"Genome-Wide DNA Methylation Signatures Predict the Early Asymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34944912","citation_count":12,"is_preprint":false},{"pmid":"33335118","id":"PMC_33335118","title":"Epigenetic differences at the HTR2A locus in progressive multiple sclerosis patients.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33335118","citation_count":10,"is_preprint":false},{"pmid":"38015635","id":"PMC_38015635","title":"Whole-genome methylation profiling reveals regions associated with painful temporomandibular disorders and active recovery processes.","date":"2023","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/38015635","citation_count":10,"is_preprint":false},{"pmid":"30782033","id":"PMC_30782033","title":"Epigenetic association analysis of clinical sub-phenotypes in patients with polycystic ovary syndrome (PCOS).","date":"2019","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30782033","citation_count":9,"is_preprint":false},{"pmid":"38830989","id":"PMC_38830989","title":"Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.","date":"2024","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38830989","citation_count":8,"is_preprint":false},{"pmid":"23874430","id":"PMC_23874430","title":"Variants in ZNRD1 gene predict HIV-1/AIDS disease progression in a Han Chinese population in Taiwan.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23874430","citation_count":7,"is_preprint":false},{"pmid":"25126410","id":"PMC_25126410","title":"Ring finger protein 39 genetic variants associate with HIV-1 plasma viral loads and its replication in cell culture.","date":"2014","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/25126410","citation_count":6,"is_preprint":false},{"pmid":"39255680","id":"PMC_39255680","title":"RNF39 facilitates antiviral immune responses by promoting K63-linked ubiquitination of STING.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39255680","citation_count":5,"is_preprint":false},{"pmid":"39245941","id":"PMC_39245941","title":"Joint genotype and ancestry analysis identify novel loci associated with atopic dermatitis in African American population.","date":"2024","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/39245941","citation_count":5,"is_preprint":false},{"pmid":"39627815","id":"PMC_39627815","title":"Genome-wide DNA methylation analysis reveals a unique methylation pattern for pleural mesothelioma compared to healthy pleura and other lung diseases.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39627815","citation_count":4,"is_preprint":false},{"pmid":"37746958","id":"PMC_37746958","title":"Causality between depression and ankylosing spondylitis in a European population: Results from a Mendelian randomization analysis.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37746958","citation_count":3,"is_preprint":false},{"pmid":"41457280","id":"PMC_41457280","title":"RNF39 promotes colorectal cancer progression by driving RINT1 degradation and suppressing ER stress-induced apoptosis.","date":"2026","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41457280","citation_count":1,"is_preprint":false},{"pmid":"40143670","id":"PMC_40143670","title":"Differential methylation in blood pressure control genes is associated to essential hypertension in African Brazilian populations.","date":"2025","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/40143670","citation_count":1,"is_preprint":false},{"pmid":"37752647","id":"PMC_37752647","title":"[DNA Methylation Profile of CD14+ Monocytes Changes in Primary Progressive Multiple Sclerosis].","date":"2023","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/37752647","citation_count":1,"is_preprint":false},{"pmid":"41741625","id":"PMC_41741625","title":"SEC14L4 promotes the development of esophageal squamous cell cancer by inhibiting the ubiquitination and degradation of DDX3X via RNF39.","date":"2026","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41741625","citation_count":0,"is_preprint":false},{"pmid":"37790540","id":"PMC_37790540","title":"Smoking-informed methylation and expression QTLs in human brain and colocalization with smoking-associated genetic loci.","date":"2023","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37790540","citation_count":0,"is_preprint":false},{"pmid":"42010415","id":"PMC_42010415","title":"Epigenome-wide analysis of DNA-methylation signatures following climate-related disasters.","date":"2026","source":"BMC medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42010415","citation_count":0,"is_preprint":false},{"pmid":"42152106","id":"PMC_42152106","title":"Identification of a different DNA methylation pattern for pain related genes in children with intellectual disability: a cross-sectional study.","date":"2026","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/42152106","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22949,"output_tokens":1952,"usd":0.049064,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8830,"output_tokens":2848,"usd":0.057675,"stage2_stop_reason":"end_turn"},"total_usd":0.106739,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"LIRF (RNF39) encodes a novel protein containing RING finger and B30.2 domains in its N- and C-terminal portions, respectively, each encoded by a single exon suggesting exon shuffling. Heterologously expressed LIRF-EGFP fusion protein localizes specifically to the cytoplasm in COS-7 cells. LIRF is expressed as an immediate-early gene in hippocampal granule cells following induction of long-lasting LTP at perforant pathway-dentate gyrus synapses, with expression returning to baseline within 150 min.\",\n      \"method\": \"EGFP fusion protein live-cell localization in COS-7 cells; in vivo LTP induction with temporal expression profiling; domain analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct subcellular localization experiment and in vivo expression kinetics, single lab, single paper\",\n      \"pmids\": [\"11716498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF39 functions as an E3 ubiquitin ligase that mediates K48-linked ubiquitination of the RNA helicase DDX3X, leading to its proteasomal degradation. This suppresses RIG-I-like receptor (RLR)-dependent antiviral innate immune signaling. Rnf39 deficiency enhances RNA virus-triggered innate immune responses and attenuates viral replication in cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), proteasome inhibitor rescue, Rnf39 knockout/knockdown with viral infection readout, innate immune signaling reporter assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, K48-specific ubiquitination assay, proteasomal degradation rescue, and KO phenotype with defined immune signaling readout in single rigorous study\",\n      \"pmids\": [\"33674311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF39 interacts with STING in macrophages and HEK293T cells and promotes K63-linked ubiquitination of STING, facilitating formation of the STING-TBK1 complex and thereby accelerating the cGAS-dependent DNA-sensing innate immune pathway. Rnf39 deficiency inhibits innate immune responses to DNA viral infection and accelerates viral replication. HSV-1 infection induces RNF39 expression in an IFN-I-dependent manner, revealing a positive feedback mechanism.\",\n      \"method\": \"Co-immunoprecipitation, K63-specific ubiquitination assay, Rnf39 knockdown/knockout with DNA viral infection (HSV-1) readout, IFN-I signaling reporter assays, STING-TBK1 complex formation assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, K63-specific ubiquitination assay, KO phenotype with defined innate immune readout, IFN-I feedback validated, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39255680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF39 directly interacts with RINT1 and catalyzes K48-linked polyubiquitination and proteasomal degradation of RINT1 in colorectal adenocarcinoma cells. This degradation suppresses the unfolded protein response (UPR) and CHOP expression, limiting ER stress-induced apoptosis and promoting tumor progression. The transcription factor MEF2D directly activates RNF39 transcription. RNF39 E3 ligase activity is required for its pro-tumorigenic function, and the anti-tumor phenotypes of RNF39 loss are partially reversed by simultaneous RINT1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linked), shRNA knockdown, CRISPR/Cas9 knockout, overexpression rescue, in vivo xenograft, chromatin immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including ubiquitination assay with linkage specificity, genetic rescue, in vivo xenograft, ChIP, and epistasis via double knockdown in single rigorous study\",\n      \"pmids\": [\"41457280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SEC14L4 inhibits RNF39-mediated ubiquitination and proteasomal degradation of DDX3X in esophageal squamous cell carcinoma (ESCC) cells. SEC14L4 directly interacts with DDX3X (confirmed by Co-IP and mass spectrometry), and its overexpression stabilizes DDX3X by preventing RNF39-dependent ubiquitination. DDX3X overexpression rescues the oncogenic phenotypes induced by SEC14L4.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, shRNA knockdown, overexpression rescue, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with MS confirmation, ubiquitination assay, and genetic rescue, single lab, single paper; mechanistic role of RNF39 inferred from inhibition by SEC14L4 rather than direct RNF39 manipulation\",\n      \"pmids\": [\"41741625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RNF39 protein knockdown inhibits HIV-1 expression in cell lines, and patients with a specific RNF39 haplotype (ht1-GG/GG) show lower RNF39 expression levels and lower HIV-1 viral loads, indicating RNF39 positively supports HIV-1 replication.\",\n      \"method\": \"RNF39 knockdown in cell lines with HIV-1 replication readout; genetic association study linking haplotype to RNF39 expression and viral load\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment in cell culture without mechanistic pathway detail; haplotype-expression link is correlative\",\n      \"pmids\": [\"25126410\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF39 is a RING finger E3 ubiquitin ligase that negatively regulates antiviral innate immunity by mediating K48-linked ubiquitination and proteasomal degradation of DDX3X (suppressing RLR/RNA virus sensing), while positively regulating the cGAS-STING DNA-sensing pathway by promoting K63-linked ubiquitination of STING to facilitate STING-TBK1 complex formation; it also drives colorectal cancer progression by targeting RINT1 for K48-linked degradation to suppress ER stress-induced apoptosis, and was originally identified as an immediate-early gene product that localizes to the cytoplasm following hippocampal LTP induction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF39 is a RING finger E3 ubiquitin ligase that acts as a substrate-specific regulator of innate antiviral signaling and, in cancer cells, of the ER stress response [#1, #2, #3]. It carries N-terminal RING finger and C-terminal B30.2 domains and was first identified as a cytoplasmically localized immediate-early gene product induced in hippocampal granule cells following long-term potentiation [#0]. In RNA-sensing immunity, RNF39 catalyzes K48-linked polyubiquitination and proteasomal degradation of the RNA helicase DDX3X, thereby dampening RIG-I-like receptor antiviral responses; its loss enhances RNA virus-triggered immunity and restricts viral replication [#1]. In the DNA-sensing arm, RNF39 conversely promotes K63-linked ubiquitination of STING to facilitate STING-TBK1 complex assembly and accelerate cGAS-dependent type I interferon responses, with HSV-1 inducing RNF39 in an IFN-I-dependent positive feedback loop [#2]. In colorectal adenocarcinoma, RNF39 is transcriptionally activated by MEF2D and drives tumor progression by targeting RINT1 for K48-linked degradation, suppressing the unfolded protein response, CHOP expression, and ER stress-induced apoptosis in a manner dependent on its E3 ligase activity [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the molecular identity of RNF39 as a RING/B30.2-domain protein and placed it as an activity-induced immediate-early gene, raising the question of what cytoplasmic function its E3-type architecture serves.\",\n      \"evidence\": \"EGFP fusion live-cell localization in COS-7 cells and in vivo LTP induction with temporal expression profiling\",\n      \"pmids\": [\"11716498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No catalytic activity or substrate demonstrated at this stage\",\n        \"Functional role of LTP-induced expression in neurons not defined\",\n        \"Domain composition inferred from sequence, not biochemically validated as an active ligase\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"First functional link of RNF39 to viral biology, indicating RNF39 levels positively influence HIV-1 replication, though without a defined molecular mechanism.\",\n      \"evidence\": \"RNF39 knockdown in cell lines with HIV-1 replication readout plus correlative haplotype-expression-viral load genetic association\",\n      \"pmids\": [\"25126410\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single knockdown experiment without mechanistic pathway detail; haplotype link is correlative\",\n        \"No substrate or ubiquitination activity identified\",\n        \"Direction of effect not reconciled with later antiviral findings\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined RNF39 as a bona fide E3 ligase and identified its first substrate, showing it negatively regulates RNA-sensing innate immunity by degrading DDX3X.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage-specific ubiquitination assay, proteasome inhibitor rescue, and Rnf39 knockout with viral infection and immune reporter readouts\",\n      \"pmids\": [\"33674311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Domain requirements (RING vs B30.2) for DDX3X recognition not dissected\",\n        \"In vivo organismal relevance not tested\",\n        \"Whether DDX3X is the sole RLR-pathway substrate unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed RNF39 as a bifunctional immune regulator that, in contrast to its RNA-pathway role, positively drives DNA-sensing immunity via non-degradative K63 ubiquitination of STING.\",\n      \"evidence\": \"Reciprocal Co-IP, K63-specific ubiquitination assay, STING-TBK1 complex formation assay, and Rnf39 knockdown/knockout with HSV-1 infection and IFN-I reporter readouts\",\n      \"pmids\": [\"39255680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for K48 vs K63 linkage choice between substrates unknown\",\n        \"STING ubiquitination site not mapped\",\n        \"How opposing RNA and DNA pathway roles are coordinated in a single cell unresolved\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended RNF39 beyond immunity to oncogenesis, identifying RINT1 as a degradation substrate and MEF2D as an upstream transcriptional activator that together drive colorectal cancer by limiting ER stress apoptosis.\",\n      \"evidence\": \"Co-IP, K48-linked ubiquitination assay, shRNA/CRISPR knockout, overexpression and double-knockdown epistasis rescue, in vivo xenograft, ChIP and luciferase reporter assays\",\n      \"pmids\": [\"41457280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RINT1 degradation occurs in non-cancer or immune contexts not addressed\",\n        \"Connection between RNF39's immune substrates and its tumor role unexplored\",\n        \"RINT1 recognition determinants on RNF39 not mapped\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an upstream antagonist of RNF39 activity, showing SEC14L4 stabilizes DDX3X by blocking RNF39-mediated ubiquitination in esophageal squamous cell carcinoma.\",\n      \"evidence\": \"Co-IP with mass spectrometry, ubiquitination assay, shRNA knockdown and DDX3X-overexpression rescue, in vivo tumor models\",\n      \"pmids\": [\"41741625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RNF39 role inferred from inhibition by SEC14L4 rather than direct RNF39 manipulation\",\n        \"Mechanism by which SEC14L4 shields DDX3X from RNF39 not defined\",\n        \"Whether SEC14L4 affects RNF39's other substrates unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF39 selects between K48 (degradative) and K63 (non-degradative) ubiquitination across its substrates, and what governs its opposing roles in RNA versus DNA antiviral sensing, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model linking RING/B30.2 domains to substrate or linkage selection\",\n        \"No study integrating its neuronal, antiviral, and oncogenic functions\",\n        \"Regulation of RNF39 abundance/activity outside IFN-I and MEF2D inputs uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DDX3X\", \"STING1\", \"TBK1\", \"RINT1\", \"MEF2D\", \"SEC14L4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}