{"gene":"FBXO2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1998,"finding":"NFB42 (FBXO2) contains an F-box motif, interacts with Skp1p (OCP2/SKP1), and full-length NFB42 (but not an F-box deletion mutant) inhibits cell proliferation when transfected into neuroblastoma and CHO cells, placing it in the ubiquitin-proteasome pathway.","method":"Transfection-based growth assay, co-immunoprecipitation with Skp1p, F-box deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction and functional mutagenesis, single lab","pmids":["9857061"],"is_preprint":false},{"year":2003,"finding":"FBXO2 (NFB42) binds the phosphorylated HSV-1 replication initiator protein UL9, leading to its polyubiquitination and degradation by the 26S proteasome; interaction is phosphorylation-dependent.","method":"Co-expression in 293T cells, proteasome inhibitor (MG132) rescue, in vivo polyubiquitination assay, yeast two-hybrid","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal assays (ubiquitination, proteasome inhibition, phosphorylation-dependence) in single study","pmids":["12904574"],"is_preprint":false},{"year":2004,"finding":"HSV-1 infection induces nuclear shuttling of NFB42 (FBXO2), allowing it to bind nuclear phosphorylated UL9 protein and mediate its export to the cytosol for ubiquitination and proteasomal degradation, thereby promoting viral latency in neurons.","method":"Live-cell imaging of nuclear shuttling in 293T cells and primary hippocampal neurons, co-immunoprecipitation, proteasome inhibitor rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — orthogonal methods (localization, co-IP, functional rescue), replicated in two cell types","pmids":["15010529"],"is_preprint":false},{"year":2004,"finding":"OCP1 (FBXO2) forms a heterodimeric complex with OCP2 (Skp1) and directly binds connexin 26 (Cx26), as demonstrated by pull-down assays and co-immunoprecipitation from organ of Corti extracts, suggesting Cx26 is a substrate of SCF(OCP1).","method":"Electrophoretic mobility-shift assay, pull-down with immobilized OCP1, in vitro transcription-translation binding, co-immunoprecipitation from organ of Corti","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple binding assays including in vivo co-IP, single lab","pmids":["15109709"],"is_preprint":false},{"year":2005,"finding":"Fbs1 (FBXO2) preferentially recognizes the Man3GlcNAc2 core pentasaccharide of N-linked high-mannose glycans; thermodynamic analysis showed the chitobiose and α1→6-linked Man residue are required for binding.","method":"In vitro binding assays with chemically synthesized sugar chains, thermodynamic (ITC-type) analysis","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with defined synthetic substrates","pmids":["15857118"],"is_preprint":false},{"year":2007,"finding":"Crystal structures of the Skp1-Fbs1 complex and Fbs1 sugar-binding domain (SBD) bound to glycoprotein revealed that Fbs1 primarily recognizes Man3GlcNAc2 via the SBD, and a linker segment between the F-box and SBD domains undergoes relative motion potentially enabling recognition of different acceptor lysines for ubiquitination.","method":"X-ray crystallography of Skp1-Fbs1 complex and SBD-glycoprotein complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional interpretation, moderate citation count","pmids":["17389369"],"is_preprint":false},{"year":2007,"finding":"In vivo, the majority of Fbs1 (FBXO2) exists as Fbs1-Skp1 heterodimers or monomers rather than canonical SCF complexes; restricted SCF complex formation is due to the short linker between the F-box and sugar-binding domains. Additionally, Fbs1 independently suppresses glycoprotein aggregation via its N-terminal sequence, functioning as a chaperone independent of ubiquitin ligase activity.","method":"Gel filtration, immunoprecipitation, in vitro aggregation assay, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal biochemical methods establishing dual functions","pmids":["17215248"],"is_preprint":false},{"year":2007,"finding":"Fbx2 (FBXO2) knockout mice develop age-related cochlear degeneration beginning at 2 months; cochlear Fbx2 binds Skp1 but forms a novel heterodimeric complex rather than canonical SCF complex in this tissue, as other SCF components show little complex formation with Fbx2/Skp1.","method":"Targeted gene knockout mouse model, co-immunoprecipitation, histological analysis, Western blot","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with defined phenotype plus biochemical characterization of complex","pmids":["17494702"],"is_preprint":false},{"year":2011,"finding":"Fbs1 (FBXO2) directly binds Nogo receptor 2 (NgR2) through its substrate recognition domain, leading to NgR2 polyubiquitination and proteasomal degradation.","method":"Pull-down assay, co-immunoprecipitation, in vitro binding assay, ubiquitination assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple binding assays but single lab","pmids":["22206664"],"is_preprint":false},{"year":2014,"finding":"Fbxo2 binds APP (amyloid precursor protein), a high-mannose glycoprotein, and promotes its ubiquitin-mediated degradation; loss of Fbxo2 in knockout mice increases APP levels and its cleavage products in hippocampal neurons, and reduces APP at the cell surface.","method":"In vitro ubiquitination assay, Fbxo2 KO mouse brain analysis, cultured hippocampal neurons, hippocampal slices, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo evidence with defined substrate, KO mouse model","pmids":["24469452"],"is_preprint":false},{"year":2015,"finding":"Loss of Fbxo2 in knockout mice increases GluN1 and GluN2A (but not GluN2B) NMDA receptor subunit levels, promotes greater surface localization of GluN1 and GluN2A, and increases axo-dendritic shaft synapses without altering dendritic spine density or neurophysiology.","method":"Fbxo2 KO mouse model, Western blot, surface biotinylation, immunohistochemistry, electrophysiology","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple quantitative phenotypic readouts, in vitro and in vivo","pmids":["25878288"],"is_preprint":false},{"year":2015,"finding":"FBG1/FBXO2 degrades misfolded A1AT-Z via both the ubiquitin-proteasome system and Beclin1-dependent autophagy; FBG1 acts as a safety ubiquitin ligase to re-ubiquitinate ER proteins that have undergone de-ubiquitination.","method":"Chemical and genetic inhibition of proteasome/autophagy, FBG1 knockdown/overexpression in hepatic cell lines and mice, half-life assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple degradation pathway dissection with genetic and chemical tools, single lab","pmids":["26295339"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the Skp1-FBG3 complex at 2.6 Å resolution compared with Fbs1 revealed that four loop regions in FBG3 (β2-β3, β5-β6, β7-β8, β9-β10) prevent formation of the carbohydrate-binding pocket, explaining why FBG3 lacks sugar-binding despite high sequence identity with Fbs1.","method":"X-ray crystallography, structure-based mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutational validation","pmids":["26460611"],"is_preprint":false},{"year":2016,"finding":"FBXO2 targets the insulin receptor (IR) for ubiquitin-dependent proteasomal degradation as a substrate of SCF(FBXO2); adenoviral overexpression of FBXO2 in mice caused hyperglycemia and insulin resistance, while ablation alleviated diabetic phenotypes in obese mice.","method":"Protein purification and LC-MS/MS substrate screening, in vitro ubiquitination, adenoviral overexpression/ablation in mouse models, glucose/insulin tolerance tests","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1-2 — proteomics-based substrate identification, in vitro ubiquitination, in vivo mouse models","pmids":["27932386"],"is_preprint":false},{"year":2016,"finding":"FBXO2 knockdown partially restores ΔF508-CFTR-mediated Cl⁻ transport in primary human CF airway epithelia, indicating FBXO2 participates in ubiquitin-mediated proteasomal degradation of ΔF508-CFTR as part of distinct multiprotein complexes from SYVN1.","method":"siRNA knockdown, CFTR functional Cl⁻ transport assay, CFTR maturation assay in polarized airway epithelia","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue assay in primary human cells, single lab","pmids":["27756846"],"is_preprint":false},{"year":2018,"finding":"FBXO2 binds high-mannose N-glycans on EBV glycoprotein B (gB) via its sugar-binding domain and targets gB for ubiquitin-proteasome degradation; FBXO2 depletion stabilizes gB and promotes its transport from ER to plasma membrane, enhancing viral membrane fusion and entry.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, gB localization by confocal microscopy, viral infectivity assay, FBXO2 knockdown","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including functional viral assay, localization, and ubiquitination","pmids":["30052682"],"is_preprint":false},{"year":2020,"finding":"Fbxo2 functions as a component of the SCF ubiquitin ligase complex to mediate CNS lysophagy (clearance of damaged lysosomes); loss of Fbxo2 in mouse primary cortical cultures delayed clearance of damaged lysosomes and decreased viability after lysosomal damage, and Fbxo2 deficiency in an NPC mouse model exacerbated neurodegeneration and reduced survival.","method":"Primary cortical culture KO, lysosomal damage assay, live-cell imaging, NPC mouse model with Fbxo2 deficiency, motor function testing, survival analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo KO with defined cellular and organismal phenotypes","pmids":["32931479"],"is_preprint":false},{"year":2020,"finding":"FBXO2 targets glycosylated FBN1 (fibrillin-1) for ubiquitin-dependent proteasomal degradation; FBXO2-mediated FBN1 degradation promotes endometrial cancer cell proliferation via cell cycle (CDK4, CyclinD1, CyclinD2, CyclinA1) and autophagy (ATG4A, ATG4D) pathways.","method":"Ubiquitination-proteome approach for substrate identification, co-immunoprecipitation, ubiquitination assay, RNA-seq pathway analysis, in vitro and in vivo proliferation assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics-identified substrate with ubiquitination validation, single lab","pmids":["32984335"],"is_preprint":false},{"year":2020,"finding":"FBXO2 knockout in osteosarcoma cells stabilizes IL-6 receptor (IL-6R, a glycoprotein substrate), inhibiting STAT3 phosphorylation and downstream target gene expression; the glycoprotein recognition activity of FBXO2 is required for this function.","method":"CRISPR-Cas9 KO, immunoprecipitation, STAT3 luciferase reporter assay, in vivo xenograft","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic KO with pathway mechanistic follow-up, single lab","pmids":["32549792"],"is_preprint":false},{"year":2021,"finding":"FBXO2/SCF ubiquitin ligase complex recognizes GlcNAc residues on Group A Streptococcus (GAS) surface carbohydrates via its sugar-binding motif, promoting ubiquitination of intracellular GAS and xenophagic bacterial degradation; FBXO2 knockout reduced ubiquitin accumulation on GAS and impaired xenophagy.","method":"FBXO2 KO cells, GAS infection assay, ubiquitin accumulation quantification, confocal microscopy, genetic rescue with SCF components","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple functional readouts and defined sugar-binding mechanism","pmids":["34515398"],"is_preprint":false},{"year":2022,"finding":"FBXO2 directly targets glycosylated SUN2 for ubiquitination and proteasomal degradation; transcription factor SOX6 promotes FBXO2 expression by binding a response element in the FBXO2 promoter, establishing a SOX6-FBXO2-SUN2 axis in ovarian cancer.","method":"Co-immunoprecipitation, ubiquitination assay, SOX6 promoter luciferase assay, siRNA knockdown/overexpression in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — substrate identification with ubiquitination and transcriptional regulation, single lab","pmids":["35525855"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly interacts with LCN2 via its FBA domain, promoting K27-linked polyubiquitination of LCN2 and its proteasomal degradation, thereby suppressing ferroptosis; FBXO2 also activates PINK1/Parkin-dependent mitophagy under oxidative stress.","method":"Co-immunoprecipitation, ubiquitination assay (K27-linkage specific), proteomics, AAV9-mediated overexpression in vivo, FBXO2 KO mice","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods with in vivo validation, single lab","pmids":["40791152"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly binds to p53 and promotes its ubiquitination and proteasomal degradation; p53 knockdown partially reverses the growth arrest caused by FBXO2 knockdown in papillary thyroid carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, epistasis rescue experiment, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding shown by co-IP, ubiquitination validated, epistasis confirms pathway placement, single lab","pmids":["39343799"],"is_preprint":false},{"year":2025,"finding":"FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at K49, K67, K262, and K265; this disrupts KICSTOR complex assembly (impairing GATOR1 lysosomal recruitment) and promotes mTORC1 activation and hepatocellular carcinoma progression.","method":"Co-immunoprecipitation, in vitro ubiquitination with site-specific mutants, colocalization imaging, mTORC1 activity assays, in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple substrates sites identified with mutagenesis, mechanistic pathway placement, in vitro and in vivo","pmids":["41401028"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly binds WEE1 through its FBA domain, promoting WEE1 ubiquitination and degradation; WEE1 depletion partially abolishes the tumorigenic effects of FBXO2 silencing in renal cell carcinoma xenograft models.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, domain mapping, in vivo xenograft rescue experiment","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — substrate identified by co-IP/MS and validated by ubiquitination assay and in vivo epistasis, single lab","pmids":["40676478"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly binds YTHDF2 via its C-terminal region and promotes ubiquitination at K286, leading to YTHDF2 degradation; YTHDF2 enhances PCa progression by modulating m6A methylation of CDKN1C mRNA.","method":"Co-IP/mass spectrometry, Western blot, ubiquitination assay with site-specific mutants, rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — substrate identification by co-IP-MS, ubiquitination site validated by mutagenesis, functional epistasis, single lab","pmids":["41461633"],"is_preprint":false},{"year":2025,"finding":"FBXO2 targets USP49 deubiquitinase for ubiquitin-mediated proteasomal degradation; FBXO2 depletion stabilizes USP49 and suppresses HCC progression and sorafenib resistance.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, cycloheximide chase, functional rescue by USP49 silencing, xenograft models","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination and stability assays with functional in vivo epistasis, single lab","pmids":["41035649"],"is_preprint":false},{"year":2025,"finding":"FUT2 scaffolds FBXO2 to facilitate K362 site-specific ubiquitination and proteasomal degradation of transcription factor NR2F2, suppressing LCN2 expression and reversing immunosuppression in pancreatic cancer radiotherapy.","method":"In vivo CRISPR screen, co-immunoprecipitation, ubiquitination assay with site-specific mutants, gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific ubiquitination validated, in vivo CRISPR screen, single lab","pmids":["41436429"],"is_preprint":false},{"year":2025,"finding":"FBXO2 promotes K63-linked ubiquitination of IL6ST (gp130), activating STAT3 signaling during decidualization; cadmium suppresses FBXO2, impairing IL6ST/STAT3 signaling and decidualization.","method":"Proteomic analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage), FBXO2 overexpression rescue in vitro and in vivo","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination linkage specified, functional rescue validated, single lab","pmids":["41076860"],"is_preprint":false},{"year":2026,"finding":"FBXO2 interacts with FABP5 and promotes its lysosomal degradation via chaperone-mediated autophagy; this decreases intracellular PUFAs and increases resistance to ferroptosis in colorectal cancer cells.","method":"Co-immunoprecipitation, lysosomal degradation assay, FABP5 stability assay, PUFA supplementation rescue","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding and functional degradation shown with pathway rescue, single lab","pmids":["41604941"],"is_preprint":false}],"current_model":"FBXO2 is a neuronally enriched F-box protein that functions primarily as a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, recognizing high-mannose N-linked glycans on misfolded or regulatory glycoproteins (including GluN1, APP, IR, CFTR, gB, SUN2, and others) via its sugar-binding domain (SBD), and targeting them for K48-linked polyubiquitination and proteasomal degradation; beyond canonical SCF activity, FBXO2 also exists as a Fbs1-Skp1 heterodimer that acts as a chaperone to suppress glycoprotein aggregation, participates in lysophagy and xenophagy by recognizing glycan moieties on damaged lysosomes and bacterial surfaces, and can ubiquitinate non-glycosylated substrates (including KPTN, WEE1, USP49, p53, LCN2, and YTHDF2) through its FBA domain, thereby modulating mTORC1 signaling, cell cycle progression, ferroptosis, and mitophagy."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing that FBXO2 is an F-box protein in the ubiquitin-proteasome pathway resolved its molecular identity: interaction with Skp1 and F-box-dependent growth inhibition placed it within the SCF E3 ligase family.","evidence":"Co-immunoprecipitation with Skp1, F-box deletion mutagenesis, and transfection-based proliferation assay in neuroblastoma and CHO cells","pmids":["9857061"],"confidence":"Medium","gaps":["No endogenous substrate identified","Mechanism of growth inhibition not defined","SCF complex formation with CUL1/RBX1 not demonstrated"]},{"year":2003,"claim":"Identification of HSV-1 UL9 as a phosphorylation-dependent substrate established that FBXO2 can recognize non-glycoprotein targets and linked it to viral latency regulation through nuclear shuttling and cytosolic degradation.","evidence":"Co-expression in 293T, polyubiquitination assay, proteasome inhibitor rescue, yeast two-hybrid; live-cell imaging of nuclear shuttling in neurons","pmids":["12904574","15010529"],"confidence":"High","gaps":["Physiological relevance in HSV latency in vivo not proven","Phosphorylation sites on UL9 required for recognition not mapped"]},{"year":2005,"claim":"Defining the glycan specificity of FBXO2's sugar-binding domain for the Man3GlcNAc2 core pentasaccharide answered a central question about how it selects substrates: recognition is based on the conserved high-mannose glycan core rather than protein-protein contacts.","evidence":"In vitro binding assays with synthetic sugar chains and thermodynamic analysis; crystal structures of Skp1-Fbs1 and SBD-glycoprotein complexes","pmids":["15857118","17389369"],"confidence":"High","gaps":["How FBXO2 distinguishes misfolded from native glycoproteins bearing the same glycan not resolved","Structural basis for acceptor lysine selection not fully elucidated"]},{"year":2007,"claim":"Discovery that FBXO2 predominantly exists as Fbs1-Skp1 heterodimers (not canonical SCF complexes) and independently functions as a glycoprotein aggregation chaperone revealed a dual-function mechanism distinct from conventional F-box proteins.","evidence":"Gel filtration, immunoprecipitation, in vitro aggregation assay, domain deletion analysis; Fbxo2 KO mouse with cochlear degeneration phenotype","pmids":["17215248","17494702"],"confidence":"High","gaps":["Regulation of switch between chaperone and E3 ligase modes unknown","Cochlear substrate(s) mediating degeneration not identified"]},{"year":2014,"claim":"Demonstration that FBXO2 targets APP and NMDA receptor subunit GluN1 for degradation in hippocampal neurons established its role as a neuronal glycoprotein quality-control E3 ligase with consequences for synaptic receptor abundance.","evidence":"In vitro ubiquitination, Fbxo2 KO mouse brain analysis, surface biotinylation, electrophysiology","pmids":["24469452","25878288"],"confidence":"High","gaps":["Whether FBXO2 acts on newly synthesized versus surface-recycled receptor pools not distinguished","Impact on Alzheimer's disease pathology in vivo not tested"]},{"year":2016,"claim":"Identification of insulin receptor and ΔF508-CFTR as FBXO2 substrates extended its role from neuronal proteostasis to systemic metabolic regulation and ER-associated degradation of disease-causing misfolded proteins.","evidence":"LC-MS/MS substrate screening, in vitro ubiquitination, adenoviral overexpression/ablation in diabetic mouse models; siRNA knockdown and Cl⁻ transport rescue in primary human airway epithelia","pmids":["27932386","27756846"],"confidence":"High","gaps":["Glycan-dependence of CFTR recognition not directly shown","Whether therapeutic modulation of FBXO2 can rescue CF phenotypes in vivo not tested"]},{"year":2018,"claim":"Showing that FBXO2 restricts EBV entry by degrading glycoprotein B via glycan recognition expanded its function to antiviral host defense at the ER level.","evidence":"Co-IP, ubiquitination assay, proteasome inhibitor rescue, viral infectivity assay with FBXO2 knockdown","pmids":["30052682"],"confidence":"High","gaps":["Whether FBXO2 targets glycoproteins of other enveloped viruses not explored","In vivo antiviral role not demonstrated"]},{"year":2020,"claim":"Establishing FBXO2 as a mediator of lysophagy — recognizing glycan moieties exposed on damaged lysosomal membranes — revealed a fundamentally new class of substrates (organelle membranes) and linked FBXO2 loss to neurodegeneration in Niemann-Pick type C mice.","evidence":"Primary cortical culture KO, lysosomal damage assay, NPC mouse model with Fbxo2 deficiency, survival analysis","pmids":["32931479"],"confidence":"High","gaps":["Specific lysosomal glycoprotein substrates recognized not identified","Whether FBXO2 acts upstream or in parallel to galectin-based lysophagy signals not resolved"]},{"year":2021,"claim":"Demonstrating that FBXO2 directly ubiquitinates intracellular Group A Streptococcus by recognizing surface GlcNAc residues established it as a pattern-recognition receptor for xenophagy, broadening its role from organelle quality control to cell-autonomous immunity.","evidence":"FBXO2 KO cells, GAS infection assay, ubiquitin accumulation quantification, genetic rescue with SCF components","pmids":["34515398"],"confidence":"High","gaps":["Range of bacterial species recognized unknown","Redundancy with other glycan-sensing ubiquitin ligases not assessed"]},{"year":2025,"claim":"A burst of substrate identifications revealed that FBXO2 ubiquitinates multiple non-glycosylated substrates (KPTN, WEE1, p53, USP49, YTHDF2, LCN2, NR2F2) via its FBA domain, establishing a glycan-independent substrate recognition mode with broad implications for mTORC1 signaling, cell cycle, ferroptosis, and epitranscriptomic regulation.","evidence":"Co-IP/mass spectrometry, site-specific ubiquitination mutagenesis, domain mapping, in vivo xenograft and AAV9-based rescue across multiple cancer types and neuronal systems","pmids":["41401028","40676478","39343799","41035649","41461633","40791152","41436429"],"confidence":"Medium","gaps":["FBA-domain substrate selectivity determinants not structurally characterized","Most non-glycoprotein substrates identified by single labs and await independent replication","How glycan-dependent and glycan-independent recognition modes are coordinated or regulated remains unclear"]},{"year":null,"claim":"The structural basis of FBA-domain-mediated recognition of non-glycoprotein substrates, the regulatory switch between chaperone and E3 ligase activities, and the relative physiological importance of glycan-dependent versus glycan-independent ubiquitination in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of FBA domain bound to a non-glycoprotein substrate","In vivo contribution of individual substrate degradation events to neuronal or metabolic phenotypes not dissected","Post-translational regulation of FBXO2 itself (beyond SOX6 transcription) largely unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,9,10,13,15,17,19,20,21,22,23,24,25,26,27,28]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,13,15,19,23]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11,15]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[16,29]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,5,6,13,15,19,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,16,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13,18,23,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,17,22,24,26]}],"complexes":["SCF(FBXO2)","Fbs1-Skp1 heterodimer"],"partners":["SKP1","APP","KPTN","GLUN1","INSR","LCN2","WEE1","YTHDF2"],"other_free_text":[]},"mechanistic_narrative":"FBXO2 is a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that targets glycoproteins and non-glycoprotein substrates for ubiquitin-dependent degradation, functioning in ER-associated quality control, innate immunity, organelle homeostasis, and signaling regulation across neuronal and non-neuronal tissues. Its sugar-binding domain (SBD) recognizes high-mannose N-linked glycans (Man3GlcNAc2 core) on substrates including APP, GluN1, insulin receptor, CFTR, EBV glycoprotein B, and bacterial surface carbohydrates, directing them for K48-linked polyubiquitination and proteasomal degradation, while also mediating lysophagy and xenophagy by detecting exposed glycan moieties on damaged lysosomes and intracellular bacteria [PMID:15857118, PMID:24469452, PMID:27932386, PMID:30052682, PMID:32931479, PMID:34515398]. Beyond glycan-dependent recognition, FBXO2 ubiquitinates non-glycosylated substrates (KPTN, WEE1, p53, USP49, YTHDF2, LCN2) through its F-box-associated (FBA) domain, thereby modulating mTORC1 signaling, cell cycle progression, ferroptosis, and mitophagy [PMID:41401028, PMID:40676478, PMID:39343799, PMID:40791152]. In vivo, the majority of FBXO2 exists as Fbs1-Skp1 heterodimers rather than canonical SCF complexes, and this heterodimer independently suppresses glycoprotein aggregation as a chaperone; Fbxo2 knockout mice develop age-related cochlear degeneration and elevated NMDA receptor subunit levels, demonstrating its physiological importance in neuronal proteostasis [PMID:17215248, PMID:17494702, PMID:25878288]."},"prefetch_data":{"uniprot":{"accession":"Q9UK22","full_name":"F-box only protein 2","aliases":[],"length_aa":296,"mass_kda":33.3,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation. Prevents formation of cytosolic aggregates of unfolded glycoproteins that have been retrotranslocated into the cytosol. Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type (By similarity)","subcellular_location":"Cytoplasm; Microsome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UK22/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO2","total_profiled":1310},"omim":[{"mim_id":"615901","title":"NCCRP1, F-BOX-ASSOCIATED DOMAIN CONTAINING; NCCRP1","url":"https://www.omim.org/entry/615901"},{"mim_id":"611251","title":"DISPATCHED RND TRANSPORTER FAMILY, MEMBER 3; DISP3","url":"https://www.omim.org/entry/611251"},{"mim_id":"609111","title":"F-BOX ONLY PROTEIN 44; FBXO44","url":"https://www.omim.org/entry/609111"},{"mim_id":"607112","title":"F-BOX ONLY PROTEIN 2; FBXO2","url":"https://www.omim.org/entry/607112"},{"mim_id":"604467","title":"MONOCYTE-TO-MACROPHAGE DIFFERENTIATION-ASSOCIATED PROTEIN; MMD","url":"https://www.omim.org/entry/604467"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":374.1},{"tissue":"pituitary 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\"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction and functional mutagenesis, single lab\",\n      \"pmids\": [\"9857061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FBXO2 (NFB42) binds the phosphorylated HSV-1 replication initiator protein UL9, leading to its polyubiquitination and degradation by the 26S proteasome; interaction is phosphorylation-dependent.\",\n      \"method\": \"Co-expression in 293T cells, proteasome inhibitor (MG132) rescue, in vivo polyubiquitination assay, yeast two-hybrid\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal assays (ubiquitination, proteasome inhibition, phosphorylation-dependence) in single study\",\n      \"pmids\": [\"12904574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HSV-1 infection induces nuclear shuttling of NFB42 (FBXO2), allowing it to bind nuclear phosphorylated UL9 protein and mediate its export to the cytosol for ubiquitination and proteasomal degradation, thereby promoting viral latency in neurons.\",\n      \"method\": \"Live-cell imaging of nuclear shuttling in 293T cells and primary hippocampal neurons, co-immunoprecipitation, proteasome inhibitor rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods (localization, co-IP, functional rescue), replicated in two cell types\",\n      \"pmids\": [\"15010529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OCP1 (FBXO2) forms a heterodimeric complex with OCP2 (Skp1) and directly binds connexin 26 (Cx26), as demonstrated by pull-down assays and co-immunoprecipitation from organ of Corti extracts, suggesting Cx26 is a substrate of SCF(OCP1).\",\n      \"method\": \"Electrophoretic mobility-shift assay, pull-down with immobilized OCP1, in vitro transcription-translation binding, co-immunoprecipitation from organ of Corti\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple binding assays including in vivo co-IP, single lab\",\n      \"pmids\": [\"15109709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fbs1 (FBXO2) preferentially recognizes the Man3GlcNAc2 core pentasaccharide of N-linked high-mannose glycans; thermodynamic analysis showed the chitobiose and α1→6-linked Man residue are required for binding.\",\n      \"method\": \"In vitro binding assays with chemically synthesized sugar chains, thermodynamic (ITC-type) analysis\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with defined synthetic substrates\",\n      \"pmids\": [\"15857118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structures of the Skp1-Fbs1 complex and Fbs1 sugar-binding domain (SBD) bound to glycoprotein revealed that Fbs1 primarily recognizes Man3GlcNAc2 via the SBD, and a linker segment between the F-box and SBD domains undergoes relative motion potentially enabling recognition of different acceptor lysines for ubiquitination.\",\n      \"method\": \"X-ray crystallography of Skp1-Fbs1 complex and SBD-glycoprotein complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional interpretation, moderate citation count\",\n      \"pmids\": [\"17389369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In vivo, the majority of Fbs1 (FBXO2) exists as Fbs1-Skp1 heterodimers or monomers rather than canonical SCF complexes; restricted SCF complex formation is due to the short linker between the F-box and sugar-binding domains. Additionally, Fbs1 independently suppresses glycoprotein aggregation via its N-terminal sequence, functioning as a chaperone independent of ubiquitin ligase activity.\",\n      \"method\": \"Gel filtration, immunoprecipitation, in vitro aggregation assay, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods establishing dual functions\",\n      \"pmids\": [\"17215248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fbx2 (FBXO2) knockout mice develop age-related cochlear degeneration beginning at 2 months; cochlear Fbx2 binds Skp1 but forms a novel heterodimeric complex rather than canonical SCF complex in this tissue, as other SCF components show little complex formation with Fbx2/Skp1.\",\n      \"method\": \"Targeted gene knockout mouse model, co-immunoprecipitation, histological analysis, Western blot\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined phenotype plus biochemical characterization of complex\",\n      \"pmids\": [\"17494702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fbs1 (FBXO2) directly binds Nogo receptor 2 (NgR2) through its substrate recognition domain, leading to NgR2 polyubiquitination and proteasomal degradation.\",\n      \"method\": \"Pull-down assay, co-immunoprecipitation, in vitro binding assay, ubiquitination assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple binding assays but single lab\",\n      \"pmids\": [\"22206664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fbxo2 binds APP (amyloid precursor protein), a high-mannose glycoprotein, and promotes its ubiquitin-mediated degradation; loss of Fbxo2 in knockout mice increases APP levels and its cleavage products in hippocampal neurons, and reduces APP at the cell surface.\",\n      \"method\": \"In vitro ubiquitination assay, Fbxo2 KO mouse brain analysis, cultured hippocampal neurons, hippocampal slices, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo evidence with defined substrate, KO mouse model\",\n      \"pmids\": [\"24469452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Fbxo2 in knockout mice increases GluN1 and GluN2A (but not GluN2B) NMDA receptor subunit levels, promotes greater surface localization of GluN1 and GluN2A, and increases axo-dendritic shaft synapses without altering dendritic spine density or neurophysiology.\",\n      \"method\": \"Fbxo2 KO mouse model, Western blot, surface biotinylation, immunohistochemistry, electrophysiology\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple quantitative phenotypic readouts, in vitro and in vivo\",\n      \"pmids\": [\"25878288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBG1/FBXO2 degrades misfolded A1AT-Z via both the ubiquitin-proteasome system and Beclin1-dependent autophagy; FBG1 acts as a safety ubiquitin ligase to re-ubiquitinate ER proteins that have undergone de-ubiquitination.\",\n      \"method\": \"Chemical and genetic inhibition of proteasome/autophagy, FBG1 knockdown/overexpression in hepatic cell lines and mice, half-life assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple degradation pathway dissection with genetic and chemical tools, single lab\",\n      \"pmids\": [\"26295339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the Skp1-FBG3 complex at 2.6 Å resolution compared with Fbs1 revealed that four loop regions in FBG3 (β2-β3, β5-β6, β7-β8, β9-β10) prevent formation of the carbohydrate-binding pocket, explaining why FBG3 lacks sugar-binding despite high sequence identity with Fbs1.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutational validation\",\n      \"pmids\": [\"26460611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO2 targets the insulin receptor (IR) for ubiquitin-dependent proteasomal degradation as a substrate of SCF(FBXO2); adenoviral overexpression of FBXO2 in mice caused hyperglycemia and insulin resistance, while ablation alleviated diabetic phenotypes in obese mice.\",\n      \"method\": \"Protein purification and LC-MS/MS substrate screening, in vitro ubiquitination, adenoviral overexpression/ablation in mouse models, glucose/insulin tolerance tests\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — proteomics-based substrate identification, in vitro ubiquitination, in vivo mouse models\",\n      \"pmids\": [\"27932386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO2 knockdown partially restores ΔF508-CFTR-mediated Cl⁻ transport in primary human CF airway epithelia, indicating FBXO2 participates in ubiquitin-mediated proteasomal degradation of ΔF508-CFTR as part of distinct multiprotein complexes from SYVN1.\",\n      \"method\": \"siRNA knockdown, CFTR functional Cl⁻ transport assay, CFTR maturation assay in polarized airway epithelia\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue assay in primary human cells, single lab\",\n      \"pmids\": [\"27756846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXO2 binds high-mannose N-glycans on EBV glycoprotein B (gB) via its sugar-binding domain and targets gB for ubiquitin-proteasome degradation; FBXO2 depletion stabilizes gB and promotes its transport from ER to plasma membrane, enhancing viral membrane fusion and entry.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor rescue, gB localization by confocal microscopy, viral infectivity assay, FBXO2 knockdown\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including functional viral assay, localization, and ubiquitination\",\n      \"pmids\": [\"30052682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fbxo2 functions as a component of the SCF ubiquitin ligase complex to mediate CNS lysophagy (clearance of damaged lysosomes); loss of Fbxo2 in mouse primary cortical cultures delayed clearance of damaged lysosomes and decreased viability after lysosomal damage, and Fbxo2 deficiency in an NPC mouse model exacerbated neurodegeneration and reduced survival.\",\n      \"method\": \"Primary cortical culture KO, lysosomal damage assay, live-cell imaging, NPC mouse model with Fbxo2 deficiency, motor function testing, survival analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo KO with defined cellular and organismal phenotypes\",\n      \"pmids\": [\"32931479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO2 targets glycosylated FBN1 (fibrillin-1) for ubiquitin-dependent proteasomal degradation; FBXO2-mediated FBN1 degradation promotes endometrial cancer cell proliferation via cell cycle (CDK4, CyclinD1, CyclinD2, CyclinA1) and autophagy (ATG4A, ATG4D) pathways.\",\n      \"method\": \"Ubiquitination-proteome approach for substrate identification, co-immunoprecipitation, ubiquitination assay, RNA-seq pathway analysis, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics-identified substrate with ubiquitination validation, single lab\",\n      \"pmids\": [\"32984335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO2 knockout in osteosarcoma cells stabilizes IL-6 receptor (IL-6R, a glycoprotein substrate), inhibiting STAT3 phosphorylation and downstream target gene expression; the glycoprotein recognition activity of FBXO2 is required for this function.\",\n      \"method\": \"CRISPR-Cas9 KO, immunoprecipitation, STAT3 luciferase reporter assay, in vivo xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic KO with pathway mechanistic follow-up, single lab\",\n      \"pmids\": [\"32549792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO2/SCF ubiquitin ligase complex recognizes GlcNAc residues on Group A Streptococcus (GAS) surface carbohydrates via its sugar-binding motif, promoting ubiquitination of intracellular GAS and xenophagic bacterial degradation; FBXO2 knockout reduced ubiquitin accumulation on GAS and impaired xenophagy.\",\n      \"method\": \"FBXO2 KO cells, GAS infection assay, ubiquitin accumulation quantification, confocal microscopy, genetic rescue with SCF components\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple functional readouts and defined sugar-binding mechanism\",\n      \"pmids\": [\"34515398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO2 directly targets glycosylated SUN2 for ubiquitination and proteasomal degradation; transcription factor SOX6 promotes FBXO2 expression by binding a response element in the FBXO2 promoter, establishing a SOX6-FBXO2-SUN2 axis in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, SOX6 promoter luciferase assay, siRNA knockdown/overexpression in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — substrate identification with ubiquitination and transcriptional regulation, single lab\",\n      \"pmids\": [\"35525855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly interacts with LCN2 via its FBA domain, promoting K27-linked polyubiquitination of LCN2 and its proteasomal degradation, thereby suppressing ferroptosis; FBXO2 also activates PINK1/Parkin-dependent mitophagy under oxidative stress.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K27-linkage specific), proteomics, AAV9-mediated overexpression in vivo, FBXO2 KO mice\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo validation, single lab\",\n      \"pmids\": [\"40791152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly binds to p53 and promotes its ubiquitination and proteasomal degradation; p53 knockdown partially reverses the growth arrest caused by FBXO2 knockdown in papillary thyroid carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, epistasis rescue experiment, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding shown by co-IP, ubiquitination validated, epistasis confirms pathway placement, single lab\",\n      \"pmids\": [\"39343799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at K49, K67, K262, and K265; this disrupts KICSTOR complex assembly (impairing GATOR1 lysosomal recruitment) and promotes mTORC1 activation and hepatocellular carcinoma progression.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination with site-specific mutants, colocalization imaging, mTORC1 activity assays, in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple substrates sites identified with mutagenesis, mechanistic pathway placement, in vitro and in vivo\",\n      \"pmids\": [\"41401028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly binds WEE1 through its FBA domain, promoting WEE1 ubiquitination and degradation; WEE1 depletion partially abolishes the tumorigenic effects of FBXO2 silencing in renal cell carcinoma xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, domain mapping, in vivo xenograft rescue experiment\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate identified by co-IP/MS and validated by ubiquitination assay and in vivo epistasis, single lab\",\n      \"pmids\": [\"40676478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly binds YTHDF2 via its C-terminal region and promotes ubiquitination at K286, leading to YTHDF2 degradation; YTHDF2 enhances PCa progression by modulating m6A methylation of CDKN1C mRNA.\",\n      \"method\": \"Co-IP/mass spectrometry, Western blot, ubiquitination assay with site-specific mutants, rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate identification by co-IP-MS, ubiquitination site validated by mutagenesis, functional epistasis, single lab\",\n      \"pmids\": [\"41461633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 targets USP49 deubiquitinase for ubiquitin-mediated proteasomal degradation; FBXO2 depletion stabilizes USP49 and suppresses HCC progression and sorafenib resistance.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, cycloheximide chase, functional rescue by USP49 silencing, xenograft models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination and stability assays with functional in vivo epistasis, single lab\",\n      \"pmids\": [\"41035649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FUT2 scaffolds FBXO2 to facilitate K362 site-specific ubiquitination and proteasomal degradation of transcription factor NR2F2, suppressing LCN2 expression and reversing immunosuppression in pancreatic cancer radiotherapy.\",\n      \"method\": \"In vivo CRISPR screen, co-immunoprecipitation, ubiquitination assay with site-specific mutants, gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific ubiquitination validated, in vivo CRISPR screen, single lab\",\n      \"pmids\": [\"41436429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 promotes K63-linked ubiquitination of IL6ST (gp130), activating STAT3 signaling during decidualization; cadmium suppresses FBXO2, impairing IL6ST/STAT3 signaling and decidualization.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage), FBXO2 overexpression rescue in vitro and in vivo\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination linkage specified, functional rescue validated, single lab\",\n      \"pmids\": [\"41076860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXO2 interacts with FABP5 and promotes its lysosomal degradation via chaperone-mediated autophagy; this decreases intracellular PUFAs and increases resistance to ferroptosis in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal degradation assay, FABP5 stability assay, PUFA supplementation rescue\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding and functional degradation shown with pathway rescue, single lab\",\n      \"pmids\": [\"41604941\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO2 is a neuronally enriched F-box protein that functions primarily as a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, recognizing high-mannose N-linked glycans on misfolded or regulatory glycoproteins (including GluN1, APP, IR, CFTR, gB, SUN2, and others) via its sugar-binding domain (SBD), and targeting them for K48-linked polyubiquitination and proteasomal degradation; beyond canonical SCF activity, FBXO2 also exists as a Fbs1-Skp1 heterodimer that acts as a chaperone to suppress glycoprotein aggregation, participates in lysophagy and xenophagy by recognizing glycan moieties on damaged lysosomes and bacterial surfaces, and can ubiquitinate non-glycosylated substrates (including KPTN, WEE1, USP49, p53, LCN2, and YTHDF2) through its FBA domain, thereby modulating mTORC1 signaling, cell cycle progression, ferroptosis, and mitophagy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXO2 is a substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex that targets glycoproteins and non-glycoprotein substrates for ubiquitin-dependent degradation, functioning in ER-associated quality control, innate immunity, organelle homeostasis, and signaling regulation across neuronal and non-neuronal tissues. Its sugar-binding domain (SBD) recognizes high-mannose N-linked glycans (Man3GlcNAc2 core) on substrates including APP, GluN1, insulin receptor, CFTR, EBV glycoprotein B, and bacterial surface carbohydrates, directing them for K48-linked polyubiquitination and proteasomal degradation, while also mediating lysophagy and xenophagy by detecting exposed glycan moieties on damaged lysosomes and intracellular bacteria [PMID:15857118, PMID:24469452, PMID:27932386, PMID:30052682, PMID:32931479, PMID:34515398]. Beyond glycan-dependent recognition, FBXO2 ubiquitinates non-glycosylated substrates (KPTN, WEE1, p53, USP49, YTHDF2, LCN2) through its F-box-associated (FBA) domain, thereby modulating mTORC1 signaling, cell cycle progression, ferroptosis, and mitophagy [PMID:41401028, PMID:40676478, PMID:39343799, PMID:40791152]. In vivo, the majority of FBXO2 exists as Fbs1-Skp1 heterodimers rather than canonical SCF complexes, and this heterodimer independently suppresses glycoprotein aggregation as a chaperone; Fbxo2 knockout mice develop age-related cochlear degeneration and elevated NMDA receptor subunit levels, demonstrating its physiological importance in neuronal proteostasis [PMID:17215248, PMID:17494702, PMID:25878288].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that FBXO2 is an F-box protein in the ubiquitin-proteasome pathway resolved its molecular identity: interaction with Skp1 and F-box-dependent growth inhibition placed it within the SCF E3 ligase family.\",\n      \"evidence\": \"Co-immunoprecipitation with Skp1, F-box deletion mutagenesis, and transfection-based proliferation assay in neuroblastoma and CHO cells\",\n      \"pmids\": [\"9857061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous substrate identified\", \"Mechanism of growth inhibition not defined\", \"SCF complex formation with CUL1/RBX1 not demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of HSV-1 UL9 as a phosphorylation-dependent substrate established that FBXO2 can recognize non-glycoprotein targets and linked it to viral latency regulation through nuclear shuttling and cytosolic degradation.\",\n      \"evidence\": \"Co-expression in 293T, polyubiquitination assay, proteasome inhibitor rescue, yeast two-hybrid; live-cell imaging of nuclear shuttling in neurons\",\n      \"pmids\": [\"12904574\", \"15010529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance in HSV latency in vivo not proven\", \"Phosphorylation sites on UL9 required for recognition not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining the glycan specificity of FBXO2's sugar-binding domain for the Man3GlcNAc2 core pentasaccharide answered a central question about how it selects substrates: recognition is based on the conserved high-mannose glycan core rather than protein-protein contacts.\",\n      \"evidence\": \"In vitro binding assays with synthetic sugar chains and thermodynamic analysis; crystal structures of Skp1-Fbs1 and SBD-glycoprotein complexes\",\n      \"pmids\": [\"15857118\", \"17389369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FBXO2 distinguishes misfolded from native glycoproteins bearing the same glycan not resolved\", \"Structural basis for acceptor lysine selection not fully elucidated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that FBXO2 predominantly exists as Fbs1-Skp1 heterodimers (not canonical SCF complexes) and independently functions as a glycoprotein aggregation chaperone revealed a dual-function mechanism distinct from conventional F-box proteins.\",\n      \"evidence\": \"Gel filtration, immunoprecipitation, in vitro aggregation assay, domain deletion analysis; Fbxo2 KO mouse with cochlear degeneration phenotype\",\n      \"pmids\": [\"17215248\", \"17494702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of switch between chaperone and E3 ligase modes unknown\", \"Cochlear substrate(s) mediating degeneration not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that FBXO2 targets APP and NMDA receptor subunit GluN1 for degradation in hippocampal neurons established its role as a neuronal glycoprotein quality-control E3 ligase with consequences for synaptic receptor abundance.\",\n      \"evidence\": \"In vitro ubiquitination, Fbxo2 KO mouse brain analysis, surface biotinylation, electrophysiology\",\n      \"pmids\": [\"24469452\", \"25878288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FBXO2 acts on newly synthesized versus surface-recycled receptor pools not distinguished\", \"Impact on Alzheimer's disease pathology in vivo not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of insulin receptor and ΔF508-CFTR as FBXO2 substrates extended its role from neuronal proteostasis to systemic metabolic regulation and ER-associated degradation of disease-causing misfolded proteins.\",\n      \"evidence\": \"LC-MS/MS substrate screening, in vitro ubiquitination, adenoviral overexpression/ablation in diabetic mouse models; siRNA knockdown and Cl⁻ transport rescue in primary human airway epithelia\",\n      \"pmids\": [\"27932386\", \"27756846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan-dependence of CFTR recognition not directly shown\", \"Whether therapeutic modulation of FBXO2 can rescue CF phenotypes in vivo not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that FBXO2 restricts EBV entry by degrading glycoprotein B via glycan recognition expanded its function to antiviral host defense at the ER level.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, proteasome inhibitor rescue, viral infectivity assay with FBXO2 knockdown\",\n      \"pmids\": [\"30052682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FBXO2 targets glycoproteins of other enveloped viruses not explored\", \"In vivo antiviral role not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing FBXO2 as a mediator of lysophagy — recognizing glycan moieties exposed on damaged lysosomal membranes — revealed a fundamentally new class of substrates (organelle membranes) and linked FBXO2 loss to neurodegeneration in Niemann-Pick type C mice.\",\n      \"evidence\": \"Primary cortical culture KO, lysosomal damage assay, NPC mouse model with Fbxo2 deficiency, survival analysis\",\n      \"pmids\": [\"32931479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysosomal glycoprotein substrates recognized not identified\", \"Whether FBXO2 acts upstream or in parallel to galectin-based lysophagy signals not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that FBXO2 directly ubiquitinates intracellular Group A Streptococcus by recognizing surface GlcNAc residues established it as a pattern-recognition receptor for xenophagy, broadening its role from organelle quality control to cell-autonomous immunity.\",\n      \"evidence\": \"FBXO2 KO cells, GAS infection assay, ubiquitin accumulation quantification, genetic rescue with SCF components\",\n      \"pmids\": [\"34515398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Range of bacterial species recognized unknown\", \"Redundancy with other glycan-sensing ubiquitin ligases not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A burst of substrate identifications revealed that FBXO2 ubiquitinates multiple non-glycosylated substrates (KPTN, WEE1, p53, USP49, YTHDF2, LCN2, NR2F2) via its FBA domain, establishing a glycan-independent substrate recognition mode with broad implications for mTORC1 signaling, cell cycle, ferroptosis, and epitranscriptomic regulation.\",\n      \"evidence\": \"Co-IP/mass spectrometry, site-specific ubiquitination mutagenesis, domain mapping, in vivo xenograft and AAV9-based rescue across multiple cancer types and neuronal systems\",\n      \"pmids\": [\"41401028\", \"40676478\", \"39343799\", \"41035649\", \"41461633\", \"40791152\", \"41436429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FBA-domain substrate selectivity determinants not structurally characterized\", \"Most non-glycoprotein substrates identified by single labs and await independent replication\", \"How glycan-dependent and glycan-independent recognition modes are coordinated or regulated remains unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of FBA-domain-mediated recognition of non-glycoprotein substrates, the regulatory switch between chaperone and E3 ligase activities, and the relative physiological importance of glycan-dependent versus glycan-independent ubiquitination in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of FBA domain bound to a non-glycoprotein substrate\", \"In vivo contribution of individual substrate degradation events to neuronal or metabolic phenotypes not dissected\", \"Post-translational regulation of FBXO2 itself (beyond SOX6 transcription) largely unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 9, 10, 13, 15, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 13, 15, 19, 23]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11, 15]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [16, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5, 6, 13, 15, 19, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 16, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13, 18, 23, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 17, 22, 24, 26]}\n    ],\n    \"complexes\": [\n      \"SCF(FBXO2)\",\n      \"Fbs1-Skp1 heterodimer\"\n    ],\n    \"partners\": [\n      \"SKP1\",\n      \"APP\",\n      \"KPTN\",\n      \"GluN1\",\n      \"INSR\",\n      \"LCN2\",\n      \"WEE1\",\n      \"YTHDF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}