{"gene":"RNF19A","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2001,"finding":"Dorfin/RNF19A contains two RING-finger motifs and an IBR motif at its N-terminus, binds specifically to ubiquitin-conjugating enzymes UbcH7 and UbcH8 through the RING-finger/IBR domain, and mediates ubiquitin ligase (E3) activity; partial deletion of the RING-finger/IBR domain eliminated these interactions and ubiquitination activity. Dorfin is a short-lived protein that accumulates upon proteasome inhibition. It is localized to the centrosome.","method":"Co-immunoprecipitation, domain deletion mutagenesis, proteasome inhibitor treatment (MG132), subcellular localization by immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding confirmed, mutagenesis of active domain, multiple orthogonal methods in foundational characterization paper","pmids":["11237715"],"is_preprint":false},{"year":2002,"finding":"Dorfin/RNF19A physically binds and ubiquitylates mutant SOD1 proteins (from familial ALS patients) but not wild-type SOD1, enhancing their proteasomal degradation; overexpression of Dorfin protects neural cells from mutant SOD1 toxicity and reduces SOD1 inclusion bodies. Dorfin localizes to inclusion bodies in familial and sporadic ALS motor neurons.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, overexpression with toxicity rescue assay, immunohistochemistry/immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitination assay, co-IP, cell-based toxicity rescue, substrate specificity shown by mutagenesis/variant panel","pmids":["12145308"],"is_preprint":false},{"year":2003,"finding":"Dorfin/RNF19A localizes to ubiquitylated inclusions (Lewy bodies, glial cell inclusions, hyaline inclusions) in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and ALS, showing a distribution pattern parallel to ubiquitin. However, direct binding of alpha-synuclein to Dorfin was not detected (negative result).","method":"Immunohistochemistry with affinity-purified antibody, double immunofluorescence, filter trap assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization established by multiple methods across disease types; negative binding result explicitly reported","pmids":["12875980"],"is_preprint":false},{"year":2004,"finding":"Valosin-containing protein (VCP/p97) directly binds to Dorfin/RNF19A through the C-terminal region of Dorfin, forms an endogenous ~400–600 kDa complex with Dorfin, and VCP ATPase activity is required for the E3 ubiquitin ligase activity of Dorfin toward mutant SOD1; a dominant-negative VCP(K524A) reduced Dorfin E3 activity but had no effect on Parkin autoubiquitylation. Both proteins co-localize in aggresomes and ubiquitylated inclusions in ALS and PD neurons.","method":"Mass spectrometry identification, glycerol gradient centrifugation, co-immunoprecipitation, in vitro direct binding, dominant-negative VCP functional assay, immunofluorescence co-localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding shown in vitro, functional consequence of VCP ATPase on Dorfin E3 activity demonstrated by dominant-negative, multiple orthogonal methods","pmids":["15456787"],"is_preprint":false},{"year":2004,"finding":"Dorfin/RNF19A significantly reduces mutant SOD1 levels in mitochondria, thereby decreasing cytochrome c release and caspase cascade activation, and preventing neuronal cell death in a neuronal cell model of familial ALS.","method":"Overexpression in neuronal cell model, subcellular fractionation (mitochondrial fraction), cytochrome c release assay, caspase activation assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with biochemical pathway readouts (cytochrome c, caspase), single lab","pmids":["15030390"],"is_preprint":false},{"year":2006,"finding":"Dorfin/RNF19A binds the intracellular carboxyl terminus of the calcium-sensing receptor (CaR) (identified by yeast two-hybrid and confirmed by co-immunoprecipitation), ubiquitinates CaR, and promotes its proteasomal degradation from the endoplasmic reticulum; mutation of all putative intracellular lysine residues abolished CaR ubiquitination. VCP/p97 associates with both CaR and Dorfin. A dominant-negative Dorfin fragment had opposite (stabilizing) effects on CaR.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, dominant-negative construct, lysine mutagenesis, tunicamycin/MG132 treatment, endoglycosidase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — substrate identified by yeast two-hybrid and confirmed by Co-IP, lysine mutagenesis abolishes ubiquitination, dominant-negative shows opposing effect, multiple orthogonal methods","pmids":["16513638"],"is_preprint":false},{"year":2006,"finding":"Dorfin-CHIP chimeric proteins containing the substrate-binding domain of Dorfin and the U-box domain of CHIP are more stable in cells than wild-type Dorfin, more effectively ubiquitylate mutant SOD1 in vivo, degrade mutant SOD1 more rapidly, reduce aggresome formation, and rescue neuronal cells from mutant SOD1 toxicity better than wild-type Dorfin.","method":"Chimeric protein engineering, in vivo ubiquitination assay, cell viability assay, aggresome quantification, pulse-chase/protein stability assay","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain dissection via chimera, multiple readouts in cell-based assays, single lab","pmids":["17157513"],"is_preprint":false},{"year":2009,"finding":"Rnf19a interacts with Psmc3, a component of the 19S regulatory cap of the 26S proteasome, in rat spermatids; during spermatid development, Rnf19a and Psmc3 are found in Golgi-derived proacrosomal vesicles, along acrosomal membranes, the acroplaxome, the marginal ring, and in the developing head-tail coupling apparatus, implicating the ubiquitin-proteasome system in acrosome biogenesis and spermatid head shaping.","method":"Co-immunoprecipitation, immunofluorescence co-localization during spermatogenesis, cDNA cloning and sequence analysis","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction shown, subcellular localization tracked dynamically during development, single lab","pmids":["19517565"],"is_preprint":false},{"year":2010,"finding":"Overexpression of human Dorfin/RNF19A in G93A mutant SOD1 transgenic mice decreased mutant SOD1 protein levels in spinal cord, ameliorated neurological phenotypes, and reduced motor neuron degeneration in vivo.","method":"Transgenic mouse overexpression, immunoblotting of spinal cord proteins, neurological phenotype scoring, motor neuron histology","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with biochemical and histological readouts, single lab","pmids":["19610091"],"is_preprint":false},{"year":2015,"finding":"Dorfin/RNF19A is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-knockout mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus but normal LTP in CA1, impaired contextual fear conditioning, and decreased ubiquitination of multiple brain proteins identified by proteomics.","method":"Co-immunoprecipitation (PSD-95 interaction), knockout mouse phenotyping, electrophysiology (LTP), behavioral testing, proteomic ubiquitinome analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for PSD-95 interaction, knockout mouse with multiple orthogonal in vivo phenotypic readouts (electrophysiology, behavior, proteomics)","pmids":["26553645"],"is_preprint":false},{"year":2017,"finding":"RNF19A is recruited by NLRP11 to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, leading to proteasomal degradation of TRAF6 and attenuation of TLR signaling; deficiency of either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, promoting NF-κB and MAPK activation and increased proinflammatory cytokine production.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA/shRNA knockdown, overexpression, NF-κB/MAPK pathway readouts, cytokine measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assay, two-component (NLRP11 and RNF19A) loss-of-function with consistent phenotype, multiple orthogonal methods","pmids":["29215004"],"is_preprint":false},{"year":2021,"finding":"RNF19A ubiquitinates BARD1, causing dissociation of the BRCA1-BARD1 heterodimer and exposing a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in cytoplasmic export of BARD1. This suppresses homologous recombination and increases cancer cell sensitivity to PARP inhibitors.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear export sequence mapping, cellular fractionation, HR assay, PARP inhibitor sensitivity assay, overexpression and knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, direct ubiquitination assay, NES exposure mechanism dissected, functional HR assay readout, multiple orthogonal methods","pmids":["34789768"],"is_preprint":false},{"year":2022,"finding":"RNF19A mediates K48-linked ubiquitination and proteasomal degradation of TBK1; silencing of RNF19A enhanced type I interferon production and suppressed RNA viral replication, indicating that RNF19A acts as a negative regulator of the RIG-I signaling pathway.","method":"Co-immunoprecipitation, K48-linked ubiquitination assay, siRNA knockdown, viral replication assay, IFN production measurement","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination shown, loss-of-function with antiviral phenotype, single lab","pmids":["34990937"],"is_preprint":false},{"year":2023,"finding":"RNF19A ubiquitinates RIG-I (DDX58), mediating its degradation and negatively regulating neuroinflammation during Japanese encephalitis virus infection; H3K27me3 modification of the Rnf19a locus (mediated by EZH2) increases upon JEV infection, downregulating Rnf19a expression and thereby relieving suppression of RIG-I.","method":"ChIP-sequencing (H3K27me3), EZH2 knockdown/inhibitor treatment, ubiquitination assay (RIG-I as substrate), co-immunoprecipitation, cytokine measurements, in vitro and in vivo JEV infection model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, ubiquitination assay, and functional cytokine readouts; single lab with multiple orthogonal methods","pmids":["37480121"],"is_preprint":false},{"year":2023,"finding":"RNF19A ubiquitylates TRIP13, promoting its degradation; RNF19A is transcriptionally activated by androgen receptor (AR) and HIF1A in prostate cancer cells, establishing an AR/HIF1A–RNF19A–TRIP13 signaling axis.","method":"CRISPR screening (656 E3 ligases), ubiquitination proteomic analysis, quantitative proteomics, transcriptomics, co-immunoprecipitation","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination proteomics and Co-IP identify substrate, transcriptional regulation confirmed by reporter/ChIP assay context, single lab","pmids":["36623445"],"is_preprint":false},{"year":2024,"finding":"RNF19A directly interacts with ILK (integrin-linked kinase) and promotes its K48-linked ubiquitination and proteasomal degradation, thereby inactivating the AKT/mTOR signaling pathway and suppressing bladder cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, rescue experiments (ILK overexpression/knockdown), western blot for p-AKT/p-mTOR/p-S6K1","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, cycloheximide chase, and rescue experiments show mechanistic pathway; single lab","pmids":["39508245"],"is_preprint":false},{"year":2025,"finding":"RNF19A promotes K48-linked ubiquitination and degradation of MKP-1 (DUSP1) in fibroblast-like synoviocytes, activating the MAPK signaling pathway; this facilitates nuclear translocation of the transcription factor ZBTB20, which in turn transcriptionally upregulates RNF19A, forming a positive feedback loop contributing to methotrexate resistance in rheumatoid arthritis.","method":"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, western blot for MAPK pathway, nuclear/cytoplasmic fractionation, ChIP/reporter assay for ZBTB20 regulation, in vivo validation","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, feedback loop validated in vitro and in vivo; single lab","pmids":["40293542"],"is_preprint":false},{"year":2026,"finding":"RNF19A interacts with MST1 (STK4), mediates K48-linked ubiquitination of MST1 leading to its degradation, inhibiting the Hippo/YAP pathway by reducing YAP phosphorylation and increasing nuclear YAP levels, thereby promoting gastric cancer cell growth and metastasis.","method":"Co-immunoprecipitation, in vivo ubiquitylation assay, protein half-life assay, nuclear/cytoplasmic fractionation, immunofluorescence, xenograft and metastasis models, rescue by MST1 knockdown","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo model, rescue experiments; single lab, multiple orthogonal methods","pmids":["41506118"],"is_preprint":false}],"current_model":"RNF19A (Dorfin) is an RBR-type (RING-IBR-RING) E3 ubiquitin ligase that interacts with UbcH7 and UbcH8 via its RING/IBR domain and, in complex with partners such as VCP/p97 and NLRP11, catalyzes primarily K48-linked polyubiquitination of diverse substrates—including mutant SOD1, CaR, TRAF6, BARD1, TBK1, RIG-I, TRIP13, ILK, MKP-1, and MST1—targeting them for proteasomal degradation to regulate neuronal protein quality control, innate immune signaling, DNA damage repair (HR), and cancer-relevant pathways; it also binds PSD-95 at excitatory synapses and localizes to centrosomes and ubiquitylated inclusion bodies in neurodegenerative diseases."},"narrative":{"mechanistic_narrative":"RNF19A (Dorfin) is an RBR-type (RING-IBR-RING) E3 ubiquitin ligase that catalyzes substrate ubiquitination—predominantly K48-linked chains targeting substrates for proteasomal degradation—across neuronal protein quality control, innate immune signaling, DNA repair, and cancer pathways [PMID:11237715, PMID:12145308, PMID:29215004]. Its catalytic core comprises two RING-finger motifs and an IBR domain that bind the ubiquitin-conjugating enzymes UbcH7 and UbcH8, and deletion of this region abolishes both E2 binding and ligase activity [PMID:11237715]. RNF19A activity toward substrates such as mutant SOD1 requires direct association with the AAA-ATPase VCP/p97, which forms a large endogenous complex with RNF19A and whose ATPase activity is needed for ligase function [PMID:15456787]. In neurodegeneration, RNF19A selectively binds and ubiquitylates familial ALS mutant SOD1 (but not wild-type), enhancing its clearance, reducing mitochondrial mutant SOD1, cytochrome c release, and caspase activation, and protecting motor neurons in cell and transgenic mouse models [PMID:12145308, PMID:15030390, PMID:19610091]; it localizes to centrosomes and to ubiquitylated inclusion bodies across ALS, Parkinson's disease, and related disorders [PMID:11237715, PMID:12875980]. RNF19A also binds the postsynaptic scaffold PSD-95, and its loss in mice alters hippocampal plasticity, neurogenesis, and contextual fear memory with a reduced brain ubiquitinome [PMID:26553645]. In innate immunity, RNF19A is recruited by NLRP11 to drive K48-linked ubiquitination and degradation of TRAF6, dampening TLR-induced NF-κB/MAPK signaling [PMID:29215004], and it negatively regulates antiviral responses by degrading TBK1 and RIG-I [PMID:34990937, PMID:37480121]. Across cancers, RNF19A degrades distinct substrates to opposing functional ends: it ubiquitylates BARD1 to dissociate the BRCA1-BARD1 dimer and suppress homologous recombination [PMID:34789768], degrades TRIP13 within an AR/HIF1A-driven axis [PMID:36623445], and degrades ILK, MST1, and MKP-1 to modulate AKT/mTOR, Hippo/YAP, and MAPK signaling respectively [PMID:39508245, PMID:40293542, PMID:41506118].","teleology":[{"year":2001,"claim":"Established RNF19A as a bona fide E3 ubiquitin ligase by defining its catalytic architecture and E2 partners, answering whether the RING/IBR domains support ubiquitin transfer.","evidence":"Co-IP, domain-deletion mutagenesis, proteasome inhibition, and immunofluorescence localization","pmids":["11237715"],"confidence":"High","gaps":["No physiological substrate identified at this stage","Chain-linkage specificity not defined","Functional consequence of centrosomal localization unknown"]},{"year":2002,"claim":"Identified mutant SOD1 as a disease-relevant substrate, showing RNF19A selectively clears misfolded proteins and rescues neuronal toxicity.","evidence":"Co-IP, in vitro ubiquitination, toxicity rescue in neural cells, and ALS tissue immunohistochemistry","pmids":["12145308"],"confidence":"High","gaps":["Mechanism of mutant-versus-wild-type discrimination not resolved","In vivo relevance not yet tested at this stage"]},{"year":2003,"claim":"Mapped RNF19A to ubiquitylated inclusions across multiple neurodegenerative diseases, while ruling out alpha-synuclein as a direct binding partner.","evidence":"Affinity-purified antibody immunohistochemistry, double immunofluorescence, and filter trap assay","pmids":["12875980"],"confidence":"Medium","gaps":["Inclusion localization is correlative, not causal","Substrate(s) within inclusions other than SOD1 undefined"]},{"year":2004,"claim":"Defined VCP/p97 as an obligate cofactor whose ATPase activity is required for RNF19A E3 activity, revealing the ligase operates within a large multiprotein complex.","evidence":"Mass spectrometry, glycerol gradient, direct binding, and dominant-negative VCP(K524A) functional assay","pmids":["15456787"],"confidence":"High","gaps":["How VCP ATPase mechanistically couples to ubiquitin transfer not resolved","Whether VCP is required for all substrates or only SOD1 unknown"]},{"year":2004,"claim":"Connected substrate clearance to an organelle-level rescue, showing RNF19A reduces mitochondrial mutant SOD1 and blocks the apoptotic cascade.","evidence":"Neuronal overexpression with subcellular fractionation, cytochrome c release, and caspase activation assays","pmids":["15030390"],"confidence":"Medium","gaps":["Single-lab functional readout","Direct mitochondrial targeting mechanism unclear"]},{"year":2006,"claim":"Extended substrate range beyond aggregation-prone proteins to a membrane receptor, showing RNF19A drives ER-associated degradation of the calcium-sensing receptor.","evidence":"Yeast two-hybrid, Co-IP, lysine mutagenesis, dominant-negative, and glycosidase/ER assays","pmids":["16513638"],"confidence":"High","gaps":["Physiological context of CaR regulation by RNF19A not established in vivo"]},{"year":2006,"claim":"Demonstrated that RNF19A's substrate-binding module can be re-engineered with a more stable catalytic domain to improve mutant SOD1 clearance, mapping function to modular domains.","evidence":"Dorfin-CHIP chimeric proteins with ubiquitination, stability, aggresome, and viability readouts","pmids":["17157513"],"confidence":"Medium","gaps":["Engineered tool, not endogenous mechanism","Single-lab cell-based assays"]},{"year":2009,"claim":"Linked RNF19A to the proteasome machinery and tissue-specific developmental function via interaction with Psmc3 during spermiogenesis.","evidence":"Co-IP and dynamic immunofluorescence co-localization across spermatid development","pmids":["19517565"],"confidence":"Medium","gaps":["No substrate identified in acrosome biogenesis","Functional requirement not tested by loss-of-function"]},{"year":2010,"claim":"Provided in vivo proof that RNF19A overexpression mitigates ALS pathology, validating it as a therapeutic modifier of mutant SOD1 disease.","evidence":"G93A SOD1 transgenic mouse overexpression with immunoblot, phenotype scoring, and motor neuron histology","pmids":["19610091"],"confidence":"Medium","gaps":["Single-lab transgenic model","Endogenous RNF19A loss-of-function effect on ALS not tested"]},{"year":2015,"claim":"Defined a synaptic and behavioral role through PSD-95 interaction and knockout phenotyping, establishing RNF19A as a regulator of the brain ubiquitinome and plasticity.","evidence":"Reciprocal Co-IP, knockout electrophysiology, behavior, and proteomic ubiquitinome analysis","pmids":["26553645"],"confidence":"High","gaps":["Synaptic substrates degraded via PSD-95 association not identified","Mechanism linking ubiquitination to LTP/neurogenesis changes unresolved"]},{"year":2017,"claim":"Revealed RNF19A as an effector E3 in innate immunity, recruited by NLRP11 to degrade TRAF6 and restrain TLR-induced inflammation.","evidence":"Reciprocal Co-IP, K48-linkage-specific ubiquitination, dual loss-of-function, and NF-κB/MAPK/cytokine readouts","pmids":["29215004"],"confidence":"High","gaps":["How NLRP11 directs RNF19A substrate selectivity not fully resolved"]},{"year":2021,"claim":"Uncovered a non-degradative-localization mechanism in DNA repair, where RNF19A ubiquitylation of BARD1 dissociates BRCA1-BARD1 and exports BARD1 to suppress homologous recombination.","evidence":"Co-IP, ubiquitination assay, NES mapping, fractionation, HR assay, and PARP inhibitor sensitivity","pmids":["34789768"],"confidence":"High","gaps":["Upstream regulation of RNF19A in the DNA damage response unknown"]},{"year":2022,"claim":"Showed RNF19A negatively regulates RIG-I signaling by K48-linked degradation of TBK1, dampening type I interferon and antiviral responses.","evidence":"Co-IP, K48-linkage ubiquitination, siRNA knockdown, viral replication, and IFN measurements","pmids":["34990937"],"confidence":"Medium","gaps":["Single-lab study","In vivo antiviral relevance not established here"]},{"year":2023,"claim":"Extended antiviral negative regulation to RIG-I itself and embedded RNF19A in an epigenetic circuit, with EZH2-mediated H3K27me3 silencing of Rnf19a relieving RIG-I suppression during JEV infection.","evidence":"ChIP-seq, EZH2 perturbation, RIG-I ubiquitination, Co-IP, and in vitro/in vivo JEV models","pmids":["37480121"],"confidence":"Medium","gaps":["Direct EZH2 recruitment mechanism to the locus not detailed","Single-lab study"]},{"year":2023,"claim":"Placed RNF19A in a cancer signaling axis, identifying TRIP13 as a degradation substrate downstream of AR/HIF1A transcriptional activation in prostate cancer.","evidence":"CRISPR screen of E3 ligases, ubiquitination/quantitative proteomics, transcriptomics, and Co-IP","pmids":["36623445"],"confidence":"Medium","gaps":["Direct AR/HIF1A binding to the RNF19A promoter not fully dissected","Single-lab study"]},{"year":2024,"claim":"Demonstrated tumor-suppressive function in bladder cancer through K48-linked degradation of ILK and consequent AKT/mTOR pathway inactivation.","evidence":"Co-IP, ubiquitination assay, cycloheximide chase, rescue experiments, and phospho-AKT/mTOR/S6K1 blots","pmids":["39508245"],"confidence":"Medium","gaps":["Single-lab study","Context dependence of tumor-suppressive versus oncogenic roles unresolved"]},{"year":2025,"claim":"Identified MKP-1 (DUSP1) as a substrate within a ZBTB20-driven positive feedback loop activating MAPK signaling and promoting methotrexate resistance in rheumatoid arthritis synoviocytes.","evidence":"Co-IP, ubiquitination assay, fractionation, ChIP/reporter for ZBTB20, and in vivo validation","pmids":["40293542"],"confidence":"Medium","gaps":["Single-lab study","Generalizability of the feedback loop to other tissues unknown"]},{"year":2026,"claim":"Showed an oncogenic role in gastric cancer via MST1 (STK4) degradation, inhibiting Hippo/YAP signaling and increasing nuclear YAP to drive growth and metastasis.","evidence":"Co-IP, in vivo ubiquitylation, half-life assay, fractionation, immunofluorescence, xenograft/metastasis models, and MST1 rescue","pmids":["41506118"],"confidence":"Medium","gaps":["Single-lab study","Reconciliation of pro- and anti-tumor roles across cancer types unresolved"]},{"year":null,"claim":"How RNF19A achieves substrate selectivity across such diverse contexts—and what determines whether its ubiquitination drives degradation versus relocalization—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the RNF19A RBR catalytic mechanism in the corpus","Determinants of context-specific substrate engagement (adaptors like NLRP11/VCP versus direct binding) not unified","No reconciliation of opposing tumor-suppressive and oncogenic roles"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,5,10,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,10,11,15,17]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,10,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,12,13]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,16,17]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,9]}],"complexes":["RNF19A-VCP/p97 complex"],"partners":["VCP","UBE2L3","UBE2L6","NLRP11","DLG4","PSMC3","BARD1","ILK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NV58","full_name":"E3 ubiquitin-protein ligase RNF19A","aliases":["Double ring-finger protein","Dorfin","RING finger protein 19A","p38"],"length_aa":838,"mass_kda":90.7,"function":"E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates, such as SNCAIP or CASR. Specifically ubiquitinates pathogenic SOD1 variants, which leads to their proteasomal degradation and to neuronal protection","subcellular_location":"Membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9NV58/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF19A","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF19A","total_profiled":1310},"omim":[{"mim_id":"607119","title":"RING FINGER PROTEIN 19A, RBR E3 UBIQUITIN PROTEIN LIGASE; RNF19A","url":"https://www.omim.org/entry/607119"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF19A"},"hgnc":{"alias_symbol":["dorfin","DKFZp566B1346"],"prev_symbol":["RNF19"]},"alphafold":{"accession":"Q9NV58","domains":[{"cath_id":"3.30.40.10","chopping":"127-212","consensus_level":"medium","plddt":90.8821,"start":127,"end":212},{"cath_id":"-","chopping":"313-353","consensus_level":"medium","plddt":78.9127,"start":313,"end":353},{"cath_id":"-","chopping":"356-456","consensus_level":"high","plddt":88.6194,"start":356,"end":456},{"cath_id":"2.20.28","chopping":"214-279","consensus_level":"medium","plddt":84.1989,"start":214,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV58","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV58-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV58-F1-predicted_aligned_error_v6.png","plddt_mean":54.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF19A","jax_strain_url":"https://www.jax.org/strain/search?query=RNF19A"},"sequence":{"accession":"Q9NV58","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NV58.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NV58/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV58"}},"corpus_meta":[{"pmid":"12145308","id":"PMC_12145308","title":"Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12145308","citation_count":164,"is_preprint":false},{"pmid":"29215004","id":"PMC_29215004","title":"NLRP11 attenuates Toll-like receptor signalling by targeting TRAF6 for degradation via the ubiquitin ligase RNF19A.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29215004","citation_count":72,"is_preprint":false},{"pmid":"11237715","id":"PMC_11237715","title":"A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase activity.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11237715","citation_count":69,"is_preprint":false},{"pmid":"15456787","id":"PMC_15456787","title":"Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15456787","citation_count":65,"is_preprint":false},{"pmid":"16513638","id":"PMC_16513638","title":"Calcium-sensing receptor ubiquitination and degradation mediated by the E3 ubiquitin ligase dorfin.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16513638","citation_count":64,"is_preprint":false},{"pmid":"19517565","id":"PMC_19517565","title":"Rnf19a, a ubiquitin protein ligase, and Psmc3, a component of the 26S proteasome, tether to the acrosome membranes and the head-tail coupling apparatus during rat spermatid development.","date":"2009","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/19517565","citation_count":47,"is_preprint":false},{"pmid":"12875980","id":"PMC_12875980","title":"Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis.","date":"2003","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12875980","citation_count":43,"is_preprint":false},{"pmid":"17157513","id":"PMC_17157513","title":"Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.","date":"2006","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/17157513","citation_count":35,"is_preprint":false},{"pmid":"34789768","id":"PMC_34789768","title":"RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34789768","citation_count":23,"is_preprint":false},{"pmid":"26553645","id":"PMC_26553645","title":"Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26553645","citation_count":23,"is_preprint":false},{"pmid":"15030390","id":"PMC_15030390","title":"Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.","date":"2004","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15030390","citation_count":20,"is_preprint":false},{"pmid":"19610091","id":"PMC_19610091","title":"Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis.","date":"2010","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/19610091","citation_count":18,"is_preprint":false},{"pmid":"36623445","id":"PMC_36623445","title":"CRISPR screening reveals gleason score and castration resistance related oncodriver ring finger protein 19 A (RNF19A) in prostate cancer.","date":"2023","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/36623445","citation_count":14,"is_preprint":false},{"pmid":"18721867","id":"PMC_18721867","title":"Cooperative exonization of MaLR and AluJo elements contributed an alternative promoter and novel splice variants of RNF19.","date":"2008","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/18721867","citation_count":11,"is_preprint":false},{"pmid":"37326687","id":"PMC_37326687","title":"LncRNA KCNQ10T1 shuttled by bone marrow mesenchymal stem cell-derived exosome inhibits sepsis via regulation of miR-154-3p/RNF19A axis.","date":"2023","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/37326687","citation_count":8,"is_preprint":false},{"pmid":"34990937","id":"PMC_34990937","title":"RNF19a inhibits antiviral immune response to RNA viruses through degradation of TBK1.","date":"2022","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34990937","citation_count":7,"is_preprint":false},{"pmid":"37480121","id":"PMC_37480121","title":"H3K27me3 of Rnf19a promotes neuroinflammatory response during Japanese encephalitis virus infection.","date":"2023","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/37480121","citation_count":6,"is_preprint":false},{"pmid":"39508245","id":"PMC_39508245","title":"RNF19A inhibits bladder cancer progression by regulating ILK ubiquitination and inactivating the AKT/mTOR signalling pathway.","date":"2024","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/39508245","citation_count":3,"is_preprint":false},{"pmid":"22760261","id":"PMC_22760261","title":"Porcine dorfin: molecular cloning of the RNF19 gene, sequence comparison, mapping and expression analysis.","date":"2012","source":"Molecular biology 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uterine mesenchymal neoplasms.","date":"2026","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/42178368","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12442,"output_tokens":4904,"usd":0.055443,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13082,"output_tokens":5364,"usd":0.099755,"stage2_stop_reason":"end_turn"},"total_usd":0.155198,"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\": \"Dorfin/RNF19A contains two RING-finger motifs and an IBR motif at its N-terminus, binds specifically to ubiquitin-conjugating enzymes UbcH7 and UbcH8 through the RING-finger/IBR domain, and mediates ubiquitin ligase (E3) activity; partial deletion of the RING-finger/IBR domain eliminated these interactions and ubiquitination activity. Dorfin is a short-lived protein that accumulates upon proteasome inhibition. It is localized to the centrosome.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, proteasome inhibitor treatment (MG132), subcellular localization by immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding confirmed, mutagenesis of active domain, multiple orthogonal methods in foundational characterization paper\",\n      \"pmids\": [\"11237715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Dorfin/RNF19A physically binds and ubiquitylates mutant SOD1 proteins (from familial ALS patients) but not wild-type SOD1, enhancing their proteasomal degradation; overexpression of Dorfin protects neural cells from mutant SOD1 toxicity and reduces SOD1 inclusion bodies. Dorfin localizes to inclusion bodies in familial and sporadic ALS motor neurons.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, overexpression with toxicity rescue assay, immunohistochemistry/immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitination assay, co-IP, cell-based toxicity rescue, substrate specificity shown by mutagenesis/variant panel\",\n      \"pmids\": [\"12145308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Dorfin/RNF19A localizes to ubiquitylated inclusions (Lewy bodies, glial cell inclusions, hyaline inclusions) in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and ALS, showing a distribution pattern parallel to ubiquitin. However, direct binding of alpha-synuclein to Dorfin was not detected (negative result).\",\n      \"method\": \"Immunohistochemistry with affinity-purified antibody, double immunofluorescence, filter trap assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization established by multiple methods across disease types; negative binding result explicitly reported\",\n      \"pmids\": [\"12875980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Valosin-containing protein (VCP/p97) directly binds to Dorfin/RNF19A through the C-terminal region of Dorfin, forms an endogenous ~400–600 kDa complex with Dorfin, and VCP ATPase activity is required for the E3 ubiquitin ligase activity of Dorfin toward mutant SOD1; a dominant-negative VCP(K524A) reduced Dorfin E3 activity but had no effect on Parkin autoubiquitylation. Both proteins co-localize in aggresomes and ubiquitylated inclusions in ALS and PD neurons.\",\n      \"method\": \"Mass spectrometry identification, glycerol gradient centrifugation, co-immunoprecipitation, in vitro direct binding, dominant-negative VCP functional assay, immunofluorescence co-localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding shown in vitro, functional consequence of VCP ATPase on Dorfin E3 activity demonstrated by dominant-negative, multiple orthogonal methods\",\n      \"pmids\": [\"15456787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Dorfin/RNF19A significantly reduces mutant SOD1 levels in mitochondria, thereby decreasing cytochrome c release and caspase cascade activation, and preventing neuronal cell death in a neuronal cell model of familial ALS.\",\n      \"method\": \"Overexpression in neuronal cell model, subcellular fractionation (mitochondrial fraction), cytochrome c release assay, caspase activation assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with biochemical pathway readouts (cytochrome c, caspase), single lab\",\n      \"pmids\": [\"15030390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Dorfin/RNF19A binds the intracellular carboxyl terminus of the calcium-sensing receptor (CaR) (identified by yeast two-hybrid and confirmed by co-immunoprecipitation), ubiquitinates CaR, and promotes its proteasomal degradation from the endoplasmic reticulum; mutation of all putative intracellular lysine residues abolished CaR ubiquitination. VCP/p97 associates with both CaR and Dorfin. A dominant-negative Dorfin fragment had opposite (stabilizing) effects on CaR.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, dominant-negative construct, lysine mutagenesis, tunicamycin/MG132 treatment, endoglycosidase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — substrate identified by yeast two-hybrid and confirmed by Co-IP, lysine mutagenesis abolishes ubiquitination, dominant-negative shows opposing effect, multiple orthogonal methods\",\n      \"pmids\": [\"16513638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Dorfin-CHIP chimeric proteins containing the substrate-binding domain of Dorfin and the U-box domain of CHIP are more stable in cells than wild-type Dorfin, more effectively ubiquitylate mutant SOD1 in vivo, degrade mutant SOD1 more rapidly, reduce aggresome formation, and rescue neuronal cells from mutant SOD1 toxicity better than wild-type Dorfin.\",\n      \"method\": \"Chimeric protein engineering, in vivo ubiquitination assay, cell viability assay, aggresome quantification, pulse-chase/protein stability assay\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain dissection via chimera, multiple readouts in cell-based assays, single lab\",\n      \"pmids\": [\"17157513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rnf19a interacts with Psmc3, a component of the 19S regulatory cap of the 26S proteasome, in rat spermatids; during spermatid development, Rnf19a and Psmc3 are found in Golgi-derived proacrosomal vesicles, along acrosomal membranes, the acroplaxome, the marginal ring, and in the developing head-tail coupling apparatus, implicating the ubiquitin-proteasome system in acrosome biogenesis and spermatid head shaping.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization during spermatogenesis, cDNA cloning and sequence analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction shown, subcellular localization tracked dynamically during development, single lab\",\n      \"pmids\": [\"19517565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of human Dorfin/RNF19A in G93A mutant SOD1 transgenic mice decreased mutant SOD1 protein levels in spinal cord, ameliorated neurological phenotypes, and reduced motor neuron degeneration in vivo.\",\n      \"method\": \"Transgenic mouse overexpression, immunoblotting of spinal cord proteins, neurological phenotype scoring, motor neuron histology\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with biochemical and histological readouts, single lab\",\n      \"pmids\": [\"19610091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Dorfin/RNF19A is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-knockout mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus but normal LTP in CA1, impaired contextual fear conditioning, and decreased ubiquitination of multiple brain proteins identified by proteomics.\",\n      \"method\": \"Co-immunoprecipitation (PSD-95 interaction), knockout mouse phenotyping, electrophysiology (LTP), behavioral testing, proteomic ubiquitinome analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for PSD-95 interaction, knockout mouse with multiple orthogonal in vivo phenotypic readouts (electrophysiology, behavior, proteomics)\",\n      \"pmids\": [\"26553645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNF19A is recruited by NLRP11 to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, leading to proteasomal degradation of TRAF6 and attenuation of TLR signaling; deficiency of either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, promoting NF-κB and MAPK activation and increased proinflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), siRNA/shRNA knockdown, overexpression, NF-κB/MAPK pathway readouts, cytokine measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, linkage-specific ubiquitination assay, two-component (NLRP11 and RNF19A) loss-of-function with consistent phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29215004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF19A ubiquitinates BARD1, causing dissociation of the BRCA1-BARD1 heterodimer and exposing a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in cytoplasmic export of BARD1. This suppresses homologous recombination and increases cancer cell sensitivity to PARP inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear export sequence mapping, cellular fractionation, HR assay, PARP inhibitor sensitivity assay, overexpression and knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, direct ubiquitination assay, NES exposure mechanism dissected, functional HR assay readout, multiple orthogonal methods\",\n      \"pmids\": [\"34789768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF19A mediates K48-linked ubiquitination and proteasomal degradation of TBK1; silencing of RNF19A enhanced type I interferon production and suppressed RNA viral replication, indicating that RNF19A acts as a negative regulator of the RIG-I signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, K48-linked ubiquitination assay, siRNA knockdown, viral replication assay, IFN production measurement\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination shown, loss-of-function with antiviral phenotype, single lab\",\n      \"pmids\": [\"34990937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF19A ubiquitinates RIG-I (DDX58), mediating its degradation and negatively regulating neuroinflammation during Japanese encephalitis virus infection; H3K27me3 modification of the Rnf19a locus (mediated by EZH2) increases upon JEV infection, downregulating Rnf19a expression and thereby relieving suppression of RIG-I.\",\n      \"method\": \"ChIP-sequencing (H3K27me3), EZH2 knockdown/inhibitor treatment, ubiquitination assay (RIG-I as substrate), co-immunoprecipitation, cytokine measurements, in vitro and in vivo JEV infection model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, ubiquitination assay, and functional cytokine readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37480121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF19A ubiquitylates TRIP13, promoting its degradation; RNF19A is transcriptionally activated by androgen receptor (AR) and HIF1A in prostate cancer cells, establishing an AR/HIF1A–RNF19A–TRIP13 signaling axis.\",\n      \"method\": \"CRISPR screening (656 E3 ligases), ubiquitination proteomic analysis, quantitative proteomics, transcriptomics, co-immunoprecipitation\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination proteomics and Co-IP identify substrate, transcriptional regulation confirmed by reporter/ChIP assay context, single lab\",\n      \"pmids\": [\"36623445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF19A directly interacts with ILK (integrin-linked kinase) and promotes its K48-linked ubiquitination and proteasomal degradation, thereby inactivating the AKT/mTOR signaling pathway and suppressing bladder cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, rescue experiments (ILK overexpression/knockdown), western blot for p-AKT/p-mTOR/p-S6K1\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, cycloheximide chase, and rescue experiments show mechanistic pathway; single lab\",\n      \"pmids\": [\"39508245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF19A promotes K48-linked ubiquitination and degradation of MKP-1 (DUSP1) in fibroblast-like synoviocytes, activating the MAPK signaling pathway; this facilitates nuclear translocation of the transcription factor ZBTB20, which in turn transcriptionally upregulates RNF19A, forming a positive feedback loop contributing to methotrexate resistance in rheumatoid arthritis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown, western blot for MAPK pathway, nuclear/cytoplasmic fractionation, ChIP/reporter assay for ZBTB20 regulation, in vivo validation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, feedback loop validated in vitro and in vivo; single lab\",\n      \"pmids\": [\"40293542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RNF19A interacts with MST1 (STK4), mediates K48-linked ubiquitination of MST1 leading to its degradation, inhibiting the Hippo/YAP pathway by reducing YAP phosphorylation and increasing nuclear YAP levels, thereby promoting gastric cancer cell growth and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitylation assay, protein half-life assay, nuclear/cytoplasmic fractionation, immunofluorescence, xenograft and metastasis models, rescue by MST1 knockdown\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo model, rescue experiments; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41506118\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF19A (Dorfin) is an RBR-type (RING-IBR-RING) E3 ubiquitin ligase that interacts with UbcH7 and UbcH8 via its RING/IBR domain and, in complex with partners such as VCP/p97 and NLRP11, catalyzes primarily K48-linked polyubiquitination of diverse substrates—including mutant SOD1, CaR, TRAF6, BARD1, TBK1, RIG-I, TRIP13, ILK, MKP-1, and MST1—targeting them for proteasomal degradation to regulate neuronal protein quality control, innate immune signaling, DNA damage repair (HR), and cancer-relevant pathways; it also binds PSD-95 at excitatory synapses and localizes to centrosomes and ubiquitylated inclusion bodies in neurodegenerative diseases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF19A (Dorfin) is an RBR-type (RING-IBR-RING) E3 ubiquitin ligase that catalyzes substrate ubiquitination—predominantly K48-linked chains targeting substrates for proteasomal degradation—across neuronal protein quality control, innate immune signaling, DNA repair, and cancer pathways [#0, #1, #10]. Its catalytic core comprises two RING-finger motifs and an IBR domain that bind the ubiquitin-conjugating enzymes UbcH7 and UbcH8, and deletion of this region abolishes both E2 binding and ligase activity [#0]. RNF19A activity toward substrates such as mutant SOD1 requires direct association with the AAA-ATPase VCP/p97, which forms a large endogenous complex with RNF19A and whose ATPase activity is needed for ligase function [#3]. In neurodegeneration, RNF19A selectively binds and ubiquitylates familial ALS mutant SOD1 (but not wild-type), enhancing its clearance, reducing mitochondrial mutant SOD1, cytochrome c release, and caspase activation, and protecting motor neurons in cell and transgenic mouse models [#1, #4, #8]; it localizes to centrosomes and to ubiquitylated inclusion bodies across ALS, Parkinson's disease, and related disorders [#0, #2]. RNF19A also binds the postsynaptic scaffold PSD-95, and its loss in mice alters hippocampal plasticity, neurogenesis, and contextual fear memory with a reduced brain ubiquitinome [#9]. In innate immunity, RNF19A is recruited by NLRP11 to drive K48-linked ubiquitination and degradation of TRAF6, dampening TLR-induced NF-κB/MAPK signaling [#10], and it negatively regulates antiviral responses by degrading TBK1 and RIG-I [#12, #13]. Across cancers, RNF19A degrades distinct substrates to opposing functional ends: it ubiquitylates BARD1 to dissociate the BRCA1-BARD1 dimer and suppress homologous recombination [#11], degrades TRIP13 within an AR/HIF1A-driven axis [#14], and degrades ILK, MST1, and MKP-1 to modulate AKT/mTOR, Hippo/YAP, and MAPK signaling respectively [#15, #16, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RNF19A as a bona fide E3 ubiquitin ligase by defining its catalytic architecture and E2 partners, answering whether the RING/IBR domains support ubiquitin transfer.\",\n      \"evidence\": \"Co-IP, domain-deletion mutagenesis, proteasome inhibition, and immunofluorescence localization\",\n      \"pmids\": [\"11237715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Chain-linkage specificity not defined\", \"Functional consequence of centrosomal localization unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified mutant SOD1 as a disease-relevant substrate, showing RNF19A selectively clears misfolded proteins and rescues neuronal toxicity.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, toxicity rescue in neural cells, and ALS tissue immunohistochemistry\",\n      \"pmids\": [\"12145308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mutant-versus-wild-type discrimination not resolved\", \"In vivo relevance not yet tested at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped RNF19A to ubiquitylated inclusions across multiple neurodegenerative diseases, while ruling out alpha-synuclein as a direct binding partner.\",\n      \"evidence\": \"Affinity-purified antibody immunohistochemistry, double immunofluorescence, and filter trap assay\",\n      \"pmids\": [\"12875980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inclusion localization is correlative, not causal\", \"Substrate(s) within inclusions other than SOD1 undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined VCP/p97 as an obligate cofactor whose ATPase activity is required for RNF19A E3 activity, revealing the ligase operates within a large multiprotein complex.\",\n      \"evidence\": \"Mass spectrometry, glycerol gradient, direct binding, and dominant-negative VCP(K524A) functional assay\",\n      \"pmids\": [\"15456787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VCP ATPase mechanistically couples to ubiquitin transfer not resolved\", \"Whether VCP is required for all substrates or only SOD1 unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected substrate clearance to an organelle-level rescue, showing RNF19A reduces mitochondrial mutant SOD1 and blocks the apoptotic cascade.\",\n      \"evidence\": \"Neuronal overexpression with subcellular fractionation, cytochrome c release, and caspase activation assays\",\n      \"pmids\": [\"15030390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional readout\", \"Direct mitochondrial targeting mechanism unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended substrate range beyond aggregation-prone proteins to a membrane receptor, showing RNF19A drives ER-associated degradation of the calcium-sensing receptor.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, lysine mutagenesis, dominant-negative, and glycosidase/ER assays\",\n      \"pmids\": [\"16513638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context of CaR regulation by RNF19A not established in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that RNF19A's substrate-binding module can be re-engineered with a more stable catalytic domain to improve mutant SOD1 clearance, mapping function to modular domains.\",\n      \"evidence\": \"Dorfin-CHIP chimeric proteins with ubiquitination, stability, aggresome, and viability readouts\",\n      \"pmids\": [\"17157513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Engineered tool, not endogenous mechanism\", \"Single-lab cell-based assays\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked RNF19A to the proteasome machinery and tissue-specific developmental function via interaction with Psmc3 during spermiogenesis.\",\n      \"evidence\": \"Co-IP and dynamic immunofluorescence co-localization across spermatid development\",\n      \"pmids\": [\"19517565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate identified in acrosome biogenesis\", \"Functional requirement not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided in vivo proof that RNF19A overexpression mitigates ALS pathology, validating it as a therapeutic modifier of mutant SOD1 disease.\",\n      \"evidence\": \"G93A SOD1 transgenic mouse overexpression with immunoblot, phenotype scoring, and motor neuron histology\",\n      \"pmids\": [\"19610091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab transgenic model\", \"Endogenous RNF19A loss-of-function effect on ALS not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a synaptic and behavioral role through PSD-95 interaction and knockout phenotyping, establishing RNF19A as a regulator of the brain ubiquitinome and plasticity.\",\n      \"evidence\": \"Reciprocal Co-IP, knockout electrophysiology, behavior, and proteomic ubiquitinome analysis\",\n      \"pmids\": [\"26553645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic substrates degraded via PSD-95 association not identified\", \"Mechanism linking ubiquitination to LTP/neurogenesis changes unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed RNF19A as an effector E3 in innate immunity, recruited by NLRP11 to degrade TRAF6 and restrain TLR-induced inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP, K48-linkage-specific ubiquitination, dual loss-of-function, and NF-κB/MAPK/cytokine readouts\",\n      \"pmids\": [\"29215004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NLRP11 directs RNF19A substrate selectivity not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-degradative-localization mechanism in DNA repair, where RNF19A ubiquitylation of BARD1 dissociates BRCA1-BARD1 and exports BARD1 to suppress homologous recombination.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, NES mapping, fractionation, HR assay, and PARP inhibitor sensitivity\",\n      \"pmids\": [\"34789768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream regulation of RNF19A in the DNA damage response unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RNF19A negatively regulates RIG-I signaling by K48-linked degradation of TBK1, dampening type I interferon and antiviral responses.\",\n      \"evidence\": \"Co-IP, K48-linkage ubiquitination, siRNA knockdown, viral replication, and IFN measurements\",\n      \"pmids\": [\"34990937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"In vivo antiviral relevance not established here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended antiviral negative regulation to RIG-I itself and embedded RNF19A in an epigenetic circuit, with EZH2-mediated H3K27me3 silencing of Rnf19a relieving RIG-I suppression during JEV infection.\",\n      \"evidence\": \"ChIP-seq, EZH2 perturbation, RIG-I ubiquitination, Co-IP, and in vitro/in vivo JEV models\",\n      \"pmids\": [\"37480121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct EZH2 recruitment mechanism to the locus not detailed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed RNF19A in a cancer signaling axis, identifying TRIP13 as a degradation substrate downstream of AR/HIF1A transcriptional activation in prostate cancer.\",\n      \"evidence\": \"CRISPR screen of E3 ligases, ubiquitination/quantitative proteomics, transcriptomics, and Co-IP\",\n      \"pmids\": [\"36623445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AR/HIF1A binding to the RNF19A promoter not fully dissected\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated tumor-suppressive function in bladder cancer through K48-linked degradation of ILK and consequent AKT/mTOR pathway inactivation.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, cycloheximide chase, rescue experiments, and phospho-AKT/mTOR/S6K1 blots\",\n      \"pmids\": [\"39508245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Context dependence of tumor-suppressive versus oncogenic roles unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified MKP-1 (DUSP1) as a substrate within a ZBTB20-driven positive feedback loop activating MAPK signaling and promoting methotrexate resistance in rheumatoid arthritis synoviocytes.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, fractionation, ChIP/reporter for ZBTB20, and in vivo validation\",\n      \"pmids\": [\"40293542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Generalizability of the feedback loop to other tissues unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed an oncogenic role in gastric cancer via MST1 (STK4) degradation, inhibiting Hippo/YAP signaling and increasing nuclear YAP to drive growth and metastasis.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitylation, half-life assay, fractionation, immunofluorescence, xenograft/metastasis models, and MST1 rescue\",\n      \"pmids\": [\"41506118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Reconciliation of pro- and anti-tumor roles across cancer types unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF19A achieves substrate selectivity across such diverse contexts—and what determines whether its ubiquitination drives degradation versus relocalization—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the RNF19A RBR catalytic mechanism in the corpus\", \"Determinants of context-specific substrate engagement (adaptors like NLRP11/VCP versus direct binding) not unified\", \"No reconciliation of opposing tumor-suppressive and oncogenic roles\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 5, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 10, 11, 15, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 10, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 12, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16, 17]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [\"RNF19A-VCP/p97 complex\"],\n    \"partners\": [\"VCP\", \"UBE2L3\", \"UBE2L6\", \"NLRP11\", \"DLG4\", \"PSMC3\", \"BARD1\", \"ILK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}