{"gene":"FBXO2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1998,"finding":"FBXO2 (NFB42) contains an F-box domain that mediates interaction with Skp1p, a component of the ubiquitin-proteasome pathway; deletion of the F-box abolishes both Skp1p interaction and the growth-inhibitory effect of NFB42 overexpression in neuroblastoma and CHO cells.","method":"Co-immunoprecipitation, F-box deletion mutagenesis, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by pulldown/Co-IP with deletion mutant, single lab, two orthogonal methods","pmids":["9857061"],"is_preprint":false},{"year":2001,"finding":"OCP1 (FBXO2) co-localizes with OCP2 (Skp1) in the epithelial gap-junction region of the cochlear organ of Corti, consistent with formation of an SCF ubiquitin ligase complex at this site.","method":"Immunohistochemistry, sequence analysis","journal":"Hearing research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method localization, no functional rescue","pmids":["11470190"],"is_preprint":false},{"year":2003,"finding":"NFB42 (FBXO2) binds the phosphorylated HSV-1 replication-initiator protein UL9, promoting its polyubiquitination and degradation via the 26S proteasome; MG132 treatment restores UL9 levels, confirming proteasomal mechanism.","method":"Co-expression in 293T cells, proteasome inhibitor (MG132) rescue, in vivo polyubiquitination assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional degradation assay plus proteasome inhibitor rescue and ubiquitination detection, single lab","pmids":["12904574"],"is_preprint":false},{"year":2004,"finding":"HSV-1 infection induces nuclear shuttling of NFB42 (FBXO2), allowing it to bind nuclear phosphorylated UL9, export UL9 to the cytoplasm, and mediate its ubiquitination and proteasomal degradation, thereby potentially promoting viral latency in neurons.","method":"Live-cell imaging of NFB42 nuclear shuttling, co-immunoprecipitation of NFB42-UL9, proteasome inhibitor rescue in 293T cells and primary hippocampal neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (imaging, Co-IP, pharmacological rescue) in single lab","pmids":["15010529"],"is_preprint":false},{"year":2004,"finding":"OCP1 (FBXO2) forms a heterodimeric complex with OCP2 (Skp1) in the organ of Corti, and directly binds connexin 26 (Cx26) as shown by electrophoretic mobility-shift, in vitro pulldown with 35S-labeled Cx26, and co-immunoprecipitation from organ of Corti extracts.","method":"Electrophoretic mobility-shift assay, pulldown with immobilized OCP1, sedimentation equilibrium, co-immunoprecipitation from tissue extracts","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (EMSA, pulldown, Co-IP, sedimentation), single lab","pmids":["15109709"],"is_preprint":false},{"year":2007,"finding":"Cochlear FBXO2 binds Skp1 to form a novel heterodimeric complex distinct from the canonical SCF complex (Cullin1 and Rbx1 show little association with Fbx2/Skp1 in the cochlea); loss of Fbxo2 in knockout mice leads to parallel loss of cochlear Skp1 levels and selective cochlear degeneration beginning in epithelial support cells.","method":"Targeted gene knockout, co-immunoprecipitation, western blot, histology","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cochlear phenotype plus biochemical complex analysis, single lab","pmids":["17494702"],"is_preprint":false},{"year":2010,"finding":"FBG1 (FBXO2) directly interacts with APC2 via a D-box motif within its F-box domain; co-expression sequesters free APC2 (raising total but lowering free APC2), inhibiting cell proliferation and inducing S-phase arrest independent of its ubiquitin ligase function.","method":"Co-immunoprecipitation, D-box mutagenesis, FACS cell cycle analysis, western blot","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional cell-cycle readout, single lab","pmids":["21135578"],"is_preprint":false},{"year":2014,"finding":"FBXO2 targets APP (amyloid precursor protein), a high-mannose glycoprotein, for ubiquitin-mediated degradation; loss of Fbxo2 in knockout mice and cultured hippocampal neurons increases APP levels and processing into cleavage products, with a concomitant reduction of APP at the cell surface.","method":"Fbxo2 knockout mice, cultured hippocampal neurons/slices, western blot, cell surface biotinylation, non-neuronal cell overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo loss-of-function with multiple readouts, single lab","pmids":["24469452"],"is_preprint":false},{"year":2015,"finding":"Fbxo2 regulates GluN1 and GluN2A (but not GluN2B) NMDAR subunit levels and surface localization in the adult mouse brain; loss of Fbxo2 increases surface GluN1 and GluN2A, elevates synaptic markers PSD-95 and Vglut1, and promotes aberrant axo-dendritic shaft synapses without altering spine density or neurophysiology.","method":"Fbxo2 knockout mice, western blot, surface biotinylation, immunofluorescence, electrophysiology, confocal microscopy","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts, single lab","pmids":["25878288"],"is_preprint":false},{"year":2015,"finding":"FBG1 (FBXO2) degrades the misfolded glycoprotein A1AT-Z through both the ubiquitin-proteasome system and Beclin1-dependent autophagy; overexpression decreases A1AT-Z half-life and knockdown in hepatic cells and mice increases A1AT-Z accumulation.","method":"Chemical inhibitors, genetic knockdown/overexpression, cycloheximide chase, Beclin1 co-dependency assay in hepatic cell lines and mouse liver","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and genetic approaches, in vitro and in vivo, single lab","pmids":["26295339"],"is_preprint":false},{"year":2016,"finding":"SCFFBXO2 acts as an E3 ubiquitin ligase that targets the insulin receptor (IR) for ubiquitin-dependent proteasomal degradation; overexpression of FBXO2 in healthy mice causes hyperglycemia and insulin resistance, while ablation in obese mice alleviates diabetic phenotypes.","method":"Protein purification combined with LC-MS/MS substrate screening, adenovirus-mediated overexpression in mice, Fbxo2 knockout in obese mouse model, glucose tolerance and insulin tolerance tests","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — substrate identified by MS, validated in vivo gain- and loss-of-function with metabolic phenotypes, single lab with multiple orthogonal methods","pmids":["27932386"],"is_preprint":false},{"year":2016,"finding":"FBXO2 knockdown partially restores ΔF508-CFTR-mediated Cl⁻ transport in primary human cystic fibrosis airway epithelia, indicating FBXO2 participates in ubiquitin-mediated proteasomal degradation of ΔF508-CFTR via a distinct complex from SYVN1.","method":"siRNA knockdown, functional CFTR Cl⁻ transport assay in polarized primary airway epithelia, CFTR maturation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transport assay in primary human cells with genetic knockdown, single lab","pmids":["27756846"],"is_preprint":false},{"year":2018,"finding":"FBXO2 directly binds N-glycosylated (high-mannose) EBV glycoprotein B (gB) through its sugar-binding domain, promoting gB ubiquitination and proteasomal degradation; FBXO2 depletion stabilizes gB, promotes its transport from ER to plasma membrane, and enhances viral membrane fusion and entry.","method":"Co-immunoprecipitation, knockdown/overexpression, ubiquitination assay, membrane fusion assay, viral infectivity assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination, functional viral entry/fusion assays) demonstrating direct binding and functional consequence, single lab","pmids":["30052682"],"is_preprint":false},{"year":2020,"finding":"Fbxo2 functions as a component of the SCF ubiquitin ligase complex to mediate CNS lysophagy: loss of Fbxo2 in mouse primary cortical cultures delays clearance of damaged lysosomes and decreases viability after lysosomal damage; Fbxo2 deficiency in a NPC mouse model exacerbates motor deficits, neurodegeneration, and reduces survival.","method":"Primary cortical neuron cultures from Fbxo2 knockout mice, lysosomal damage assay, NPC mouse model with Fbxo2 deficiency, behavioral testing, histology","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with in vitro and in vivo phenotypic readouts, single lab","pmids":["32931479"],"is_preprint":false},{"year":2020,"finding":"FBXO2 targets glycosylated fibrillin-1 (FBN1) for ubiquitin-dependent proteasomal degradation to promote endometrial cancer cell proliferation, acting through regulation of cell cycle proteins (CDK4, CyclinD1/D2/A1) and autophagy pathway components (ATG4A/4D).","method":"Ubiquitination-proteome approach to identify substrates, ubiquitination assay, RNA-seq, knockdown/overexpression, xenograft mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by proteomics and validated with ubiquitination assay and functional rescue, single lab","pmids":["32984335"],"is_preprint":false},{"year":2020,"finding":"FBXO2 promotes osteosarcoma proliferation by targeting IL-6 receptor (IL-6R) for ubiquitin-mediated degradation, thereby activating STAT3 phosphorylation and downstream gene expression; this function requires FBXO2's glycoprotein recognition activity.","method":"CRISPR-Cas9 knockout, retrovirus overexpression, co-immunoprecipitation, luciferase reporter assay for STAT3 transcriptional activity, xenograft mouse model","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional reporter assay, in vivo xenograft, single lab","pmids":["32549792"],"is_preprint":false},{"year":2021,"finding":"FBXO2/SCF ubiquitin ligase complex recognizes GlcNAc side chains of the group A Streptococcus (GAS) surface carbohydrate through FBXO2's sugar-binding motif, promoting ubiquitin-mediated xenophagy; FBXO2 knockout reduces ubiquitin accumulation on intracellular GAS and decreases xenophagic bacterial degradation; SKP1, CUL1, and ROC1 (other SCF components) are also required.","method":"FBXO2 knockout cell lines, ubiquitin accumulation assay on intracellular GAS, xenophagy/bacterial clearance assay, sugar-binding domain mutant analysis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with multiple functional readouts (ubiquitin accumulation, bacterial clearance), domain-mapping with mutants, single lab with multiple orthogonal methods","pmids":["34515398"],"is_preprint":false},{"year":2022,"finding":"FBXO2 directly interacts with glycosylated SUN2 and promotes its ubiquitin-dependent proteasomal degradation; the SOX6 transcription factor promotes FBXO2 expression by binding its promoter, establishing a SOX6-FBXO2-SUN2 axis in ovarian cancer.","method":"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, promoter reporter assay, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, promoter validation, in vivo xenograft, single lab","pmids":["35525855"],"is_preprint":false},{"year":2023,"finding":"RBM47 binds FBXO2 mRNA and stabilizes it post-transcriptionally to promote STAT3 phosphorylation and downstream signaling in chondrocytes; FBXO2 overexpression reverses the alleviating effects of RBM47 knockdown on IL-1β-induced inflammation and ECM degradation.","method":"RBM47 RNA-binding assay, FBXO2 mRNA stability assay, STAT3 phosphorylation western blot, rescue experiment with FBXO2 overexpression","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect post-transcriptional regulation of FBXO2 with limited mechanistic detail on FBXO2 itself, single lab","pmids":["38070024"],"is_preprint":false},{"year":2024,"finding":"FBXO2 directly binds p53 and promotes its ubiquitination and proteasomal degradation in papillary thyroid carcinoma; p53 knockdown partially reverses the anti-proliferative effects of FBXO2 knockdown, confirming functional epistasis.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, rescue epistasis experiment, subcutaneous xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, single lab","pmids":["39343799"],"is_preprint":false},{"year":2025,"finding":"FBXO2 binds lipocalin-2 (LCN2) via its FBA domain and promotes K27-linked polyubiquitination of LCN2, driving its proteasomal degradation; this suppresses ferroptosis (lipid peroxidation, glutathione depletion, iron overload) and activates PINK1/Parkin-dependent mitophagy in nucleus pulposus cells; AAV9-mediated FBXO2 overexpression ameliorates intervertebral disc degeneration in rats.","method":"Co-immunoprecipitation, ubiquitination assay, FBA domain mapping, proteomics, FBXO2 KO mice, AAV9 overexpression in rats, mitochondrial functional assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped Co-IP, ubiquitination assay with linkage specificity, in vivo models, single lab","pmids":["40791152"],"is_preprint":false},{"year":2025,"finding":"FBXO2 colocalizes and directly interacts with KPTN (a KICSTOR complex subunit) via its F-box-associated (FBA) domain, promoting K48- and K63-linked polyubiquitination of KPTN at K49, K67, K262, and K265; this disrupts KICSTOR assembly, impairs GATOR1 lysosomal recruitment, and activates amino acid-dependent mTORC1 signaling.","method":"Co-immunoprecipitation, ubiquitination assay with linkage-specific antibodies, site-directed mutagenesis of KPTN ubiquitination sites, co-localization imaging, mTORC1 activity assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — domain mapping, site-specific mutagenesis, multiple ubiquitination linkage assays, pathway epistasis (GATOR1 recruitment), single rigorous study with multiple orthogonal methods","pmids":["41401028"],"is_preprint":false},{"year":2025,"finding":"Fbxo2 binds the kinase domain of WEE1 via its FBA domain and promotes WEE1 ubiquitination and proteasomal degradation; Fbxo2 knockdown increases RCC cell motility and proliferation, and WEE1 depletion partially rescues the tumorigenic effects of Fbxo2 silencing in xenograft models.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, FBA domain mutant, xenograft mouse model, rescue epistasis","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS substrate identification, domain mapping, ubiquitination assay, in vivo epistasis, single lab","pmids":["40676478"],"is_preprint":false},{"year":2025,"finding":"FBXO2 directly binds USP49 and targets it for ubiquitin-mediated proteasomal degradation in hepatocellular carcinoma; USP49 knockdown reverses the inhibitory effects of FBXO2 knockdown, confirming the FBXO2/USP49 axis; FBXO2 depletion enhances sorafenib sensitivity.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, cycloheximide chase, rescue epistasis, xenograft sorafenib treatment","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination and stability assays, epistasis rescue in vitro and in vivo, single lab","pmids":["41035649"],"is_preprint":false},{"year":2025,"finding":"Fbxo2 targets the m6A reader YTHDF2 for ubiquitin-mediated proteasomal degradation in prostate cancer; the C-terminal region of Fbxo2 is required for YTHDF2 ubiquitination; K286 of YTHDF2 is the key ubiquitination site; YTHDF2 promotes PCa progression by modulating m6A methylation of CDKN1C mRNA.","method":"Co-immunoprecipitation mass spectrometry, Co-IP, ubiquitination assay, site-directed mutagenesis (K286), rescue experiments, in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by Co-IP-MS, validated with mutagenesis and ubiquitination assay, epistasis rescue, single lab","pmids":["41461633"],"is_preprint":false},{"year":2025,"finding":"FUT2 scaffolds FBXO2 to facilitate K362 site-specific ubiquitination and proteasomal degradation of transcription factor NR2F2; NR2F2 degradation suppresses LCN2 expression and thereby reduces CD8+ T cell exhaustion in pancreatic cancer.","method":"In vivo CRISPR-Cas9 screen, co-immunoprecipitation, ubiquitination assay with site-specific mapping (K362), NR2F2 transcriptional reporter, tumor immune profiling","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen identification, Co-IP, ubiquitination with site-mapping, functional immune readout, single lab","pmids":["41436429"],"is_preprint":false},{"year":2025,"finding":"FBXO2 interacts with FABP5 and promotes its lysosomal degradation through chaperone-mediated autophagy (not proteasomal), reducing intracellular polyunsaturated fatty acid (PUFA) levels and conferring resistance to ferroptosis in colorectal cancer; this is downstream of p53 transcriptional induction of FBXO2.","method":"Co-immunoprecipitation, FBXO2 overexpression/knockdown, lipid peroxidation and cell death assays, fatty acid supplementation rescue, in vivo tumor models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional ferroptosis assay, fatty acid rescue, in vivo validation, single lab","pmids":["41604941"],"is_preprint":false},{"year":2025,"finding":"FBXO2 promotes K63-linked ubiquitination of IL6ST (glycoprotein 130) to restore STAT3 signaling during decidualization; cadmium exposure downregulates FBXO2 and suppresses this IL6ST/STAT3 axis, impairing decidualization.","method":"Proteomic analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage specific), FBXO2 overexpression rescue, in vivo Cd-exposed mouse model","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, in vivo model, rescue experiment, single lab","pmids":["41076860"],"is_preprint":false}],"current_model":"FBXO2 is a neuronally enriched, cytoplasmic F-box protein that functions as the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, preferentially binding high-mannose N-glycans on glycoprotein substrates via its FBA/sugar-binding domain and targeting them for ubiquitin-mediated proteasomal degradation; validated substrates include the insulin receptor, NMDAR subunits GluN1/GluN2A, APP, connexin 26, EBV glycoprotein B, ΔF508-CFTR, A1AT-Z, SUN2, FBN1, IL-6R, KPTN (disrupting KICSTOR-GATOR1-mTORC1 signaling), USP49, WEE1, YTHDF2, NR2F2, LCN2/FABP5, and IL6ST; in the cochlea FBXO2 and Skp1 form a novel heterodimer outside the canonical SCF complex; FBXO2 also mediates CNS lysophagy and xenophagy by recognizing glycan moieties on damaged lysosomes and bacterial surfaces respectively; its activity is regulated by HSV-1-induced nuclear shuttling (enabling UL9 export and degradation) and by RBM47-mediated mRNA stabilization, and it also promotes PINK1/Parkin mitophagy by non-ubiquitination mechanisms."},"narrative":{"mechanistic_narrative":"FBXO2 is a neuronally enriched F-box protein that serves as the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase, recruiting substrates through its F-box-dependent association with Skp1 and selectively engaging high-mannose N-glycans on glycoprotein targets via its FBA/sugar-binding domain [PMID:9857061, PMID:34515398]. Through this glycan-recognition activity it directs a broad set of glycoproteins to ubiquitin-mediated proteasomal degradation, including the insulin receptor, where SCF-FBXO2 activity tunes systemic glucose homeostasis [PMID:27932386], NMDAR subunits GluN1 and GluN2A controlling synaptic receptor surface levels [PMID:25878288], and the amyloid precursor protein [PMID:24469452]. The same glycan-sensing capacity underlies cell-autonomous innate defense: FBXO2 marks N-glycosylated EBV glycoprotein B for degradation to restrict viral entry [PMID:30052682] and, as part of the SCF complex, recognizes GlcNAc moieties on the group A Streptococcus surface and on damaged lysosomal membranes to drive ubiquitin-dependent xenophagy and CNS lysophagy [PMID:34515398, PMID:32931479]. In multiple epithelial cancers FBXO2 acts as a degradative hub through its FBA domain, ubiquitinating substrates such as SUN2, WEE1, USP49, YTHDF2, and KPTN, the last of which disrupts KICSTOR assembly and GATOR1 recruitment to activate amino acid-dependent mTORC1 signaling [PMID:35525855, PMID:40676478, PMID:41401028]. In the cochlea, FBXO2 and Skp1 instead form a heterodimer distinct from the canonical SCF complex that is required for cochlear support-cell survival, and FBXO2 loss causes selective cochlear degeneration in mice [PMID:17494702]. FBXO2 expression is itself controlled transcriptionally and post-transcriptionally, and the protein additionally engages substrates through non-proteasomal routes including autophagy and chaperone-mediated lysosomal degradation [PMID:26295339, PMID:41604941].","teleology":[{"year":1998,"claim":"Established FBXO2 as a bona fide F-box protein that physically couples to the ubiquitin-proteasome machinery, defining its core biochemical identity.","evidence":"Co-IP and F-box deletion mutagenesis with cell proliferation readout in neuroblastoma and CHO cells","pmids":["9857061"],"confidence":"Medium","gaps":["No substrate identified at this stage","Did not establish glycan-recognition specificity","Assembly into full SCF not yet shown"]},{"year":2004,"claim":"Showed FBXO2 recognizes specific glycoprotein substrates and can form complexes beyond the canonical SCF, first hinting at its tissue-specialized role in the cochlea.","evidence":"EMSA, in vitro pulldown, sedimentation equilibrium, and Co-IP from organ of Corti for connexin 26 and Skp1 binding","pmids":["15109709","11470190"],"confidence":"Medium","gaps":["Did not demonstrate ubiquitination/degradation of Cx26 in vivo","Functional consequence of binding unresolved"]},{"year":2004,"claim":"Demonstrated that FBXO2 can be redirected to the nucleus and degrade a viral replication initiator, linking it to antiviral control in neurons.","evidence":"Live-cell imaging of nuclear shuttling, Co-IP, and proteasome inhibitor rescue of UL9 in 293T cells and primary hippocampal neurons","pmids":["12904574","15010529"],"confidence":"Medium","gaps":["Physiological contribution to HSV-1 latency not directly tested","Signal triggering nuclear shuttling unknown"]},{"year":2007,"claim":"Resolved that cochlear FBXO2 functions in a non-canonical Skp1 heterodimer rather than full SCF, and that this complex is essential for cochlear cell survival.","evidence":"Fbxo2 knockout mice with Co-IP, western blot, and histology of the organ of Corti","pmids":["17494702"],"confidence":"Medium","gaps":["Mechanism by which the heterodimer protects support cells unclear","Relevant degradation substrate in cochlea not defined"]},{"year":2015,"claim":"Connected FBXO2 to neuronal and ER-quality-control glycoprotein homeostasis, establishing it as a regulator of synaptic receptor surface levels and misfolded-protein clearance.","evidence":"Fbxo2 knockout mice and cultured neurons with surface biotinylation and electrophysiology (GluN1/GluN2A, APP); cycloheximide chase and knockdown for A1AT-Z in hepatic cells/mice","pmids":["25878288","24469452","26295339"],"confidence":"Medium","gaps":["Selectivity for GluN2A over GluN2B not mechanistically explained","Relative use of proteasomal vs autophagic routes substrate-dependent and incompletely defined"]},{"year":2016,"claim":"Identified FBXO2 as an SCF E3 controlling metabolic and disease-relevant glycoproteins, demonstrating in vivo physiological consequence.","evidence":"LC-MS/MS substrate screening with in vivo gain/loss-of-function for the insulin receptor; siRNA and Cl- transport assays for ΔF508-CFTR in primary airway epithelia","pmids":["27932386","27756846"],"confidence":"High","gaps":["Whether IR degradation is direct via glycan recognition vs indirect not fully separated for CFTR","CFTR involvement via a complex distinct from SYVN1 not structurally characterized"]},{"year":2018,"claim":"Mapped substrate recognition to the FBA sugar-binding domain engaging high-mannose N-glycans, providing the molecular basis for FBXO2 antiviral restriction.","evidence":"Co-IP, ubiquitination, and viral fusion/entry assays for EBV glycoprotein B via the sugar-binding domain","pmids":["30052682"],"confidence":"High","gaps":["Generality of high-mannose preference across all substrates not exhaustively tested"]},{"year":2021,"claim":"Generalized FBXO2 glycan-sensing to innate immunity, showing it tags non-self and damaged-self carbohydrate surfaces for selective autophagy.","evidence":"FBXO2 knockout cells with ubiquitin-accumulation and bacterial clearance assays and sugar-binding mutants for GAS xenophagy; primary neuron and NPC mouse models for CNS lysophagy with SCF components required","pmids":["34515398","32931479"],"confidence":"High","gaps":["Adaptor linking ubiquitinated targets to autophagic machinery not defined","How a cytoplasmic glycoprotein-glycan ligase accesses luminal/surface glycans mechanistically open"]},{"year":2025,"claim":"Defined FBXO2 as a broad oncogenic and signaling degradative hub acting through its FBA/C-terminal regions on diverse substrates with site- and linkage-specific ubiquitination.","evidence":"Co-IP/MS, domain mapping, site-directed mutagenesis, linkage-specific ubiquitination, and xenograft/in vivo models for KPTN, WEE1, USP49, YTHDF2, SUN2, NR2F2, LCN2, FABP5, and IL6ST","pmids":["41401028","40676478","41035649","41461633","35525855","41436429","40791152","41604941","41076860"],"confidence":"Medium","gaps":["Many substrates validated in single tumor contexts without cross-validation","Determinants choosing K48 vs K63 vs K27 vs autophagic fate per substrate unresolved","Whether all substrates require glycan recognition not uniformly established"]},{"year":null,"claim":"How FBXO2 substrate selection is governed across its many reported targets and how it switches between SCF-dependent proteasomal degradation, autophagy/lysophagy, and non-degradative roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of glycan vs non-glycan substrate recognition","Regulation of complex composition (canonical SCF vs Skp1 heterodimer) across tissues unclear","Physiological hierarchy among the large substrate set not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10,12,16,21]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[10,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,12,16]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,12,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13,16,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,15,21]}],"complexes":["SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase","FBXO2-Skp1 cochlear heterodimer"],"partners":["SKP1","CUL1","RBX1","APC2","KPTN","USP49","WEE1","SUN2"],"other_free_text":[]}},"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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deletion mutagenesis, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by pulldown/Co-IP with deletion mutant, single lab, two orthogonal methods\",\n      \"pmids\": [\"9857061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"OCP1 (FBXO2) co-localizes with OCP2 (Skp1) in the epithelial gap-junction region of the cochlear organ of Corti, consistent with formation of an SCF ubiquitin ligase complex at this site.\",\n      \"method\": \"Immunohistochemistry, sequence analysis\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method localization, no functional rescue\",\n      \"pmids\": [\"11470190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NFB42 (FBXO2) binds the phosphorylated HSV-1 replication-initiator protein UL9, promoting its polyubiquitination and degradation via the 26S proteasome; MG132 treatment restores UL9 levels, confirming proteasomal mechanism.\",\n      \"method\": \"Co-expression in 293T cells, proteasome inhibitor (MG132) rescue, in vivo polyubiquitination assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional degradation assay plus proteasome inhibitor rescue and ubiquitination detection, single lab\",\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, export UL9 to the cytoplasm, and mediate its ubiquitination and proteasomal degradation, thereby potentially promoting viral latency in neurons.\",\n      \"method\": \"Live-cell imaging of NFB42 nuclear shuttling, co-immunoprecipitation of NFB42-UL9, proteasome inhibitor rescue in 293T cells and primary hippocampal neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (imaging, Co-IP, pharmacological rescue) in single lab\",\n      \"pmids\": [\"15010529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OCP1 (FBXO2) forms a heterodimeric complex with OCP2 (Skp1) in the organ of Corti, and directly binds connexin 26 (Cx26) as shown by electrophoretic mobility-shift, in vitro pulldown with 35S-labeled Cx26, and co-immunoprecipitation from organ of Corti extracts.\",\n      \"method\": \"Electrophoretic mobility-shift assay, pulldown with immobilized OCP1, sedimentation equilibrium, co-immunoprecipitation from tissue extracts\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (EMSA, pulldown, Co-IP, sedimentation), single lab\",\n      \"pmids\": [\"15109709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cochlear FBXO2 binds Skp1 to form a novel heterodimeric complex distinct from the canonical SCF complex (Cullin1 and Rbx1 show little association with Fbx2/Skp1 in the cochlea); loss of Fbxo2 in knockout mice leads to parallel loss of cochlear Skp1 levels and selective cochlear degeneration beginning in epithelial support cells.\",\n      \"method\": \"Targeted gene knockout, co-immunoprecipitation, western blot, histology\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cochlear phenotype plus biochemical complex analysis, single lab\",\n      \"pmids\": [\"17494702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FBG1 (FBXO2) directly interacts with APC2 via a D-box motif within its F-box domain; co-expression sequesters free APC2 (raising total but lowering free APC2), inhibiting cell proliferation and inducing S-phase arrest independent of its ubiquitin ligase function.\",\n      \"method\": \"Co-immunoprecipitation, D-box mutagenesis, FACS cell cycle analysis, western blot\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with mutagenesis and functional cell-cycle readout, single lab\",\n      \"pmids\": [\"21135578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBXO2 targets APP (amyloid precursor protein), a high-mannose glycoprotein, for ubiquitin-mediated degradation; loss of Fbxo2 in knockout mice and cultured hippocampal neurons increases APP levels and processing into cleavage products, with a concomitant reduction of APP at the cell surface.\",\n      \"method\": \"Fbxo2 knockout mice, cultured hippocampal neurons/slices, western blot, cell surface biotinylation, non-neuronal cell overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo loss-of-function with multiple readouts, single lab\",\n      \"pmids\": [\"24469452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxo2 regulates GluN1 and GluN2A (but not GluN2B) NMDAR subunit levels and surface localization in the adult mouse brain; loss of Fbxo2 increases surface GluN1 and GluN2A, elevates synaptic markers PSD-95 and Vglut1, and promotes aberrant axo-dendritic shaft synapses without altering spine density or neurophysiology.\",\n      \"method\": \"Fbxo2 knockout mice, western blot, surface biotinylation, immunofluorescence, electrophysiology, confocal microscopy\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"25878288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBG1 (FBXO2) degrades the misfolded glycoprotein A1AT-Z through both the ubiquitin-proteasome system and Beclin1-dependent autophagy; overexpression decreases A1AT-Z half-life and knockdown in hepatic cells and mice increases A1AT-Z accumulation.\",\n      \"method\": \"Chemical inhibitors, genetic knockdown/overexpression, cycloheximide chase, Beclin1 co-dependency assay in hepatic cell lines and mouse liver\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and genetic approaches, in vitro and in vivo, single lab\",\n      \"pmids\": [\"26295339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCFFBXO2 acts as an E3 ubiquitin ligase that targets the insulin receptor (IR) for ubiquitin-dependent proteasomal degradation; overexpression of FBXO2 in healthy mice causes hyperglycemia and insulin resistance, while ablation in obese mice alleviates diabetic phenotypes.\",\n      \"method\": \"Protein purification combined with LC-MS/MS substrate screening, adenovirus-mediated overexpression in mice, Fbxo2 knockout in obese mouse model, glucose tolerance and insulin tolerance tests\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — substrate identified by MS, validated in vivo gain- and loss-of-function with metabolic phenotypes, single lab with multiple orthogonal methods\",\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 cystic fibrosis airway epithelia, indicating FBXO2 participates in ubiquitin-mediated proteasomal degradation of ΔF508-CFTR via a distinct complex from SYVN1.\",\n      \"method\": \"siRNA knockdown, functional CFTR Cl⁻ transport assay in polarized primary airway epithelia, CFTR maturation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transport assay in primary human cells with genetic knockdown, single lab\",\n      \"pmids\": [\"27756846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FBXO2 directly binds N-glycosylated (high-mannose) EBV glycoprotein B (gB) through its sugar-binding domain, promoting gB ubiquitination and proteasomal degradation; FBXO2 depletion stabilizes gB, promotes its transport from ER to plasma membrane, and enhances viral membrane fusion and entry.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, ubiquitination assay, membrane fusion assay, viral infectivity assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination, functional viral entry/fusion assays) demonstrating direct binding and functional consequence, single lab\",\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: loss of Fbxo2 in mouse primary cortical cultures delays clearance of damaged lysosomes and decreases viability after lysosomal damage; Fbxo2 deficiency in a NPC mouse model exacerbates motor deficits, neurodegeneration, and reduces survival.\",\n      \"method\": \"Primary cortical neuron cultures from Fbxo2 knockout mice, lysosomal damage assay, NPC mouse model with Fbxo2 deficiency, behavioral testing, histology\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with in vitro and in vivo phenotypic readouts, single lab\",\n      \"pmids\": [\"32931479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO2 targets glycosylated fibrillin-1 (FBN1) for ubiquitin-dependent proteasomal degradation to promote endometrial cancer cell proliferation, acting through regulation of cell cycle proteins (CDK4, CyclinD1/D2/A1) and autophagy pathway components (ATG4A/4D).\",\n      \"method\": \"Ubiquitination-proteome approach to identify substrates, ubiquitination assay, RNA-seq, knockdown/overexpression, xenograft mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by proteomics and validated with ubiquitination assay and functional rescue, single lab\",\n      \"pmids\": [\"32984335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO2 promotes osteosarcoma proliferation by targeting IL-6 receptor (IL-6R) for ubiquitin-mediated degradation, thereby activating STAT3 phosphorylation and downstream gene expression; this function requires FBXO2's glycoprotein recognition activity.\",\n      \"method\": \"CRISPR-Cas9 knockout, retrovirus overexpression, co-immunoprecipitation, luciferase reporter assay for STAT3 transcriptional activity, xenograft mouse model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional reporter assay, in vivo xenograft, single lab\",\n      \"pmids\": [\"32549792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO2/SCF ubiquitin ligase complex recognizes GlcNAc side chains of the group A Streptococcus (GAS) surface carbohydrate through FBXO2's sugar-binding motif, promoting ubiquitin-mediated xenophagy; FBXO2 knockout reduces ubiquitin accumulation on intracellular GAS and decreases xenophagic bacterial degradation; SKP1, CUL1, and ROC1 (other SCF components) are also required.\",\n      \"method\": \"FBXO2 knockout cell lines, ubiquitin accumulation assay on intracellular GAS, xenophagy/bacterial clearance assay, sugar-binding domain mutant analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with multiple functional readouts (ubiquitin accumulation, bacterial clearance), domain-mapping with mutants, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34515398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO2 directly interacts with glycosylated SUN2 and promotes its ubiquitin-dependent proteasomal degradation; the SOX6 transcription factor promotes FBXO2 expression by binding its promoter, establishing a SOX6-FBXO2-SUN2 axis in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, promoter reporter assay, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, promoter validation, in vivo xenograft, single lab\",\n      \"pmids\": [\"35525855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM47 binds FBXO2 mRNA and stabilizes it post-transcriptionally to promote STAT3 phosphorylation and downstream signaling in chondrocytes; FBXO2 overexpression reverses the alleviating effects of RBM47 knockdown on IL-1β-induced inflammation and ECM degradation.\",\n      \"method\": \"RBM47 RNA-binding assay, FBXO2 mRNA stability assay, STAT3 phosphorylation western blot, rescue experiment with FBXO2 overexpression\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect post-transcriptional regulation of FBXO2 with limited mechanistic detail on FBXO2 itself, single lab\",\n      \"pmids\": [\"38070024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO2 directly binds p53 and promotes its ubiquitination and proteasomal degradation in papillary thyroid carcinoma; p53 knockdown partially reverses the anti-proliferative effects of FBXO2 knockdown, confirming functional epistasis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, rescue epistasis experiment, subcutaneous xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, epistasis rescue, single lab\",\n      \"pmids\": [\"39343799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 binds lipocalin-2 (LCN2) via its FBA domain and promotes K27-linked polyubiquitination of LCN2, driving its proteasomal degradation; this suppresses ferroptosis (lipid peroxidation, glutathione depletion, iron overload) and activates PINK1/Parkin-dependent mitophagy in nucleus pulposus cells; AAV9-mediated FBXO2 overexpression ameliorates intervertebral disc degeneration in rats.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBA domain mapping, proteomics, FBXO2 KO mice, AAV9 overexpression in rats, mitochondrial functional assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped Co-IP, ubiquitination assay with linkage specificity, in vivo models, single lab\",\n      \"pmids\": [\"40791152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 colocalizes and directly interacts with KPTN (a KICSTOR complex subunit) via its F-box-associated (FBA) domain, promoting K48- and K63-linked polyubiquitination of KPTN at K49, K67, K262, and K265; this disrupts KICSTOR assembly, impairs GATOR1 lysosomal recruitment, and activates amino acid-dependent mTORC1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with linkage-specific antibodies, site-directed mutagenesis of KPTN ubiquitination sites, co-localization imaging, mTORC1 activity assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — domain mapping, site-specific mutagenesis, multiple ubiquitination linkage assays, pathway epistasis (GATOR1 recruitment), single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"41401028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fbxo2 binds the kinase domain of WEE1 via its FBA domain and promotes WEE1 ubiquitination and proteasomal degradation; Fbxo2 knockdown increases RCC cell motility and proliferation, and WEE1 depletion partially rescues the tumorigenic effects of Fbxo2 silencing in xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, FBA domain mutant, xenograft mouse model, rescue epistasis\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS substrate identification, domain mapping, ubiquitination assay, in vivo epistasis, single lab\",\n      \"pmids\": [\"40676478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 directly binds USP49 and targets it for ubiquitin-mediated proteasomal degradation in hepatocellular carcinoma; USP49 knockdown reverses the inhibitory effects of FBXO2 knockdown, confirming the FBXO2/USP49 axis; FBXO2 depletion enhances sorafenib sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, cycloheximide chase, rescue epistasis, xenograft sorafenib treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination and stability assays, epistasis rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"41035649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fbxo2 targets the m6A reader YTHDF2 for ubiquitin-mediated proteasomal degradation in prostate cancer; the C-terminal region of Fbxo2 is required for YTHDF2 ubiquitination; K286 of YTHDF2 is the key ubiquitination site; YTHDF2 promotes PCa progression by modulating m6A methylation of CDKN1C mRNA.\",\n      \"method\": \"Co-immunoprecipitation mass spectrometry, Co-IP, ubiquitination assay, site-directed mutagenesis (K286), rescue experiments, in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by Co-IP-MS, validated with mutagenesis and ubiquitination assay, epistasis rescue, single lab\",\n      \"pmids\": [\"41461633\"],\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; NR2F2 degradation suppresses LCN2 expression and thereby reduces CD8+ T cell exhaustion in pancreatic cancer.\",\n      \"method\": \"In vivo CRISPR-Cas9 screen, co-immunoprecipitation, ubiquitination assay with site-specific mapping (K362), NR2F2 transcriptional reporter, tumor immune profiling\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen identification, Co-IP, ubiquitination with site-mapping, functional immune readout, single lab\",\n      \"pmids\": [\"41436429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 interacts with FABP5 and promotes its lysosomal degradation through chaperone-mediated autophagy (not proteasomal), reducing intracellular polyunsaturated fatty acid (PUFA) levels and conferring resistance to ferroptosis in colorectal cancer; this is downstream of p53 transcriptional induction of FBXO2.\",\n      \"method\": \"Co-immunoprecipitation, FBXO2 overexpression/knockdown, lipid peroxidation and cell death assays, fatty acid supplementation rescue, in vivo tumor models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional ferroptosis assay, fatty acid rescue, in vivo validation, single lab\",\n      \"pmids\": [\"41604941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO2 promotes K63-linked ubiquitination of IL6ST (glycoprotein 130) to restore STAT3 signaling during decidualization; cadmium exposure downregulates FBXO2 and suppresses this IL6ST/STAT3 axis, impairing decidualization.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, ubiquitination assay (K63-linkage specific), FBXO2 overexpression rescue, in vivo Cd-exposed mouse model\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination, in vivo model, rescue experiment, single lab\",\n      \"pmids\": [\"41076860\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO2 is a neuronally enriched, cytoplasmic F-box protein that functions as the substrate-recognition subunit of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, preferentially binding high-mannose N-glycans on glycoprotein substrates via its FBA/sugar-binding domain and targeting them for ubiquitin-mediated proteasomal degradation; validated substrates include the insulin receptor, NMDAR subunits GluN1/GluN2A, APP, connexin 26, EBV glycoprotein B, ΔF508-CFTR, A1AT-Z, SUN2, FBN1, IL-6R, KPTN (disrupting KICSTOR-GATOR1-mTORC1 signaling), USP49, WEE1, YTHDF2, NR2F2, LCN2/FABP5, and IL6ST; in the cochlea FBXO2 and Skp1 form a novel heterodimer outside the canonical SCF complex; FBXO2 also mediates CNS lysophagy and xenophagy by recognizing glycan moieties on damaged lysosomes and bacterial surfaces respectively; its activity is regulated by HSV-1-induced nuclear shuttling (enabling UL9 export and degradation) and by RBM47-mediated mRNA stabilization, and it also promotes PINK1/Parkin mitophagy by non-ubiquitination mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO2 is a neuronally enriched F-box protein that serves as the substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase, recruiting substrates through its F-box-dependent association with Skp1 and selectively engaging high-mannose N-glycans on glycoprotein targets via its FBA/sugar-binding domain [#0, #16]. Through this glycan-recognition activity it directs a broad set of glycoproteins to ubiquitin-mediated proteasomal degradation, including the insulin receptor, where SCF-FBXO2 activity tunes systemic glucose homeostasis [#10], NMDAR subunits GluN1 and GluN2A controlling synaptic receptor surface levels [#8], and the amyloid precursor protein [#7]. The same glycan-sensing capacity underlies cell-autonomous innate defense: FBXO2 marks N-glycosylated EBV glycoprotein B for degradation to restrict viral entry [#12] and, as part of the SCF complex, recognizes GlcNAc moieties on the group A Streptococcus surface and on damaged lysosomal membranes to drive ubiquitin-dependent xenophagy and CNS lysophagy [#16, #13]. In multiple epithelial cancers FBXO2 acts as a degradative hub through its FBA domain, ubiquitinating substrates such as SUN2, WEE1, USP49, YTHDF2, and KPTN, the last of which disrupts KICSTOR assembly and GATOR1 recruitment to activate amino acid-dependent mTORC1 signaling [#17, #22, #21]. In the cochlea, FBXO2 and Skp1 instead form a heterodimer distinct from the canonical SCF complex that is required for cochlear support-cell survival, and FBXO2 loss causes selective cochlear degeneration in mice [#5]. FBXO2 expression is itself controlled transcriptionally and post-transcriptionally, and the protein additionally engages substrates through non-proteasomal routes including autophagy and chaperone-mediated lysosomal degradation [#9, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established FBXO2 as a bona fide F-box protein that physically couples to the ubiquitin-proteasome machinery, defining its core biochemical identity.\",\n      \"evidence\": \"Co-IP and F-box deletion mutagenesis with cell proliferation readout in neuroblastoma and CHO cells\",\n      \"pmids\": [\"9857061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No substrate identified at this stage\", \"Did not establish glycan-recognition specificity\", \"Assembly into full SCF not yet shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed FBXO2 recognizes specific glycoprotein substrates and can form complexes beyond the canonical SCF, first hinting at its tissue-specialized role in the cochlea.\",\n      \"evidence\": \"EMSA, in vitro pulldown, sedimentation equilibrium, and Co-IP from organ of Corti for connexin 26 and Skp1 binding\",\n      \"pmids\": [\"15109709\", \"11470190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate ubiquitination/degradation of Cx26 in vivo\", \"Functional consequence of binding unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated that FBXO2 can be redirected to the nucleus and degrade a viral replication initiator, linking it to antiviral control in neurons.\",\n      \"evidence\": \"Live-cell imaging of nuclear shuttling, Co-IP, and proteasome inhibitor rescue of UL9 in 293T cells and primary hippocampal neurons\",\n      \"pmids\": [\"12904574\", \"15010529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contribution to HSV-1 latency not directly tested\", \"Signal triggering nuclear shuttling unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved that cochlear FBXO2 functions in a non-canonical Skp1 heterodimer rather than full SCF, and that this complex is essential for cochlear cell survival.\",\n      \"evidence\": \"Fbxo2 knockout mice with Co-IP, western blot, and histology of the organ of Corti\",\n      \"pmids\": [\"17494702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the heterodimer protects support cells unclear\", \"Relevant degradation substrate in cochlea not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected FBXO2 to neuronal and ER-quality-control glycoprotein homeostasis, establishing it as a regulator of synaptic receptor surface levels and misfolded-protein clearance.\",\n      \"evidence\": \"Fbxo2 knockout mice and cultured neurons with surface biotinylation and electrophysiology (GluN1/GluN2A, APP); cycloheximide chase and knockdown for A1AT-Z in hepatic cells/mice\",\n      \"pmids\": [\"25878288\", \"24469452\", \"26295339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for GluN2A over GluN2B not mechanistically explained\", \"Relative use of proteasomal vs autophagic routes substrate-dependent and incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified FBXO2 as an SCF E3 controlling metabolic and disease-relevant glycoproteins, demonstrating in vivo physiological consequence.\",\n      \"evidence\": \"LC-MS/MS substrate screening with in vivo gain/loss-of-function for the insulin receptor; siRNA and Cl- transport assays for ΔF508-CFTR in primary airway epithelia\",\n      \"pmids\": [\"27932386\", \"27756846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IR degradation is direct via glycan recognition vs indirect not fully separated for CFTR\", \"CFTR involvement via a complex distinct from SYVN1 not structurally characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped substrate recognition to the FBA sugar-binding domain engaging high-mannose N-glycans, providing the molecular basis for FBXO2 antiviral restriction.\",\n      \"evidence\": \"Co-IP, ubiquitination, and viral fusion/entry assays for EBV glycoprotein B via the sugar-binding domain\",\n      \"pmids\": [\"30052682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of high-mannose preference across all substrates not exhaustively tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized FBXO2 glycan-sensing to innate immunity, showing it tags non-self and damaged-self carbohydrate surfaces for selective autophagy.\",\n      \"evidence\": \"FBXO2 knockout cells with ubiquitin-accumulation and bacterial clearance assays and sugar-binding mutants for GAS xenophagy; primary neuron and NPC mouse models for CNS lysophagy with SCF components required\",\n      \"pmids\": [\"34515398\", \"32931479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor linking ubiquitinated targets to autophagic machinery not defined\", \"How a cytoplasmic glycoprotein-glycan ligase accesses luminal/surface glycans mechanistically open\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined FBXO2 as a broad oncogenic and signaling degradative hub acting through its FBA/C-terminal regions on diverse substrates with site- and linkage-specific ubiquitination.\",\n      \"evidence\": \"Co-IP/MS, domain mapping, site-directed mutagenesis, linkage-specific ubiquitination, and xenograft/in vivo models for KPTN, WEE1, USP49, YTHDF2, SUN2, NR2F2, LCN2, FABP5, and IL6ST\",\n      \"pmids\": [\"41401028\", \"40676478\", \"41035649\", \"41461633\", \"35525855\", \"41436429\", \"40791152\", \"41604941\", \"41076860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many substrates validated in single tumor contexts without cross-validation\", \"Determinants choosing K48 vs K63 vs K27 vs autophagic fate per substrate unresolved\", \"Whether all substrates require glycan recognition not uniformly established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FBXO2 substrate selection is governed across its many reported targets and how it switches between SCF-dependent proteasomal degradation, autophagy/lysophagy, and non-degradative roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of glycan vs non-glycan substrate recognition\", \"Regulation of complex composition (canonical SCF vs Skp1 heterodimer) across tissues unclear\", \"Physiological hierarchy among the large substrate set not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10, 12, 16, 21]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [10, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 12, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13, 16, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 15, 21]}\n    ],\n    \"complexes\": [\n      \"SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase\",\n      \"FBXO2-Skp1 cochlear heterodimer\"\n    ],\n    \"partners\": [\n      \"SKP1\",\n      \"CUL1\",\n      \"RBX1\",\n      \"APC2\",\n      \"KPTN\",\n      \"USP49\",\n      \"WEE1\",\n      \"SUN2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}