{"gene":"FBXL19","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2012,"finding":"FBXL19, as the F-box subunit of an SCF E3 ubiquitin ligase complex, binds ST2L (the IL-33 receptor) and mediates its polyubiquitination and proteasomal degradation. GSK3β-catalyzed phosphorylation of ST2L at Ser442 is required for FBXL19-mediated ST2L degradation. FBXL19 overexpression abrogated IL-33/ST2L pro-inflammatory and pro-apoptotic signaling and lessened lung injury severity in mouse pneumonia models.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (Ser442), proteasome inhibitor treatment, overexpression/knockdown in lung epithelial cells, mouse pneumonia models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro ubiquitination assay, mutagenesis of phosphorylation site, and in vivo mouse model across multiple orthogonal methods in a single rigorous study","pmids":["22660580"],"is_preprint":false},{"year":2013,"finding":"SCF(FBXL19) E3 ubiquitin ligase targets Rac1 for polyubiquitination and proteasomal degradation. AKT-mediated phosphorylation of Rac1 at Ser71 is required for FBXL19-mediated ubiquitination. Lys166 within Rac1 is the ubiquitination acceptor site. FBXL19 overexpression reduced cell migration and diminished lamellipodia formation; Rac1(S71A) and Rac1(K166R) mutants were resistant to FBXL19-mediated degradation.","method":"F-box protein library screening, in vitro ubiquitination assay, Co-IP, site-directed mutagenesis (Rac1 S71A, K166R), cell migration assay, FBXL19 overexpression/knockdown in MLE12 cells","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination reconstitution, reciprocal Co-IP, mutagenesis of both phosphorylation and ubiquitination sites, functional cell migration readout","pmids":["23512198"],"is_preprint":false},{"year":2013,"finding":"SCF(FBXL19) E3 ubiquitin ligase targets RhoA for ubiquitination at Lys135 and proteasomal degradation in lung epithelial cells. Erk2-mediated phosphorylation of RhoA is both necessary and sufficient for SCF(FBXL19)-mediated RhoA ubiquitination and degradation. RhoA(K135R) mutant was resistant to FBXL19-mediated degradation. FBXL19 expression reduced p27 phosphorylation, cell proliferation, LPA-induced MLC phosphorylation, and stress fiber formation.","method":"Co-IP, in vitro ubiquitination assay, site-directed mutagenesis (RhoA K135R), cycloheximide chase, FBXL19 overexpression/knockdown, cell proliferation and cytoskeleton assays","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay, Co-IP, mutagenesis of ubiquitination site, Erk2 phosphorylation requirement validated, multiple functional readouts","pmids":["23871831"],"is_preprint":false},{"year":2014,"finding":"SCF(FBXL19) interacts with and polyubiquitinates Rac3 at Lys166, targeting it for proteasomal degradation. The C-terminus of FBXL19 is required for Rac3 interaction and ubiquitination, while N-terminal truncation increases Rac3 degradation. FBXL19 overexpression attenuated TGFβ1-induced E-cadherin downregulation and esophageal cancer cell elongation, linking Rac3 degradation to TGFβ1 signaling.","method":"Co-immunoprecipitation, immunoblotting, site-directed mutagenesis (Rac3 K166R), FBXL19 truncation variants, overexpression/knockdown in esophageal cancer cells (OE19, OE33), immunostaining","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, domain mapping by truncation mutants, ubiquitination assay, functional TGFβ1/E-cadherin readout; single lab","pmids":["24684802"],"is_preprint":false},{"year":2018,"finding":"FBXL19 is an unstable protein (half-life ~3 h) degraded by the ubiquitin-proteasome system. The acetyltransferase CBP acetylates FBXL19, reducing its ubiquitination and extending its half-life. Acetylation-mimicking FBXL19 mutants exhibit longer half-lives. CBP-mediated stabilization of FBXL19 enhances SCF(FBXL19) E3 ligase activity, promoting Cdc42 ubiquitination and degradation; CBP inhibition reverses these effects.","method":"Co-IP, cycloheximide chase, proteasome inhibitor (MG132) treatment, acetyltransferase/deacetylase inhibitor assays, acetylation-mimic mutagenesis, CBP overexpression/knockdown, in vitro ubiquitination of Cdc42","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, chase, mutagenesis, inhibitor studies) in single lab","pmids":["29522376"],"is_preprint":false},{"year":2018,"finding":"FBXL19 is a CpG island-binding protein in mouse embryonic stem (ES) cells that associates with the CDK-Mediator complex. FBXL19 recruits CDK-Mediator to CpG island-associated promoters of non-transcribed developmental genes, priming them for activation during cell lineage commitment. Recognition of CpG islands by FBXL19 is essential for mouse development.","method":"Genome-wide chromatin immunoprecipitation (ChIP-seq), Co-IP/protein interaction studies identifying CDK-Mediator association, genetic knockout of FBXL19 in mouse ES cells with developmental phenotype readout, differentiation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq genome-wide occupancy, Co-IP identifying CDK-Mediator complex, genetic KO with developmental and differentiation phenotype, multiple orthogonal methods","pmids":["29809150"],"is_preprint":false},{"year":2017,"finding":"Fbxl19, via its CxxC domain, binds CpG island-containing promoters and physically interacts with Rnf20 E3 ligase. Fbxl19 promotes H2B Lys120 mono-ubiquitination (H2Bub1) at CpG island-containing gene promoters; upregulation of Fbxl19 increases global H2Bub1 in mouse ES cells while downregulation reduces it. Chromosomal binding of Fbxl19 is required for H2Bub1 at its target loci, and Fbxl19 is required for proper ES cell differentiation in collaboration with Rnf20.","method":"ChIP-seq (genome-wide occupancy mapping), Co-IP (Fbxl19-Rnf20 interaction), Fbxl19 overexpression/knockdown in mouse ES cells, quantification of global H2Bub1 by immunoblot, ES cell differentiation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, reciprocal Co-IP for Rnf20 interaction, gain/loss-of-function with H2Bub1 quantification, differentiation phenotype readout","pmids":["28453857"],"is_preprint":false},{"year":2019,"finding":"FBXL19 mediates ubiquitination and degradation of TTF1 (thyroid transcription factor 1) in follicular thyroid carcinoma (FTC133) cells but not in normal thyroid epithelial cells (Htori3). Lys151 of TTF1 is the ubiquitin acceptor site in both cell types, but cell-type-specific E3 ligases (FBXL19 in FTC133 vs. HECW1 in Htori3) govern its degradation.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis (TTF1 K151R), FBXL19 and HECW1 overexpression in FTC133 and Htori3 cells, immunoblotting","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, mutagenesis of ubiquitination site, cell-type-specific overexpression; single lab","pmids":["31238008"],"is_preprint":false},{"year":2019,"finding":"miR-26 family members suppress adipocyte progenitor cell differentiation by repressing expression of Fbxl19, a conserved miR-26 target. Fbxl19 plays a cell-autonomous role in adipocyte progenitor differentiation; its repression by miR-26 blocks adipogenesis in vivo.","method":"Genetic deletion of all miR-26-encoding loci in mice, transgenic overexpression of miR-26a, identification of Fbxl19 as miR-26 target by bioinformatics and reporter assays, cell-autonomous adipogenesis assays","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and transgenic OE in vivo, target validation; Fbxl19 specifically identified as the downstream effector but mechanism of Fbxl19 action in adipogenesis not fully resolved mechanistically","pmids":["31488578"],"is_preprint":false},{"year":2020,"finding":"SCFFBXW17 E3 ubiquitin ligase ubiquitinates FBXL19 and induces its proteasomal degradation; Lys114 of FBXL19 is identified as the ubiquitin acceptor site. Acetylation of FBXL19 attenuates SCFFBXW17-mediated FBXL19 degradation. FBXW17 overexpression reduces FBXL19 levels, attenuating SCF(FBXL19)-mediated Rac1 degradation and cell migration suppression; FBXW17 knockdown attenuates LPA-induced lamellipodia formation.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis (FBXL19 K114R), FBXW17 overexpression/knockdown, cycloheximide chase, cell migration and lamellipodia assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, mutagenesis of acceptor site, functional migration readout; single lab","pmids":["33053230"],"is_preprint":false},{"year":2020,"finding":"FBXL19 and CDK-Mediator support long-range chromatin interactions between silent developmental gene promoters and atypical distal regulatory elements in mouse ESCs. These distal elements are required for appropriate gene induction during differentiation, as shown by targeted deletions. During gene activation, most distal elements do not acquire H3K27ac and lose interaction with their target promoters, indicating an atypical enhancer mechanism.","method":"Chromatin conformation capture / 3D genome interaction assays (Hi-C or similar), targeted genomic deletions, gene expression analysis during ESC differentiation, FBXL19 and CDK-Mediator ChIP","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin conformation assays, targeted deletions with functional readout, single lab extending prior FBXL19 findings","pmids":["31996894"],"is_preprint":false},{"year":2023,"finding":"SCF(FBXL19) functions as an ISG15 E3 ligase that catalyzes ISGylation of NF-κBp65 in resting endothelial cells. TNFα and endotoxin stimulation reduce p65 ISGylation by FBXL19, promoting p65 serine phosphorylation through reduced association with the phosphatase WIP1. FBXL19 depletion increases p65 phosphorylation and endothelial cell inflammation; EC-specific FBXL19 transgenic mice show reduced lung inflammation and acute lung injury severity.","method":"In vitro ISGylation assay, Co-IP (p65-WIP1 interaction), FBXL19 knockdown in endothelial cells, EC-specific transgenic FBXL19 overexpressing mice in acute lung injury model, immunoblotting for p65 phosphorylation","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ISGylation reconstitution assay, Co-IP for WIP1 interaction, EC-specific transgenic mouse model with defined phenotype, multiple orthogonal methods","pmids":["36994728"],"is_preprint":false},{"year":2023,"finding":"FBXL19 binds FOXM1 and mediates its ubiquitination and proteasomal degradation in lung epithelial cells. In Streptococcus pneumoniae lung infection in immature mice, FBXL19 is downregulated while FOXM1 is upregulated; FBXL19 overexpression reduced lung injury and inflammation, and overexpression of FOXM1 reversed these protective effects.","method":"Co-IP (FBXL19-FOXM1 binding), MG132 proteasome inhibitor treatment, ubiquitination assay, FBXL19 overexpression in mouse model, rescue experiments with FOXM1 overexpression, immunoblotting","journal":"Journal of cardiothoracic surgery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, in vivo mouse model with rescue experiment; single lab, limited method depth in abstract","pmids":["36964598"],"is_preprint":false},{"year":2024,"finding":"FBXL19 (as an SCF E3 ligase subunit) mediates ubiquitination and proteasomal degradation of STK11 in airway epithelial cells; cigarette smoke extract accelerates this process. FBXL19 overexpression led to dose-dependent acceleration of STK11 ubiquitination and degradation. STK11 depletion augments while STK11 overexpression attenuates cigarette smoke-induced cytotoxicity.","method":"FBXL19 screening assay (panel of FBXL E3 ligase subunit transfections), cycloheximide chase for half-life determination, MG132/leupeptin treatment, STK11 overexpression/siRNA knockdown, ubiquitination assay, immunoblotting","journal":"COPD","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — panel screening identified FBXL19, ubiquitination assay, dose-dependent overexpression effect, functional cytotoxicity readout; single lab","pmids":["38712759"],"is_preprint":false},{"year":2025,"finding":"FBXL19 E3 ligase catalyzes K27-linked ubiquitination of STING1 at Lys338, Lys347, and Lys370, marking it for recognition by SQSTM1 and autophagic degradation. EXOC4/SEC8 suppresses this FBXL19-mediated ubiquitination of STING1, thereby stabilizing STING1 and enhancing antiviral type I interferon signaling.","method":"In vitro ubiquitination assay (K27-linkage specificity), site-directed mutagenesis of STING1 ubiquitination sites (K338R, K347R, K370R), Co-IP (FBXL19-STING1 and SQSTM1-STING1 interactions), EXOC4 KO mice challenged with HSV-1, microscale thermophoresis (MST) for binding","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay with linkage specificity, mutagenesis of three acceptor sites, Co-IP, conditional KO mouse with viral challenge phenotype, and MST binding assay; multiple orthogonal methods","pmids":["40413753"],"is_preprint":false},{"year":2004,"finding":"Bioinformatic identification and characterization of FBXL19 as a novel CXXC-domain family member (CXXC11) encoding a 674-amino-acid protein. Domain architecture established: CXXC domain resides within a novel FBXHA domain (aa 11-128), and F-box domain resides within an FBXHB domain (aa 404-674). FBXL19 lacks the JmjC domain present in the paralogs FBXL10/FBXL11.","method":"Bioinformatics/in silico analysis, cDNA assembly from genome sequence, sequence alignment","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of domain function","pmids":["15547684"],"is_preprint":false}],"current_model":"FBXL19 is the F-box subunit of an SCF-type E3 ubiquitin ligase complex that targets diverse substrates—including ST2L (IL-33 receptor), Rac1, RhoA, Rac3, Cdc42, TTF1, FOXM1, STK11, and STING1—for site-specific ubiquitination and proteasomal (or autophagic) degradation, with substrate recognition often gated by prior phosphorylation (by GSK3β, AKT, or Erk2); FBXL19 also functions as an ISG15 E3 ligase to ISGylate NF-κBp65 and modulates endothelial inflammation, and in the nucleus its CxxC domain binds unmethylated CpG islands to recruit CDK-Mediator and Rnf20, thereby priming developmental gene promoters for activation and promoting H2B mono-ubiquitination during stem cell differentiation; FBXL19 stability itself is regulated by CBP-mediated acetylation (stabilizing) and SCFFBXW17-mediated ubiquitination (destabilizing)."},"narrative":{"mechanistic_narrative":"FBXL19 is the substrate-recognition F-box subunit of an SCF-type E3 ubiquitin ligase that controls inflammatory, cytoskeletal, and proliferative signaling by targeting diverse substrates for site-specific ubiquitination and proteasomal degradation, frequently gated by prior substrate phosphorylation [PMID:22660580, PMID:23512198, PMID:23871831]. It degrades the IL-33 receptor ST2L following GSK3β phosphorylation at Ser442, thereby damping IL-33 pro-inflammatory signaling and lessening lung injury [PMID:22660580], and similarly degrades the FOXM1 transcription factor to limit lung inflammation [PMID:36964598]. A coherent theme is its control of Rho-family GTPase signaling: it ubiquitinates Rac1 (at Lys166, requiring AKT phosphorylation of Ser71), RhoA (at Lys135, requiring Erk2 phosphorylation), Rac3 (at Lys166), and Cdc42, suppressing cell migration, lamellipodia formation, and stress-fiber assembly [PMID:23512198, PMID:23871831, PMID:24684802, PMID:29522376]. Additional substrates include TTF1 in thyroid carcinoma cells [PMID:31238008] and STK11 in airway epithelium during cigarette-smoke stress [PMID:38712759]. Beyond canonical ubiquitination, FBXL19 acts as an ISG15 E3 ligase that ISGylates NF-κBp65 to restrain endothelial inflammation [PMID:36994728], and catalyzes K27-linked ubiquitination of STING1 (at Lys338/347/370) to route it for SQSTM1-mediated autophagic degradation and downregulate antiviral type I interferon signaling [PMID:40413753]. In the nucleus, FBXL19 binds unmethylated CpG islands via its CxxC domain and recruits the CDK-Mediator complex and the Rnf20 E3 ligase, priming silent developmental gene promoters—partly through long-range chromatin contacts—and promoting H2B Lys120 mono-ubiquitination during embryonic stem cell differentiation [PMID:29809150, PMID:28453857, PMID:31996894]. FBXL19 abundance is itself regulated: CBP-mediated acetylation stabilizes it and enhances its ligase activity, while SCFFBXW17 ubiquitinates it at Lys114 for degradation [PMID:29522376, PMID:33053230].","teleology":[{"year":2012,"claim":"Established FBXL19 as a functional SCF E3 ligase substrate receptor by showing it degrades the IL-33 receptor ST2L in a phosphorylation-gated manner, linking it to control of inflammatory signaling.","evidence":"Reciprocal Co-IP, in vitro ubiquitination, Ser442 mutagenesis, and mouse pneumonia models in lung epithelial cells","pmids":["22660580"],"confidence":"High","gaps":["Did not define the full SCF complex composition or other Skp/Cullin partners","Generality of phospho-gating beyond ST2L unknown at the time"]},{"year":2013,"claim":"Extended FBXL19 substrate scope to Rho-family GTPases, showing it degrades Rac1 and RhoA at defined lysines following AKT- or Erk2-mediated phosphorylation, establishing a role in cytoskeletal and migratory control.","evidence":"F-box library screening, in vitro ubiquitination, Co-IP, phospho- and ubiquitin-site mutagenesis, and migration/cytoskeleton assays in MLE12/lung epithelial cells","pmids":["23512198","23871831"],"confidence":"High","gaps":["Kinase-to-FBXL19 coupling mechanism not resolved","Whether different GTPases compete for the same FBXL19 pool unknown"]},{"year":2014,"claim":"Showed substrate specificity is encoded in FBXL19 domain architecture by mapping Rac3 recognition to the C-terminus, with N-terminal truncation enhancing degradation.","evidence":"Co-IP, K166R mutagenesis, FBXL19 truncation variants, and TGFβ1/E-cadherin readouts in esophageal cancer cells","pmids":["24684802"],"confidence":"Medium","gaps":["Single lab; reciprocal validation limited","Structural basis of C-terminal Rac3 binding not defined"]},{"year":2017,"claim":"Revealed a non-degradative nuclear function: FBXL19 binds CpG islands via its CxxC domain and partners with Rnf20 to promote H2Bub1 at target promoters during ES cell differentiation.","evidence":"ChIP-seq, Fbxl19-Rnf20 Co-IP, gain/loss-of-function with global H2Bub1 quantification, and differentiation assays in mouse ES cells","pmids":["28453857"],"confidence":"High","gaps":["How the same protein partitions between E3 ligase and chromatin roles unknown","Whether SCF activity contributes to H2Bub1 unresolved"]},{"year":2018,"claim":"Defined regulation of FBXL19 stability and additional GTPase substrate Cdc42, showing CBP acetylation extends FBXL19 half-life and boosts its ligase activity.","evidence":"Co-IP, cycloheximide chase, MG132, acetylation-mimic mutagenesis, CBP perturbation, and in vitro Cdc42 ubiquitination","pmids":["29522376"],"confidence":"Medium","gaps":["Acetylated residues not fully mapped","Deacetylase responsible not identified"]},{"year":2018,"claim":"Demonstrated CpG-island recognition by FBXL19 recruits CDK-Mediator to prime developmental gene promoters and is essential for mouse development.","evidence":"ChIP-seq, Co-IP for CDK-Mediator, and FBXL19 knockout with developmental/differentiation phenotypes in mouse ES cells","pmids":["29809150"],"confidence":"High","gaps":["Mechanism linking Mediator recruitment to delayed activation unclear","Relationship between Mediator recruitment and Rnf20/H2Bub1 not integrated"]},{"year":2019,"claim":"Showed FBXL19 substrate selection can be cell-type specific (TTF1 in thyroid carcinoma) and that FBXL19 itself is a miR-26 target controlling adipocyte progenitor differentiation.","evidence":"Co-IP, K151R mutagenesis, cell-type-specific overexpression (FBXL19/HECW1); miR-26 locus deletion, transgenic overexpression, and adipogenesis assays","pmids":["31238008","31488578"],"confidence":"Medium","gaps":["Determinant of cell-type-specific E3 choice unknown","Molecular mechanism of FBXL19 in adipogenesis not resolved"]},{"year":2020,"claim":"Identified FBXL19's destabilizer (SCFFBXW17) and showed FBXL19-CDK-Mediator supports long-range promoter–distal-element contacts via an atypical enhancer mechanism.","evidence":"Co-IP, K114R mutagenesis, FBXW17 perturbation, migration assays; chromatin conformation capture and targeted genomic deletions in ESCs","pmids":["33053230","31996894"],"confidence":"Medium","gaps":["How distal elements act without H3K27ac unclear","Single-lab chromatin findings"]},{"year":2023,"claim":"Expanded FBXL19's modifier repertoire to ISG15, showing it ISGylates NF-κBp65 to restrain endothelial inflammation, and confirmed FOXM1 as a degradative substrate in lung infection.","evidence":"In vitro ISGylation assay, p65-WIP1 Co-IP, EC-specific transgenic mice in lung injury; FBXL19-FOXM1 Co-IP, ubiquitination, and rescue in mouse infection model","pmids":["36994728","36964598"],"confidence":"High","gaps":["Structural basis for dual Ub/ISG15 ligase activity unknown","How stimulation switches between modifications unresolved"]},{"year":2024,"claim":"Demonstrated linkage-specific and degradation-route diversification: FBXL19 degrades STK11 in smoke-stressed airway epithelium and catalyzes K27-linked ubiquitination routing STING1 to autophagy, dampening antiviral interferon signaling.","evidence":"FBXL panel screening, chase, ubiquitination assays for STK11; K27-specific in vitro ubiquitination, triple-site STING1 mutagenesis, Co-IP, EXOC4 KO mice with HSV-1 challenge, and MST","pmids":["38712759","40413753"],"confidence":"High","gaps":["Determinants of ubiquitin linkage choice (K48 vs K27) unknown","How EXOC4 antagonism is regulated unclear"]},{"year":null,"claim":"How FBXL19 integrates its cytoplasmic degradative E3/ISG15 ligase activities with its nuclear CpG-island/chromatin-priming role, and what governs substrate and ubiquitin-linkage selection, remains unresolved.","evidence":"No single study reconciles the cytoplasmic and nuclear functions or defines the structural basis of substrate/linkage choice","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate or CpG recognition","Spatial partitioning between nucleus and cytoplasm uncharacterized","Rules for K48 vs K27 vs ISGylation outputs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,7,12,13,14]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,11,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,11,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,10]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]}],"complexes":["SCF (SKP1-Cullin-F-box) E3 ubiquitin ligase","CDK-Mediator"],"partners":["ST2L","RAC1","RHOA","RNF20","STING1","FOXM1","EXOC4","CBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PCT2","full_name":"F-box/LRR-repeat protein 19","aliases":["F-box and leucine-rich repeat protein 19"],"length_aa":694,"mass_kda":75.7,"function":"Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that plays a role in different processes including cell migration, cell proliferation or cytoskeletal reorganization (PubMed:24684802, PubMed:29522376). Mediates RHOA ubiquitination and degradation in a ERK2-dependent manner (PubMed:23871831). Induces RAC1 and RAC3 degradation by the proteasome system and thereby regulates TGFB1-induced E-cadherin down-regulation and cell migration (PubMed:23512198, PubMed:24684802). Also mediates ubiquitination and degradation of IL-33-induced receptor IL1RL1 and subsequently blocks IL-33-mediated apoptosis (By similarity). Within the nucleus, binds to DNA containing unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides (PubMed:29276034). Recruits CDK-mediator to chromatin and targets CDK8 to promoters of silent developmental genes leading to induction of these genes during cell differentiation. In addition, plays a critical role in the recruitment of RNF20 to histone H2B leading to H2B mono-ubiquitination (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6PCT2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXL19","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MED19","stoichiometry":10.0},{"gene":"MED29","stoichiometry":0.2},{"gene":"PSME3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FBXL19","total_profiled":1310},"omim":[{"mim_id":"609085","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 19; FBXL19","url":"https://www.omim.org/entry/609085"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXL19"},"hgnc":{"alias_symbol":["DKFZp434K0410","Fbl19","JHDM1C","CXXC11"],"prev_symbol":[]},"alphafold":{"accession":"Q6PCT2","domains":[{"cath_id":"-","chopping":"34-81","consensus_level":"medium","plddt":89.1002,"start":34,"end":81},{"cath_id":"3.30.40.10","chopping":"90-155","consensus_level":"medium","plddt":85.2774,"start":90,"end":155},{"cath_id":"1.20.1280","chopping":"422-460","consensus_level":"medium","plddt":90.7867,"start":422,"end":460},{"cath_id":"3.80.10.10","chopping":"545-555_570-694","consensus_level":"medium","plddt":87.7869,"start":545,"end":694}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PCT2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PCT2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PCT2-F1-predicted_aligned_error_v6.png","plddt_mean":66.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXL19","jax_strain_url":"https://www.jax.org/strain/search?query=FBXL19"},"sequence":{"accession":"Q6PCT2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PCT2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PCT2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PCT2"}},"corpus_meta":[{"pmid":"22660580","id":"PMC_22660580","title":"F-box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation.","date":"2012","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22660580","citation_count":126,"is_preprint":false},{"pmid":"23871831","id":"PMC_23871831","title":"A new mechanism of RhoA ubiquitination and degradation: roles of SCF(FBXL19) E3 ligase and Erk2.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23871831","citation_count":77,"is_preprint":false},{"pmid":"23512198","id":"PMC_23512198","title":"SCF E3 ligase F-box protein complex SCF(FBXL19) regulates cell migration by mediating Rac1 ubiquitination and degradation.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/23512198","citation_count":68,"is_preprint":false},{"pmid":"31488578","id":"PMC_31488578","title":"miR-26 suppresses adipocyte progenitor differentiation and fat production by targeting Fbxl19.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/31488578","citation_count":59,"is_preprint":false},{"pmid":"24684802","id":"PMC_24684802","title":"F-box protein complex FBXL19 regulates TGFβ1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24684802","citation_count":56,"is_preprint":false},{"pmid":"28479250","id":"PMC_28479250","title":"Long non-coding RNA FBXL19-AS1 plays oncogenic role in colorectal cancer by sponging miR-203.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28479250","citation_count":39,"is_preprint":false},{"pmid":"30610161","id":"PMC_30610161","title":"FBXL19-AS1 exerts oncogenic function by sponging miR-431-5p to regulate RAF1 expression in lung 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interactions.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31996894","citation_count":11,"is_preprint":false},{"pmid":"33474753","id":"PMC_33474753","title":"lncRNA FBXL19-AS1 is a diagnosis biomarker for paediatric patients with acute myeloid leukemia.","date":"2021","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33474753","citation_count":11,"is_preprint":false},{"pmid":"15547684","id":"PMC_15547684","title":"Identification and characterization of FBXL19 gene in silico.","date":"2004","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15547684","citation_count":10,"is_preprint":false},{"pmid":"28453857","id":"PMC_28453857","title":"Fbxl19 recruitment to CpG islands is required for Rnf20-mediated H2B mono-ubiquitination.","date":"2017","source":"Nucleic acids 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Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34564989","citation_count":7,"is_preprint":false},{"pmid":"36994728","id":"PMC_36994728","title":"ISGylation of NF-κBp65 by SCFFBXL19 E3 Ligase Diminishes Endothelial Inflammation.","date":"2023","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36994728","citation_count":6,"is_preprint":false},{"pmid":"38712759","id":"PMC_38712759","title":"FBXL19 Targeted STK11 Degradation Enhances Cigarette Smoke-Induced Airway Epithelial Cell Cytotoxicity.","date":"2024","source":"COPD","url":"https://pubmed.ncbi.nlm.nih.gov/38712759","citation_count":5,"is_preprint":false},{"pmid":"36964598","id":"PMC_36964598","title":"Protective role of FBXL19 in Streptococcus pneumoniae-induced lung injury in pneumonia immature mice.","date":"2023","source":"Journal of cardiothoracic 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zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/33164374","citation_count":4,"is_preprint":false},{"pmid":"38702967","id":"PMC_38702967","title":"Exploring the regulatory role of FBXL19-AS1 in triple-negative breast cancer through the miR-378a-3p/OTUB2 axis.","date":"2024","source":"Cell biochemistry and function","url":"https://pubmed.ncbi.nlm.nih.gov/38702967","citation_count":3,"is_preprint":false},{"pmid":"38898675","id":"PMC_38898675","title":"Significant Correlation Between Cutaneous Abundance of Streptococcus and Psoriasis Severity in Patients with FBXL19 Gene Variants.","date":"2024","source":"Acta dermato-venereologica","url":"https://pubmed.ncbi.nlm.nih.gov/38898675","citation_count":3,"is_preprint":false},{"pmid":"34278444","id":"PMC_34278444","title":"FBXL19‑AS1 promotes the progression of nasopharyngeal carcinoma by acting as a competing endogenous RNA to sponge miR‑431 and upregulate 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Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39150394","citation_count":2,"is_preprint":false},{"pmid":"37954363","id":"PMC_37954363","title":"CIZ1 aggravates gastric cancer progression via mediating FBXL19-AS1 and miR-339-3p.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37954363","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24312,"output_tokens":5315,"usd":0.07633,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13332,"output_tokens":4216,"usd":0.08603,"stage2_stop_reason":"end_turn"},"total_usd":0.16236,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"FBXL19, as the F-box subunit of an SCF E3 ubiquitin ligase complex, binds ST2L (the IL-33 receptor) and mediates its polyubiquitination and proteasomal degradation. GSK3β-catalyzed phosphorylation of ST2L at Ser442 is required for FBXL19-mediated ST2L degradation. FBXL19 overexpression abrogated IL-33/ST2L pro-inflammatory and pro-apoptotic signaling and lessened lung injury severity in mouse pneumonia models.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (Ser442), proteasome inhibitor treatment, overexpression/knockdown in lung epithelial cells, mouse pneumonia models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro ubiquitination assay, mutagenesis of phosphorylation site, and in vivo mouse model across multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"22660580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCF(FBXL19) E3 ubiquitin ligase targets Rac1 for polyubiquitination and proteasomal degradation. AKT-mediated phosphorylation of Rac1 at Ser71 is required for FBXL19-mediated ubiquitination. Lys166 within Rac1 is the ubiquitination acceptor site. FBXL19 overexpression reduced cell migration and diminished lamellipodia formation; Rac1(S71A) and Rac1(K166R) mutants were resistant to FBXL19-mediated degradation.\",\n      \"method\": \"F-box protein library screening, in vitro ubiquitination assay, Co-IP, site-directed mutagenesis (Rac1 S71A, K166R), cell migration assay, FBXL19 overexpression/knockdown in MLE12 cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination reconstitution, reciprocal Co-IP, mutagenesis of both phosphorylation and ubiquitination sites, functional cell migration readout\",\n      \"pmids\": [\"23512198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SCF(FBXL19) E3 ubiquitin ligase targets RhoA for ubiquitination at Lys135 and proteasomal degradation in lung epithelial cells. Erk2-mediated phosphorylation of RhoA is both necessary and sufficient for SCF(FBXL19)-mediated RhoA ubiquitination and degradation. RhoA(K135R) mutant was resistant to FBXL19-mediated degradation. FBXL19 expression reduced p27 phosphorylation, cell proliferation, LPA-induced MLC phosphorylation, and stress fiber formation.\",\n      \"method\": \"Co-IP, in vitro ubiquitination assay, site-directed mutagenesis (RhoA K135R), cycloheximide chase, FBXL19 overexpression/knockdown, cell proliferation and cytoskeleton assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay, Co-IP, mutagenesis of ubiquitination site, Erk2 phosphorylation requirement validated, multiple functional readouts\",\n      \"pmids\": [\"23871831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SCF(FBXL19) interacts with and polyubiquitinates Rac3 at Lys166, targeting it for proteasomal degradation. The C-terminus of FBXL19 is required for Rac3 interaction and ubiquitination, while N-terminal truncation increases Rac3 degradation. FBXL19 overexpression attenuated TGFβ1-induced E-cadherin downregulation and esophageal cancer cell elongation, linking Rac3 degradation to TGFβ1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, site-directed mutagenesis (Rac3 K166R), FBXL19 truncation variants, overexpression/knockdown in esophageal cancer cells (OE19, OE33), immunostaining\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, domain mapping by truncation mutants, ubiquitination assay, functional TGFβ1/E-cadherin readout; single lab\",\n      \"pmids\": [\"24684802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXL19 is an unstable protein (half-life ~3 h) degraded by the ubiquitin-proteasome system. The acetyltransferase CBP acetylates FBXL19, reducing its ubiquitination and extending its half-life. Acetylation-mimicking FBXL19 mutants exhibit longer half-lives. CBP-mediated stabilization of FBXL19 enhances SCF(FBXL19) E3 ligase activity, promoting Cdc42 ubiquitination and degradation; CBP inhibition reverses these effects.\",\n      \"method\": \"Co-IP, cycloheximide chase, proteasome inhibitor (MG132) treatment, acetyltransferase/deacetylase inhibitor assays, acetylation-mimic mutagenesis, CBP overexpression/knockdown, in vitro ubiquitination of Cdc42\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, chase, mutagenesis, inhibitor studies) in single lab\",\n      \"pmids\": [\"29522376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXL19 is a CpG island-binding protein in mouse embryonic stem (ES) cells that associates with the CDK-Mediator complex. FBXL19 recruits CDK-Mediator to CpG island-associated promoters of non-transcribed developmental genes, priming them for activation during cell lineage commitment. Recognition of CpG islands by FBXL19 is essential for mouse development.\",\n      \"method\": \"Genome-wide chromatin immunoprecipitation (ChIP-seq), Co-IP/protein interaction studies identifying CDK-Mediator association, genetic knockout of FBXL19 in mouse ES cells with developmental phenotype readout, differentiation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq genome-wide occupancy, Co-IP identifying CDK-Mediator complex, genetic KO with developmental and differentiation phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29809150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fbxl19, via its CxxC domain, binds CpG island-containing promoters and physically interacts with Rnf20 E3 ligase. Fbxl19 promotes H2B Lys120 mono-ubiquitination (H2Bub1) at CpG island-containing gene promoters; upregulation of Fbxl19 increases global H2Bub1 in mouse ES cells while downregulation reduces it. Chromosomal binding of Fbxl19 is required for H2Bub1 at its target loci, and Fbxl19 is required for proper ES cell differentiation in collaboration with Rnf20.\",\n      \"method\": \"ChIP-seq (genome-wide occupancy mapping), Co-IP (Fbxl19-Rnf20 interaction), Fbxl19 overexpression/knockdown in mouse ES cells, quantification of global H2Bub1 by immunoblot, ES cell differentiation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, reciprocal Co-IP for Rnf20 interaction, gain/loss-of-function with H2Bub1 quantification, differentiation phenotype readout\",\n      \"pmids\": [\"28453857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FBXL19 mediates ubiquitination and degradation of TTF1 (thyroid transcription factor 1) in follicular thyroid carcinoma (FTC133) cells but not in normal thyroid epithelial cells (Htori3). Lys151 of TTF1 is the ubiquitin acceptor site in both cell types, but cell-type-specific E3 ligases (FBXL19 in FTC133 vs. HECW1 in Htori3) govern its degradation.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis (TTF1 K151R), FBXL19 and HECW1 overexpression in FTC133 and Htori3 cells, immunoblotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, mutagenesis of ubiquitination site, cell-type-specific overexpression; single lab\",\n      \"pmids\": [\"31238008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-26 family members suppress adipocyte progenitor cell differentiation by repressing expression of Fbxl19, a conserved miR-26 target. Fbxl19 plays a cell-autonomous role in adipocyte progenitor differentiation; its repression by miR-26 blocks adipogenesis in vivo.\",\n      \"method\": \"Genetic deletion of all miR-26-encoding loci in mice, transgenic overexpression of miR-26a, identification of Fbxl19 as miR-26 target by bioinformatics and reporter assays, cell-autonomous adipogenesis assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and transgenic OE in vivo, target validation; Fbxl19 specifically identified as the downstream effector but mechanism of Fbxl19 action in adipogenesis not fully resolved mechanistically\",\n      \"pmids\": [\"31488578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SCFFBXW17 E3 ubiquitin ligase ubiquitinates FBXL19 and induces its proteasomal degradation; Lys114 of FBXL19 is identified as the ubiquitin acceptor site. Acetylation of FBXL19 attenuates SCFFBXW17-mediated FBXL19 degradation. FBXW17 overexpression reduces FBXL19 levels, attenuating SCF(FBXL19)-mediated Rac1 degradation and cell migration suppression; FBXW17 knockdown attenuates LPA-induced lamellipodia formation.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis (FBXL19 K114R), FBXW17 overexpression/knockdown, cycloheximide chase, cell migration and lamellipodia assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, mutagenesis of acceptor site, functional migration readout; single lab\",\n      \"pmids\": [\"33053230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXL19 and CDK-Mediator support long-range chromatin interactions between silent developmental gene promoters and atypical distal regulatory elements in mouse ESCs. These distal elements are required for appropriate gene induction during differentiation, as shown by targeted deletions. During gene activation, most distal elements do not acquire H3K27ac and lose interaction with their target promoters, indicating an atypical enhancer mechanism.\",\n      \"method\": \"Chromatin conformation capture / 3D genome interaction assays (Hi-C or similar), targeted genomic deletions, gene expression analysis during ESC differentiation, FBXL19 and CDK-Mediator ChIP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin conformation assays, targeted deletions with functional readout, single lab extending prior FBXL19 findings\",\n      \"pmids\": [\"31996894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SCF(FBXL19) functions as an ISG15 E3 ligase that catalyzes ISGylation of NF-κBp65 in resting endothelial cells. TNFα and endotoxin stimulation reduce p65 ISGylation by FBXL19, promoting p65 serine phosphorylation through reduced association with the phosphatase WIP1. FBXL19 depletion increases p65 phosphorylation and endothelial cell inflammation; EC-specific FBXL19 transgenic mice show reduced lung inflammation and acute lung injury severity.\",\n      \"method\": \"In vitro ISGylation assay, Co-IP (p65-WIP1 interaction), FBXL19 knockdown in endothelial cells, EC-specific transgenic FBXL19 overexpressing mice in acute lung injury model, immunoblotting for p65 phosphorylation\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ISGylation reconstitution assay, Co-IP for WIP1 interaction, EC-specific transgenic mouse model with defined phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"36994728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXL19 binds FOXM1 and mediates its ubiquitination and proteasomal degradation in lung epithelial cells. In Streptococcus pneumoniae lung infection in immature mice, FBXL19 is downregulated while FOXM1 is upregulated; FBXL19 overexpression reduced lung injury and inflammation, and overexpression of FOXM1 reversed these protective effects.\",\n      \"method\": \"Co-IP (FBXL19-FOXM1 binding), MG132 proteasome inhibitor treatment, ubiquitination assay, FBXL19 overexpression in mouse model, rescue experiments with FOXM1 overexpression, immunoblotting\",\n      \"journal\": \"Journal of cardiothoracic surgery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, in vivo mouse model with rescue experiment; single lab, limited method depth in abstract\",\n      \"pmids\": [\"36964598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXL19 (as an SCF E3 ligase subunit) mediates ubiquitination and proteasomal degradation of STK11 in airway epithelial cells; cigarette smoke extract accelerates this process. FBXL19 overexpression led to dose-dependent acceleration of STK11 ubiquitination and degradation. STK11 depletion augments while STK11 overexpression attenuates cigarette smoke-induced cytotoxicity.\",\n      \"method\": \"FBXL19 screening assay (panel of FBXL E3 ligase subunit transfections), cycloheximide chase for half-life determination, MG132/leupeptin treatment, STK11 overexpression/siRNA knockdown, ubiquitination assay, immunoblotting\",\n      \"journal\": \"COPD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — panel screening identified FBXL19, ubiquitination assay, dose-dependent overexpression effect, functional cytotoxicity readout; single lab\",\n      \"pmids\": [\"38712759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXL19 E3 ligase catalyzes K27-linked ubiquitination of STING1 at Lys338, Lys347, and Lys370, marking it for recognition by SQSTM1 and autophagic degradation. EXOC4/SEC8 suppresses this FBXL19-mediated ubiquitination of STING1, thereby stabilizing STING1 and enhancing antiviral type I interferon signaling.\",\n      \"method\": \"In vitro ubiquitination assay (K27-linkage specificity), site-directed mutagenesis of STING1 ubiquitination sites (K338R, K347R, K370R), Co-IP (FBXL19-STING1 and SQSTM1-STING1 interactions), EXOC4 KO mice challenged with HSV-1, microscale thermophoresis (MST) for binding\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay with linkage specificity, mutagenesis of three acceptor sites, Co-IP, conditional KO mouse with viral challenge phenotype, and MST binding assay; multiple orthogonal methods\",\n      \"pmids\": [\"40413753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bioinformatic identification and characterization of FBXL19 as a novel CXXC-domain family member (CXXC11) encoding a 674-amino-acid protein. Domain architecture established: CXXC domain resides within a novel FBXHA domain (aa 11-128), and F-box domain resides within an FBXHB domain (aa 404-674). FBXL19 lacks the JmjC domain present in the paralogs FBXL10/FBXL11.\",\n      \"method\": \"Bioinformatics/in silico analysis, cDNA assembly from genome sequence, sequence alignment\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of domain function\",\n      \"pmids\": [\"15547684\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXL19 is the F-box subunit of an SCF-type E3 ubiquitin ligase complex that targets diverse substrates—including ST2L (IL-33 receptor), Rac1, RhoA, Rac3, Cdc42, TTF1, FOXM1, STK11, and STING1—for site-specific ubiquitination and proteasomal (or autophagic) degradation, with substrate recognition often gated by prior phosphorylation (by GSK3β, AKT, or Erk2); FBXL19 also functions as an ISG15 E3 ligase to ISGylate NF-κBp65 and modulates endothelial inflammation, and in the nucleus its CxxC domain binds unmethylated CpG islands to recruit CDK-Mediator and Rnf20, thereby priming developmental gene promoters for activation and promoting H2B mono-ubiquitination during stem cell differentiation; FBXL19 stability itself is regulated by CBP-mediated acetylation (stabilizing) and SCFFBXW17-mediated ubiquitination (destabilizing).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXL19 is the substrate-recognition F-box subunit of an SCF-type E3 ubiquitin ligase that controls inflammatory, cytoskeletal, and proliferative signaling by targeting diverse substrates for site-specific ubiquitination and proteasomal degradation, frequently gated by prior substrate phosphorylation [#0, #1, #2]. It degrades the IL-33 receptor ST2L following GSK3\\u03b2 phosphorylation at Ser442, thereby damping IL-33 pro-inflammatory signaling and lessening lung injury [#0], and similarly degrades the FOXM1 transcription factor to limit lung inflammation [#12]. A coherent theme is its control of Rho-family GTPase signaling: it ubiquitinates Rac1 (at Lys166, requiring AKT phosphorylation of Ser71), RhoA (at Lys135, requiring Erk2 phosphorylation), Rac3 (at Lys166), and Cdc42, suppressing cell migration, lamellipodia formation, and stress-fiber assembly [#1, #2, #3, #4]. Additional substrates include TTF1 in thyroid carcinoma cells [#7] and STK11 in airway epithelium during cigarette-smoke stress [#13]. Beyond canonical ubiquitination, FBXL19 acts as an ISG15 E3 ligase that ISGylates NF-\\u03baBp65 to restrain endothelial inflammation [#11], and catalyzes K27-linked ubiquitination of STING1 (at Lys338/347/370) to route it for SQSTM1-mediated autophagic degradation and downregulate antiviral type I interferon signaling [#14]. In the nucleus, FBXL19 binds unmethylated CpG islands via its CxxC domain and recruits the CDK-Mediator complex and the Rnf20 E3 ligase, priming silent developmental gene promoters\\u2014partly through long-range chromatin contacts\\u2014and promoting H2B Lys120 mono-ubiquitination during embryonic stem cell differentiation [#5, #6, #10]. FBXL19 abundance is itself regulated: CBP-mediated acetylation stabilizes it and enhances its ligase activity, while SCFFBXW17 ubiquitinates it at Lys114 for degradation [#4, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established FBXL19 as a functional SCF E3 ligase substrate receptor by showing it degrades the IL-33 receptor ST2L in a phosphorylation-gated manner, linking it to control of inflammatory signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro ubiquitination, Ser442 mutagenesis, and mouse pneumonia models in lung epithelial cells\",\n      \"pmids\": [\"22660580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full SCF complex composition or other Skp/Cullin partners\", \"Generality of phospho-gating beyond ST2L unknown at the time\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended FBXL19 substrate scope to Rho-family GTPases, showing it degrades Rac1 and RhoA at defined lysines following AKT- or Erk2-mediated phosphorylation, establishing a role in cytoskeletal and migratory control.\",\n      \"evidence\": \"F-box library screening, in vitro ubiquitination, Co-IP, phospho- and ubiquitin-site mutagenesis, and migration/cytoskeleton assays in MLE12/lung epithelial cells\",\n      \"pmids\": [\"23512198\", \"23871831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase-to-FBXL19 coupling mechanism not resolved\", \"Whether different GTPases compete for the same FBXL19 pool unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed substrate specificity is encoded in FBXL19 domain architecture by mapping Rac3 recognition to the C-terminus, with N-terminal truncation enhancing degradation.\",\n      \"evidence\": \"Co-IP, K166R mutagenesis, FBXL19 truncation variants, and TGF\\u03b21/E-cadherin readouts in esophageal cancer cells\",\n      \"pmids\": [\"24684802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation limited\", \"Structural basis of C-terminal Rac3 binding not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-degradative nuclear function: FBXL19 binds CpG islands via its CxxC domain and partners with Rnf20 to promote H2Bub1 at target promoters during ES cell differentiation.\",\n      \"evidence\": \"ChIP-seq, Fbxl19-Rnf20 Co-IP, gain/loss-of-function with global H2Bub1 quantification, and differentiation assays in mouse ES cells\",\n      \"pmids\": [\"28453857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same protein partitions between E3 ligase and chromatin roles unknown\", \"Whether SCF activity contributes to H2Bub1 unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined regulation of FBXL19 stability and additional GTPase substrate Cdc42, showing CBP acetylation extends FBXL19 half-life and boosts its ligase activity.\",\n      \"evidence\": \"Co-IP, cycloheximide chase, MG132, acetylation-mimic mutagenesis, CBP perturbation, and in vitro Cdc42 ubiquitination\",\n      \"pmids\": [\"29522376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylated residues not fully mapped\", \"Deacetylase responsible not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated CpG-island recognition by FBXL19 recruits CDK-Mediator to prime developmental gene promoters and is essential for mouse development.\",\n      \"evidence\": \"ChIP-seq, Co-IP for CDK-Mediator, and FBXL19 knockout with developmental/differentiation phenotypes in mouse ES cells\",\n      \"pmids\": [\"29809150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Mediator recruitment to delayed activation unclear\", \"Relationship between Mediator recruitment and Rnf20/H2Bub1 not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed FBXL19 substrate selection can be cell-type specific (TTF1 in thyroid carcinoma) and that FBXL19 itself is a miR-26 target controlling adipocyte progenitor differentiation.\",\n      \"evidence\": \"Co-IP, K151R mutagenesis, cell-type-specific overexpression (FBXL19/HECW1); miR-26 locus deletion, transgenic overexpression, and adipogenesis assays\",\n      \"pmids\": [\"31238008\", \"31488578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinant of cell-type-specific E3 choice unknown\", \"Molecular mechanism of FBXL19 in adipogenesis not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified FBXL19's destabilizer (SCFFBXW17) and showed FBXL19-CDK-Mediator supports long-range promoter\\u2013distal-element contacts via an atypical enhancer mechanism.\",\n      \"evidence\": \"Co-IP, K114R mutagenesis, FBXW17 perturbation, migration assays; chromatin conformation capture and targeted genomic deletions in ESCs\",\n      \"pmids\": [\"33053230\", \"31996894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distal elements act without H3K27ac unclear\", \"Single-lab chromatin findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded FBXL19's modifier repertoire to ISG15, showing it ISGylates NF-\\u03baBp65 to restrain endothelial inflammation, and confirmed FOXM1 as a degradative substrate in lung infection.\",\n      \"evidence\": \"In vitro ISGylation assay, p65-WIP1 Co-IP, EC-specific transgenic mice in lung injury; FBXL19-FOXM1 Co-IP, ubiquitination, and rescue in mouse infection model\",\n      \"pmids\": [\"36994728\", \"36964598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for dual Ub/ISG15 ligase activity unknown\", \"How stimulation switches between modifications unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated linkage-specific and degradation-route diversification: FBXL19 degrades STK11 in smoke-stressed airway epithelium and catalyzes K27-linked ubiquitination routing STING1 to autophagy, dampening antiviral interferon signaling.\",\n      \"evidence\": \"FBXL panel screening, chase, ubiquitination assays for STK11; K27-specific in vitro ubiquitination, triple-site STING1 mutagenesis, Co-IP, EXOC4 KO mice with HSV-1 challenge, and MST\",\n      \"pmids\": [\"38712759\", \"40413753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of ubiquitin linkage choice (K48 vs K27) unknown\", \"How EXOC4 antagonism is regulated unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FBXL19 integrates its cytoplasmic degradative E3/ISG15 ligase activities with its nuclear CpG-island/chromatin-priming role, and what governs substrate and ubiquitin-linkage selection, remains unresolved.\",\n      \"evidence\": \"No single study reconciles the cytoplasmic and nuclear functions or defines the structural basis of substrate/linkage choice\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate or CpG recognition\", \"Spatial partitioning between nucleus and cytoplasm uncharacterized\", \"Rules for K48 vs K27 vs ISGylation outputs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7, 12, 13, 14]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 11, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 11, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\"SCF (SKP1-Cullin-F-box) E3 ubiquitin ligase\", \"CDK-Mediator\"],\n    \"partners\": [\"ST2L\", \"RAC1\", \"RHOA\", \"RNF20\", \"STING1\", \"FOXM1\", \"EXOC4\", \"CBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}