{"gene":"FBXO7","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2004,"finding":"Fbxo7 functions as a substrate-recognition adaptor in the SCF(Fbxo7) E3 ubiquitin ligase complex, recruiting HURP (hepatoma up-regulated protein) through its C-terminal proline-rich region in a Cdk1-cyclin B phosphorylation-dependent manner, leading to proteasome-mediated degradation of HURP. Mutation of Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbxo7 abolished Fbxo7-HURP association.","method":"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro assay with mutagenesis of both substrate and adaptor, siRNA knockdown, and co-IP; multiple orthogonal methods in single study","pmids":["15145941"],"is_preprint":false},{"year":2005,"finding":"Fbxo7 selectively binds Cdk6 (but not Cdk4 or Cdk2) and D-type cyclins, enhancing cyclin D/Cdk6 complex formation and kinase activity. Fbxo7 overexpression transforms murine fibroblasts in a Cdk6-dependent manner, and Fbxo7 knockdown decreases Cdk6 association with cyclin. Fbxo7 also interacts with p27 but its enhancement of cyclin D/Cdk6 activity is p21/p27-independent.","method":"Co-immunoprecipitation (in vitro and in vivo), siRNA knockdown, kinase assay, E2F reporter assay, transformation assay, nude mouse xenograft","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in vitro and in vivo, functional rescue by Cdk6 knockdown, kinase activity assay; multiple orthogonal methods","pmids":["16096642"],"is_preprint":false},{"year":2006,"finding":"Fbxo7 interacts with cIAP1 (inhibitor of apoptosis protein 1) in human cells, co-localizes with cIAP1 in cytoplasm, nucleus, and Golgi-like structures, and overexpression of Fbxo7 promotes ubiquitination of cIAP1, suggesting SCF(Fbxo7)-mediated ubiquitination of cIAP1.","method":"Yeast two-hybrid screen, co-immunoprecipitation, co-localization by fluorescence microscopy, ubiquitination assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay in cells; single lab, no in vitro reconstitution or mutagenesis","pmids":["16510124"],"is_preprint":false},{"year":2008,"finding":"Fbxo7 and PI31 share a conserved N-terminal FP (Fbxo7/PI31) domain that mediates homodimerization of each protein and heterodimerization between Fbxo7·Skp1 and PI31. Crystal structure of the PI31 FP domain revealed a novel alpha/beta-fold. Mutations in the FP domain ablate Fbxo7-PI31 interaction and Fbxo7 homodimerization. Knockdown of Fbxo7 does not affect PI31 levels, arguing against PI31 being a substrate of SCF(Fbxo7).","method":"Crystal structure determination, biophysical analysis (including analytical ultracentrifugation), mutagenesis, co-immunoprecipitation, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biophysical and mutational validation; multiple orthogonal methods","pmids":["18495667"],"is_preprint":false},{"year":2011,"finding":"FBXO7 isoform 1 displays predominantly diffuse nuclear localization in human cell lines and mouse primary neurons. An intact N-terminus is required for nuclear localization; PARK15-linked missense mutation (T22M) or N-terminal tagging causes cytoplasmic mislocalization. The N-terminus of wild-type (but not mutant) FBXO7 can confer nuclear localization to the cytoplasmic protein profilin. PARK15 patient cells show depletion of FBXO7 isoform 1.","method":"Immunofluorescence/localization studies, overexpression of wild-type and mutant constructs, fusion protein localization assay, patient cell analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with mutagenesis and functional fusion assay; single lab","pmids":["21347293"],"is_preprint":false},{"year":2011,"finding":"Fbxo7 knockdown in haematopoietic pro-B (Ba/F3) cells increases proliferation, decreases cell size, shortens G1, decreases p27 levels, and increases S-phase cyclins and Cdk2 activity. Fbxo7 protein levels inversely correlate with CD43 expression, suggesting regulation of B cell maturation. Homozygous Fbxo7(LacZ) mice show increased pro-B cell and pro-erythroblast populations.","method":"siRNA/shRNA knockdown, cell cycle analysis, flow cytometry, transgenic mouse model (LacZ insertion)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotypes plus in vivo mouse model; single lab","pmids":["21652635"],"is_preprint":false},{"year":2013,"finding":"Fbxo7 physically interacts with PINK1 and Parkin and participates in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression show deficiencies in Parkin translocation to mitochondria, ubiquitination of mitofusin 1, and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescues loss of Parkin. PD-causing mutations in Fbxo7 interfere with this process.","method":"Co-immunoprecipitation, siRNA knockdown with mitophagy assays (Parkin translocation, mitofusin 1 ubiquitination, mitochondrial clearance), Drosophila genetic rescue","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined mitophagy phenotypes, genetic epistasis in Drosophila; multiple orthogonal methods across two systems","pmids":["23933751"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of the Fbxo7 FP domain at 2.0 Å resolution reveals an alpha/beta fold. The Fbxo7 FP domain uses an alpha/beta interface for inter-domain protein-protein interaction (distinct from the PI31 FP domain which uses alpha-alpha or beta-beta interfaces), features a larger contact surface area and more extensive hydrophobic interactions, and has the potential to bind two protein partners simultaneously.","method":"X-ray crystallography (2.0 Å resolution, SAD phasing)","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determined with SAD phasing to 2.0 Å; rigorous structural study","pmids":["24419388"],"is_preprint":false},{"year":2014,"finding":"FBXO7 interacts with NRAGE and mediates K63-linked poly-ubiquitination of NRAGE in mammalian cells. FBXO7 overexpression accelerates NRAGE-TAK1-TAB1 complex formation and facilitates BMP receptor-NRAGE-TAK1-TAB1 complex assembly, upregulating NF-κB activity. BMP4 stimulation enhances NRAGE ubiquitination through FBXO7. This is a proteasome-independent ubiquitination.","method":"Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assay (K63-linkage specific), siRNA knockdown, reporter assay (NF-κB)","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid validated by Co-IP, K63 chain-specific ubiquitination assay, NF-κB reporter; single lab","pmids":["24947323"],"is_preprint":false},{"year":2015,"finding":"Fbxo7 stabilizes p27 protein levels during erythropoiesis. The M115I Fbxo7 variant (associated with SNP for smaller erythrocytes) binds p27 less efficiently and cells expressing Ile115 proliferate faster. Reduced Fbxo7 expression in erythroleukaemic cells fails to stabilize p27, impairs cell cycle exit, and blocks haemoglobin production. Fbxo7-deficient mice are anaemic with lower p27 levels and delayed mitophagy during terminal erythroid differentiation.","method":"Co-immunoprecipitation, protein stability assay, cell cycle analysis, mouse model, haemoglobin assay, mitophagy assay","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allelic binding assay, KD with phenotype, mouse model; single lab with multiple methods","pmids":["26095538"],"is_preprint":false},{"year":2016,"finding":"SCF(Fbxo7) ubiquitin ligase binds and ubiquitinates the proteasomal subunit PSMA2. FBXO7 is a proteasome-associated protein involved in proteasome assembly. FBXO7 knockout mice show reduced proteasome activity and early-onset motor deficits. Conditional deletion of FBXO7 in TH-positive or NEX-positive forebrain neurons causes motor defects.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome activity assay, conditional knockout mouse (Cre-lox), behavioral assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, in vitro ubiquitination, proteasome activity assay, and multiple conditional KO mouse lines with defined phenotypes; single lab but multiple orthogonal methods","pmids":["27497298"],"is_preprint":false},{"year":2016,"finding":"Fbxo7 deficiency leads to reduced cellular NAD+ levels, increased mitochondrial NADH redox index, impaired complex I activity in the electron transport chain, reduced mitochondrial membrane potential, reduced ATP, and increased cytosolic ROS. ROS activates PARP, and PARP inhibition restores NAD+, redox balance, and ATP pool, indicating PARP overactivation as a cause of decreased complex I-driven respiration in Fbxo7-deficient cells.","method":"Cellular metabolic assays (NAD+/NADH, oxygen consumption, mitochondrial membrane potential, ATP, ROS), PARP inhibitor rescue experiments, siRNA knockdown","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple metabolic assays with pharmacological rescue; single lab","pmids":["27689878"],"is_preprint":false},{"year":2016,"finding":"SCF(Fbxo7) ubiquitinates Gsk3β using K63 linkages and negatively regulates Gsk3β activity (rather than its levels or localization). SCF(Fbxo7) also ubiquitinates Tomm20; Tomm20 levels correlate positively with Fbxo7 expression (stabilizing effect). PD-associated Fbxo7 mutations do not impair Tomm20 ubiquitination.","method":"Protein array screen (high-throughput), in vitro ubiquitination assay, in vivo ubiquitination assay, ubiquitin chain restriction analysis, kinase activity assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro and in vivo ubiquitination assays with chain-type analysis, kinase activity measurement; single lab but multiple orthogonal methods","pmids":["27503909"],"is_preprint":false},{"year":2016,"finding":"Fbxo7 differentially regulates T cell development: Fbxo7-deficient immature thymocytes fail to expand due to lack of Cdk6 activity, while mature T cells show enhanced proliferation upon TCR engagement due to reduced p27 levels. These opposing effects are mediated through Fbxo7's distinct interactions with Cdk6 and p27 at different stages of T cell development.","method":"Transgenic mouse model (reduced Fbxo7 expression), flow cytometry, cell cycle analysis, Cdk6 activity assay, p27 western blot","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with mechanistic dissection via Cdk6 and p27 measurements; single lab","pmids":["27915416"],"is_preprint":false},{"year":2019,"finding":"Conditional deletion of Fbxo7 in midbrain dopamine neurons causes progressive loss of dopamine neurons and striatal dopamine levels. Mechanistically, there is increased expression of RPL23 (ribosomal stress sensor that inhibits MDM2), a corresponding activated p53 transcriptional signature biased toward pro-apoptotic genes, suggesting that FBXO7 normally suppresses the RPL23-MDM2-p53 axis to protect dopaminergic neurons.","method":"Conditional knockout mouse (dopamine neuron-specific), HPLC, immunohistochemistry, RNA-seq/transcriptional analysis, protein expression analysis","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with pathway analysis; pathway placement is correlative (increased RPL23, activated p53 signature) without direct epistasis rescue","pmids":["31144295"],"is_preprint":false},{"year":2019,"finding":"Male mice with reduced Fbxo7 expression are sterile. Despite successful meiosis and nuclear elongation, spermatids are phagocytosed by Sertoli cells during late spermiogenesis/cytoplasmic remodeling. PI31 levels are reduced in Fbxo7 mutant mice. The Drosophila ortholog (nutcracker) mutant shows the same sterility phenotype attributed to decreased DmPI31 and reduced proteasome activity, indicating conserved requirement for Fbxo7 at this developmental stage.","method":"Mouse model (hypomorphic/reduced expression), histology, electron microscopy, western blot (PI31 levels), Drosophila mutant analysis","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse and Drosophila models with histological and molecular analysis; conservation shown across species","pmids":["31649556"],"is_preprint":false},{"year":2020,"finding":"FBXO7 targets PINK1 for ubiquitylation and proteasomal degradation, thereby mediating PINK1 cellular disposal and inducing mitochondrial injury. A small molecule (BC1464) identified by computational screening abrogates FBXO7-PINK1 association, increases PINK1 levels and activity, and limits mitochondrial damage, inflammation, and neuronal death.","method":"Co-immunoprecipitation, ubiquitination assay, PINK1 stability/degradation assay, small molecule inhibitor screen, cell viability assay, murine lung inflammation model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue; single lab","pmids":["32493843"],"is_preprint":false},{"year":2020,"finding":"Fbxo7 and Pink1 reciprocally regulate each other's protein levels. Wild-type and PD familial mutant Fbxo7 stabilize the processed form of Pink1. The interaction of Fbxo7 with Bag2 further enhances Fbxo7's ability to stabilize Pink1. Pink1-mediated stabilization of Fbxo7 is observed specifically in substantia nigra pars compacta but not striatum or cerebral cortex.","method":"Co-immunoprecipitation, western blot (protein stability), regional brain fractionation, overexpression/knockdown studies","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and western blot protein stability assays; single lab, multiple cell and tissue contexts","pmids":["33291077"],"is_preprint":false},{"year":2020,"finding":"SCF(Fbxo7) mediates proteasomal degradation of UXT-V2 (ubiquitously expressed transcript isoform 2) through K48- and K63-linked polyubiquitination, reducing UXT-V2 stability. The Ubl domain of Fbxo7 contributes to interaction with UXT-V2. FBXO7 knockdown promotes UXT-V2 accumulation, and overexpression of FBXO7-ΔF-box protects UXT-V2 from degradation and enhances NF-κB reporter activity. UXT-V2 colocalizes with Fbxo7 in the nucleus.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, cycloheximide chase assay, ubiquitin chain restriction analysis, siRNA knockdown, NF-κB reporter assay, co-localization microscopy","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of ubiquitination with chain-type analysis, stability assays, reporter assay; multiple orthogonal methods, single lab","pmids":["33010352"],"is_preprint":false},{"year":2020,"finding":"p105 (NF-κB precursor) binds to FBXO7 and is ubiquitinated by it, but this leads to p105 accumulation rather than degradation (p105 is a pseudo-substrate of FBXO7). An inactive ΔF-box mutant of FBXO7 has the same effect on p105 accumulation, indicating ligase-independent stabilization. FBXO7 binding to p105 also increases p65 levels and promotes cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, ΔF-box dominant-negative mutant, western blot, cell proliferation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, ubiquitination assay, and mutant analysis; single lab with multiple methods","pmids":["32933748"],"is_preprint":false},{"year":2021,"finding":"FBXO7 interacts with GET4 (a subunit of the BAG6 complex) directly, and this interaction is reduced in PD-associated FBXO7 variants. GET4 and UBL4A (other BAG6 complex subunits) are required for proper proteasome activity. GET4 is a non-proteolytic substrate of FBXO7-SCF. Binding of GET4 to BAG6 is enhanced by active FBXO7-SCF. The cytoplasmic localization of the BAG6 complex depends on FBXO7 E3 ubiquitin ligase activity.","method":"Co-immunoprecipitation, proteasome activity assay, ubiquitination assay, subcellular localization analysis, siRNA knockdown","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome activity, and localization; single lab","pmids":["34060591"],"is_preprint":false},{"year":2021,"finding":"FBXO7 binds FOXO4 and negatively regulates intracellular FOXO4 levels through caspase 8-mediated proteolysis (not the ubiquitin-proteasome system or lysosome-autophagy pathway). In dopaminergic MN9D cells, 6-OHDA treatment reduces FOXO4 levels through FBXO7-mediated and caspase 8-mediated proteolysis.","method":"Co-immunoprecipitation, protein stability assay (caspase inhibitors, caspase 8 knockdown), western blot in neurotoxin-treated cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with pathway exclusion studies (proteasome inhibitor, lysosome inhibitor, caspase inhibitor rescue); single lab","pmids":["34800438"],"is_preprint":false},{"year":2022,"finding":"FBXO7 binds and stabilizes the co-transcriptional regulator EYA2 (by preventing its degradation by SCFFBXW7), stimulating mesenchymal gene expression and suppressing IFNα/β, chemokines CXCL9/10, and antigen presentation machinery in cancer cells. This axis is driven by AXL extracellular ligand GAS6. SCFFBXW7 antagonizes this by promoting EYA2 degradation.","method":"Co-immunoprecipitation, protein stability/ubiquitination assays, transcriptional reporter assays, siRNA knockdown, mouse tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, protein stability assays, functional gene expression data, and in vivo mouse models; multiple orthogonal methods","pmids":["35182481"],"is_preprint":false},{"year":2022,"finding":"Fbxo7 promotes Cdk6-dependent phosphorylation of PFKP (platelet-type phosphofructokinase, gatekeeper of glycolysis) and also mediates Cdk6-independent ubiquitination of PFKP. Fbxo7-deficient T cells have reduced Cdk6 activity and increased glycolysis. Metabolomic analysis of activated CD4+ T cells confirms increased glycolytic flux in Fbxo7-deficient cells alongside altered nucleotide biosynthesis and arginine metabolism.","method":"Co-immunoprecipitation, substrate screen, kinase assay, ubiquitination assay, metabolomics, siRNA knockdown, T cell activation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — substrate identification with kinase assay and ubiquitination assay, metabolomics confirmation; multiple orthogonal methods, single lab","pmids":["35670764"],"is_preprint":false},{"year":2022,"finding":"Deletion of Fbxo7 in neurons (Nestin-Cre) causes juvenile motor dysfunction, decreased dopaminergic neuron numbers, fragmented mitochondria in dopaminergic and cortical neurons, and p62- and synuclein-positive Lewy body-like aggregates. The homeostatic level of p62, regulated by the ubiquitin-proteasome system, controls intracellular inclusion body formation.","method":"Conditional knockout mouse (Nestin-Cre), behavioral assays, immunohistochemistry, electron microscopy","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with multiple histological readouts; single lab","pmids":["35701754"],"is_preprint":false},{"year":2022,"finding":"siRNA and CRISPR/Cas9-mediated reduction of FBXO7 expression induces chromosome instability (CIN) in colonic epithelial cell contexts. FBXO7 knockout clones also exhibit hallmarks of cellular transformation (increased clonogenic and anchorage-independent growth), identifying FBXO7 as a CIN gene required to maintain genome stability.","method":"siRNA knockdown, CRISPR/Cas9 knockout, chromosome enumeration (CIN assay), clonogenic assay, anchorage-independent growth assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — short- and long-term loss-of-function with defined CIN phenotype; single lab with two orthogonal KD approaches","pmids":["34791250"],"is_preprint":false},{"year":2023,"finding":"FBXO7 ubiquitinates SIRT7 via SCF-dependent K48-linked polyubiquitination, promoting proteasomal degradation of SIRT7 and blocking SIRT7 deacetylase activity, leading to increased acetylation of histone H3 at K18 and K36 and repression of RPS20 gene transcription. H2O2 treatment triggers FBXO7-mediated SIRT7 degradation and cell death. The PD-linked FBXO7-R498X mutant with reduced SCF E3 ligase activity does not affect SIRT7 stability.","method":"Co-immunoprecipitation, in vivo ubiquitination assay (K48-linkage specific), cycloheximide chase, western blot (histone acetylation), gene reporter assay, H2O2 cell death assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo K48-specific ubiquitination assay with mechanistic downstream readouts (histone acetylation, transcription) and disease mutant comparison; multiple orthogonal methods, single lab","pmids":["36646384"],"is_preprint":false},{"year":2023,"finding":"FBXO7 ubiquitinates Rbfox2 at K249 via K63-linked ubiquitin chains following PRMT5-mediated arginine dimethylation at Arg341 and Arg441, leading to Rbfox2 stabilization (not degradation). FBXO7-stabilized Rbfox2 controls alternative splicing of mesenchymal genes including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion in FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, upregulating CD44, CD9, and ID1.","method":"Co-immunoprecipitation, ubiquitination assay (K63-chain specific), mass spectrometry, alternative splicing analysis (RNA-seq), siRNA knockdown, mouse xenograft tumor model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ubiquitination site mapping by MS, K63-specific ubiquitination, splicing analysis, in vivo xenograft; multiple orthogonal methods, single lab","pmids":["37822160"],"is_preprint":false},{"year":2023,"finding":"FBXO7 is dispensable for PINK1/Parkin-dependent mitophagy in HeLa cells and induced neurons (iNeurons). FBXO7-/- cells show no defect in kinetics of phospho-ubiquitin accumulation, pUb puncta on mitochondria by super-resolution imaging, Parkin/autophagy machinery recruitment, mitophagic flux, or mitochondrial clearance quantified by global proteomics. Global proteomics of neurogenesis in FBXO7 absence reveals no obvious mitochondrial alterations.","method":"CRISPR/Cas9 knockout, super-resolution imaging, global proteomics, mitophagy flux assays, phospho-ubiquitin kinetics","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic, multi-endpoint negative result using genetic KO with super-resolution imaging and global proteomics in two independent cell systems; rigorous replication of key claims","pmids":["37334901"],"is_preprint":false},{"year":2023,"finding":"FBXO7 ubiquitinates INF2 (a factor that triggers mitochondrial division by recruiting DRP1) and promotes proteasomal degradation of INF2, thereby inhibiting INF2-DRP1-associated mitochondrial hyperfission and suppressing endometrial carcinoma cell proliferation and migration. ECa-associated FBXO7 mutants are defective in INF2 ubiquitination and degradation.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, overexpression, mitochondrial morphology analysis, mouse xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, mitochondrial morphology assay, in vivo tumor model; single lab","pmids":["37344480"],"is_preprint":false},{"year":2023,"finding":"USP7 (ubiquitin-specific protease 7) positively regulates FBXO7 stability through K48-linked deubiquitination, preventing proteasomal degradation of FBXO7. USP7 mitigates ER stress-induced cytotoxicity and apoptosis by stabilizing FBXO7.","method":"Co-immunoprecipitation, deubiquitination assay (K48-linkage specific), protein stability assay (cycloheximide chase), siRNA knockdown, cell viability/apoptosis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay with K48-chain specificity, stability assay, and functional rescue; single lab","pmids":["37874827"],"is_preprint":false},{"year":2024,"finding":"FBXO7 promotes K63-linked ubiquitination of PRMT1 at lysine 37, inducing proteasomal degradation of PRMT1. FBXO7-mediated PRMT1 downregulation impairs PRMT1-mediated arginine methylation and activation of PHGDH, resulting in impaired serine synthesis, ROS accumulation, and inhibition of hepatocellular carcinoma cell growth.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay (site mapping), protein stability assay, PHGDH methylation assay, serine synthesis assay, ROS assay, mouse tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination with site-specific mapping, downstream enzymatic activity assays, and in vivo tumor model; multiple orthogonal methods","pmids":["38839752"],"is_preprint":false},{"year":2024,"finding":"A patient mutation (L250P) in the Fbxo7 dimerization (FP) domain selectively ablates Fbxo7-PI31 interaction and causes significant reduction in both Fbxo7 and PI31 protein levels. Patient fibroblasts show reduced proteasome activity and proteasome subunit levels. PI31 interacts with MiD49/51 fission adaptor proteins; PI31 facilitates SCF(Fbxo7)-mediated ubiquitination of MiD49. The L250P mutation reduces SCF(Fbxo7)-mediated ubiquitination of a subset of substrates. Patient cells show reduced mitochondrial function, reduced mitophagy, higher ROS, and reduced viability under stress.","method":"Patient cell biochemistry, co-immunoprecipitation, ubiquitination assay, proteasome activity assay, mitochondrial function assays, mitophagy assay, ROS assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient mutation providing natural allele-specific dissection, combined with multiple biochemical assays; multiple orthogonal methods providing mechanistic insight","pmids":["38466799"],"is_preprint":false},{"year":2019,"finding":"Deletion of Fbxo7 in myelinating cells (oligodendrocytes and Schwann cells) in mice leads to motor impairment and axonal degeneration without affecting myelin biogenesis itself. Loss of Fbxo7 causes reduced proteasome activity in Schwann cells (but not cerebellar granule neurons), indicating cell-type specific sensitivity. CNS and PNS show inflammation; PNS shows fibrosis, macrophage infiltration, and edema.","method":"Conditional knockout mouse (Cnp1-Cre and Plp1-CreERT2), behavioral assays, histology, electron microscopy, proteasome activity assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent conditional KO lines with cell-type specific proteasome activity comparison; single lab","pmids":["31085610"],"is_preprint":false},{"year":2023,"finding":"Loss of Fbxo7 specifically in glutamatergic forebrain neurons (NEX-Cre) leads to changes in striatal dopamine, glutamatergic, GABAergic and dopaminergic pathways, astrogliosis, microgliosis, and alterations in synaptic membrane proteins (complement system, endocytosis and exocytosis pathways by quantitative proteomics), indicating a role of FBXO7 in corticostriatal projection integrity and synaptic function.","method":"Conditional knockout mouse (NEX-Cre), HPLC, histology, immunohistochemistry, synaptic membrane purification, quantitative mass spectrometry","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with proteomic analysis of synaptic membranes; single lab","pmids":["37753846"],"is_preprint":false},{"year":2026,"finding":"FBXO7 physically interacts with IL-6 and acts as an E3 ubiquitin ligase targeting IL-6 for K48-linked ubiquitination specifically at lysine 114, suppressing IL-6-mediated activation of the JAK1/STAT3 signaling pathway. Conditional Fbxo7 knockout mice exhibit accelerated cartilage degradation, enhanced synovial inflammation, and increased cellular senescence.","method":"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific, site-mapping by LC-MS/MS), conditional knockout mouse, histology, immunohistochemistry","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific ubiquitination mapped by MS, K48-chain specific assay, and conditional KO mouse; single lab","pmids":["42102611"],"is_preprint":false}],"current_model":"FBXO7 is a multifunctional F-box protein that acts as the substrate-recognition subunit of the SCF(FBXO7) E3 ubiquitin ligase complex—mediating degradative (K48-linked) or non-degradative (K63-linked) ubiquitination of diverse substrates including HURP, PRMT1, SIRT7, UXT-V2, INF2, IL-6, Gsk3β, Tomm20, MiD49, PFKP, NRAGE, and cIAP1—while also functioning in SCF-independent roles by selectively enhancing cyclin D/Cdk6 complex formation and activity, stabilizing p27, binding PI31 via its FP dimerization domain to regulate proteasome assembly and activity, interacting with PINK1 and Parkin to influence mitophagy (though its general requirement for PINK1/Parkin mitophagy is disputed by rigorous genetic studies), and stabilizing EYA2 to promote mesenchymal gene expression; loss of FBXO7 in neurons causes dopaminergic degeneration linked to the RPL23-MDM2-p53 apoptotic axis, reduced proteasome activity, and mitochondrial dysfunction, collectively explaining the early-onset parkinsonism (PARK15) caused by recessive FBXO7 mutations."},"narrative":{"mechanistic_narrative":"FBXO7 is the substrate-recognition subunit of an SCF(FBXO7) E3 ubiquitin ligase that ubiquitinates a broad substrate set using both degradative K48-linked and non-degradative K63-linked chains, and it also performs ligase-independent functions in cell-cycle control and proteasome regulation [PMID:15145941, PMID:16096642, PMID:27503909]. As an F-box adaptor it recruits and degrades targets such as HURP in a Cdk1-cyclin B phosphorylation-dependent manner [PMID:15145941], and it directs context-specific outcomes: K48-linked degradation of SIRT7, PRMT1, INF2, UXT-V2, and IL-6 [PMID:36646384, PMID:38839752, PMID:37344480, PMID:33010352, PMID:42102611], versus K63-linked, non-degradative ubiquitination that regulates Gsk3β activity, stabilizes Rbfox2, and stabilizes Tomm20 [PMID:27503909, PMID:37822160]. Independent of its ligase activity, FBXO7 selectively binds Cdk6 and D-type cyclins to enhance cyclin D/Cdk6 complex formation and kinase activity, and binds and stabilizes p27, coupling it to proliferation and differentiation decisions in haematopoietic, B-, and T-cell compartments [PMID:16096642, PMID:21652635, PMID:26095538, PMID:27915416]. Through its conserved N-terminal FP dimerization domain it homodimerizes and binds the proteasome inhibitor PI31, and SCF(FBXO7) ubiquitinates the proteasome subunit PSMA2, placing FBXO7 in proteasome assembly and activity control [PMID:18495667, PMID:24419388, PMID:27497298]. In neurons, conditional loss causes dopaminergic and motor degeneration accompanied by activation of the RPL23-MDM2-p53 pro-apoptotic axis, reduced proteasome activity, mitochondrial dysfunction, and Lewy body-like aggregates, explaining the early-onset parkinsonism (PARK15) caused by recessive FBXO7 mutations, including FP-domain and N-terminal mutations that disrupt localization, PI31 binding, and substrate ubiquitination [PMID:31144295, PMID:27497298, PMID:35701754, PMID:21347293, PMID:38466799]. FBXO7 interacts with PINK1/Parkin and influences mitophagy in some systems [PMID:23933751, PMID:32493843], but rigorous genetic knockout studies show FBXO7 is dispensable for PINK1/Parkin-dependent mitophagy in HeLa cells and induced neurons [PMID:37334901].","teleology":[{"year":2004,"claim":"Establishing that FBXO7 acts as a substrate-recognition adaptor defined its core biochemical identity within an SCF E3 ligase.","evidence":"siRNA knockdown, co-IP, ubiquitination and mutagenesis showing phosphorylation-dependent recruitment and degradation of HURP","pmids":["15145941"],"confidence":"High","gaps":["Did not establish the full substrate repertoire","Physiological context of HURP degradation not defined"]},{"year":2005,"claim":"Discovery that FBXO7 binds Cdk6 and D-cyclins to enhance kinase activity revealed an SCF-independent, pro-proliferative function.","evidence":"Reciprocal Co-IP, kinase assay, Cdk6-dependent transformation and xenograft assays in fibroblasts","pmids":["16096642"],"confidence":"High","gaps":["Mechanism by which FBXO7 promotes complex assembly not structurally defined","Relationship between ligase and Cdk6 roles unresolved"]},{"year":2008,"claim":"Identifying the shared FP domain and the FBXO7-PI31 interaction connected FBXO7 to proteasome regulation beyond canonical ubiquitination.","evidence":"Crystal structure of PI31 FP domain, biophysics, mutagenesis and Co-IP showing FP-mediated dimerization and PI31 heterodimerization","pmids":["18495667"],"confidence":"High","gaps":["Functional consequence of FBXO7-PI31 binding for proteasome activity not yet shown","PI31 not a substrate"]},{"year":2011,"claim":"Localization and B-cell studies linked FBXO7 N-terminal integrity to nuclear targeting and cell-cycle control during haematopoiesis.","evidence":"Mutant/fusion localization assays and patient cells; siRNA/shRNA knockdown with cell-cycle and mouse LacZ-insertion phenotypes","pmids":["21347293","21652635"],"confidence":"Medium","gaps":["Mechanistic link between mislocalization and disease not defined","Direct nuclear substrates not identified"]},{"year":2013,"claim":"Interaction with PINK1/Parkin and a high-resolution FP-domain structure positioned FBXO7 in mitophagy and refined its protein-interaction surfaces.","evidence":"Co-IP, mitophagy assays and Drosophila genetic rescue; 2.0 Å crystal structure by SAD phasing","pmids":["23933751","24419388"],"confidence":"High","gaps":["General requirement for FBXO7 in mitophagy later disputed","Whether FBXO7-Parkin interaction is direct in vivo unresolved"]},{"year":2014,"claim":"Demonstration of K63-linked, proteasome-independent ubiquitination of NRAGE established that FBXO7 can perform non-degradative signaling ubiquitination.","evidence":"Y2H, Co-IP, K63-specific ubiquitination assay and NF-κB reporter in mammalian cells","pmids":["24947323"],"confidence":"Medium","gaps":["Single-lab study without in vitro reconstitution","Physiological relevance of BMP/NF-κB axis in vivo not shown"]},{"year":2015,"claim":"Stabilization of p27 during erythropoiesis tied an allelic FBXO7 variant to erythrocyte phenotypes, linking FBXO7 to cell-cycle exit and differentiation.","evidence":"Co-IP, stability assays, allelic binding comparison, and anaemic Fbxo7-deficient mice","pmids":["26095538"],"confidence":"Medium","gaps":["Mechanism of p27 stabilization (ligase-dependent vs independent) not fully resolved","Single-lab"]},{"year":2016,"claim":"Identification of PSMA2 ubiquitination and KO-mouse motor deficits causally connected FBXO7 to proteasome assembly/activity and neurological phenotypes.","evidence":"Co-IP, in vitro ubiquitination, proteasome activity assays and multiple conditional KO mouse lines","pmids":["27497298"],"confidence":"High","gaps":["How PSMA2 ubiquitination affects assembly mechanistically not defined","Link to specific neuron loss not yet mapped"]},{"year":2016,"claim":"Substrate-array and metabolic studies expanded FBXO7's reach to Gsk3β (K63, activity regulation), Tomm20 stabilization, and mitochondrial bioenergetics via NAD+/PARP.","evidence":"Protein-array screen, in vitro/in vivo chain-specific ubiquitination, kinase assays; metabolic assays with PARP-inhibitor rescue","pmids":["27503909","27689878"],"confidence":"Medium","gaps":["Direct mechanism linking FBXO7 loss to PARP overactivation not established","Tomm20 stabilization mechanism unclear"]},{"year":2019,"claim":"Cell-type-specific conditional deletions showed FBXO7 protects dopaminergic neurons via suppression of the RPL23-MDM2-p53 axis and supports myelinating-cell and germ-cell integrity.","evidence":"Dopamine-neuron, oligodendrocyte/Schwann-cell, and germline conditional KO/hypomorph mice with HPLC, histology, transcriptomics and proteasome assays","pmids":["31144295","31085610","31649556"],"confidence":"Medium","gaps":["RPL23-p53 placement correlative, no epistasis rescue","Proteasome-activity sensitivity is cell-type specific and mechanism unclear"]},{"year":2020,"claim":"Multiple studies dissected FBXO7-PINK1 reciprocal regulation and added BAG6/GET4 and UXT-V2 as proteasome- and NF-κB-linked interactors/substrates.","evidence":"Co-IP, chain-specific ubiquitination, stability assays, small-molecule disruption, regional brain fractionation","pmids":["32493843","33291077","33010352","32933748","34060591"],"confidence":"Medium","gaps":["Opposing reports of FBXO7 degrading vs stabilizing PINK1 unreconciled","Several interactions single-lab without reciprocal in vivo validation"]},{"year":2022,"claim":"FBXO7 was shown to drive cancer-relevant programs by stabilizing EYA2 and Rbfox2, by Cdk6/PFKP-linked glycolytic control, and by maintaining genome stability.","evidence":"Co-IP, stability/ubiquitination assays, splicing and metabolomic analyses, T-cell assays, CRISPR/siRNA CIN assays, and mouse tumor models","pmids":["35182481","35670764","34791250"],"confidence":"High","gaps":["How FBXO7 chooses stabilizing vs degradative outcomes for substrates not defined","CIN mechanism not mapped to a specific substrate"]},{"year":2023,"claim":"Rigorous knockout work established that FBXO7 is dispensable for PINK1/Parkin mitophagy, while parallel studies added SIRT7, Rbfox2, and INF2 as substrates linking FBXO7 to chromatin, splicing, and mitochondrial fission.","evidence":"CRISPR KO with super-resolution imaging and global proteomics (negative result); chain-specific ubiquitination, site-mapping, splicing and mitochondrial morphology assays","pmids":["37334901","36646384","37822160","37344480","37874827","37753846"],"confidence":"High","gaps":["Reconciliation of mitophagy-positive and mitophagy-negative findings unresolved","In vivo relevance of individual cancer substrates varies by tissue"]},{"year":2024,"claim":"Site-specific PRMT1 ubiquitination and a patient FP-domain mutation (L250P) connected FBXO7 catalytic and dimerization functions to serine metabolism and to proteasome/mitochondrial defects underlying disease.","evidence":"In vitro ubiquitination with site mapping, downstream enzymatic and metabolic assays, mouse tumor model; patient-cell biochemistry with allele-specific dissection","pmids":["38839752","38466799"],"confidence":"High","gaps":["Whether reduced substrate ubiquitination or proteasome dysfunction is the primary disease driver unresolved","Full set of FP-domain-dependent substrates undefined"]},{"year":2026,"claim":"Identification of IL-6 as a K48-linked substrate extended FBXO7 function to suppression of JAK1/STAT3 inflammatory signaling in cartilage homeostasis.","evidence":"Co-IP, MS-mapped K48-specific ubiquitination at K114, and conditional KO mice with osteoarthritis-like phenotypes","pmids":["42102611"],"confidence":"Medium","gaps":["Single-lab study","Whether IL-6 degradation occurs intracellularly or extracellularly not resolved"]},{"year":null,"claim":"It remains unknown what determines FBXO7's choice between degradative (K48) and non-degradative (K63) ubiquitination and between ligase-dependent and ligase-independent functions across its many substrates.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for substrate/chain-type selection","No structure of the full SCF(FBXO7) holoenzyme with substrate","Reconciliation of conflicting mitophagy data outstanding"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,12,18,26,27,29,31,35]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,18,26,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,5,9,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,20]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,10,18,26,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,5,9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,24,32]}],"complexes":["SCF(FBXO7) E3 ubiquitin ligase","BAG6 complex (via GET4)"],"partners":["SKP1","PI31","CDK6","CDKN1B (P27)","PINK1","PRKN (PARKIN)","PSMA2","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3I1","full_name":"F-box only protein 7","aliases":[],"length_aa":522,"mass_kda":58.5,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological processes such as cell cycle, cell proliferation, or maintenance of chromosome stability (PubMed:15145941, PubMed:34791250). Recognizes and ubiquitinates BIRC2 and the cell cycle regulator DLGAP5 (PubMed:15145941, PubMed:16510124, PubMed:22212761). Plays a role downstream of PINK1 in the clearance of damaged mitochondria via selective autophagy (mitophagy) by targeting PRKN to dysfunctional depolarized mitochondria. Promotes MFN1 ubiquitination. Mediates the ubiquitination and proteasomal degradation of UXT isoform 2, thereby impairing the NF-kappa-B signaling pathway (PubMed:33010352). Inhibits NF-kappa-B pathway also by promoting the ubiquitination of TRAF2 (PubMed:22212761). Affects the assembly state and activity of the proteasome in the cells including neurons by ubiquitinating the proteasomal subunit PSMA2 via 'Lys-63'-linked polyubiquitin chains (By similarity). Promotes 'Lys-48'-linked polyubiquitination SIRT7, leading to the hydrogen peroxide-induced cell death (PubMed:36646384)","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q9Y3I1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO7","classification":"Not Classified","n_dependent_lines":99,"n_total_lines":1208,"dependency_fraction":0.08195364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO7","total_profiled":1310},"omim":[{"mim_id":"610513","title":"ATPase 13A2; ATP13A2","url":"https://www.omim.org/entry/610513"},{"mim_id":"606693","title":"KUFOR-RAKEB SYNDROME; KRS","url":"https://www.omim.org/entry/606693"},{"mim_id":"605648","title":"F-BOX ONLY PROTEIN 7; FBXO7","url":"https://www.omim.org/entry/605648"},{"mim_id":"260300","title":"PARKINSON DISEASE 15, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK15","url":"https://www.omim.org/entry/260300"},{"mim_id":"168600","title":"PARKINSON DISEASE, LATE-ONSET; PD","url":"https://www.omim.org/entry/168600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":263.7}],"url":"https://www.proteinatlas.org/search/FBXO7"},"hgnc":{"alias_symbol":["FBX7","Fbx","PARK15"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3I1","domains":[{"cath_id":"3.10.20.90","chopping":"3-79","consensus_level":"high","plddt":77.5882,"start":3,"end":79},{"cath_id":"3.40.1000.30","chopping":"182-325","consensus_level":"high","plddt":86.1389,"start":182,"end":325},{"cath_id":"-","chopping":"338-408","consensus_level":"high","plddt":82.3225,"start":338,"end":408}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3I1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3I1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3I1-F1-predicted_aligned_error_v6.png","plddt_mean":66.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO7","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO7"},"sequence":{"accession":"Q9Y3I1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3I1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3I1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3I1"}},"corpus_meta":[{"pmid":"19038853","id":"PMC_19038853","title":"FBXO7 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Mutation of Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbxo7 abolished Fbxo7-HURP association.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, ubiquitination assay, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro assay with mutagenesis of both substrate and adaptor, siRNA knockdown, and co-IP; multiple orthogonal methods in single study\",\n      \"pmids\": [\"15145941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fbxo7 selectively binds Cdk6 (but not Cdk4 or Cdk2) and D-type cyclins, enhancing cyclin D/Cdk6 complex formation and kinase activity. Fbxo7 overexpression transforms murine fibroblasts in a Cdk6-dependent manner, and Fbxo7 knockdown decreases Cdk6 association with cyclin. Fbxo7 also interacts with p27 but its enhancement of cyclin D/Cdk6 activity is p21/p27-independent.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), siRNA knockdown, kinase assay, E2F reporter assay, transformation assay, nude mouse xenograft\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in vitro and in vivo, functional rescue by Cdk6 knockdown, kinase activity assay; multiple orthogonal methods\",\n      \"pmids\": [\"16096642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fbxo7 interacts with cIAP1 (inhibitor of apoptosis protein 1) in human cells, co-localizes with cIAP1 in cytoplasm, nucleus, and Golgi-like structures, and overexpression of Fbxo7 promotes ubiquitination of cIAP1, suggesting SCF(Fbxo7)-mediated ubiquitination of cIAP1.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, co-localization by fluorescence microscopy, ubiquitination assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay in cells; single lab, no in vitro reconstitution or mutagenesis\",\n      \"pmids\": [\"16510124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fbxo7 and PI31 share a conserved N-terminal FP (Fbxo7/PI31) domain that mediates homodimerization of each protein and heterodimerization between Fbxo7·Skp1 and PI31. Crystal structure of the PI31 FP domain revealed a novel alpha/beta-fold. Mutations in the FP domain ablate Fbxo7-PI31 interaction and Fbxo7 homodimerization. Knockdown of Fbxo7 does not affect PI31 levels, arguing against PI31 being a substrate of SCF(Fbxo7).\",\n      \"method\": \"Crystal structure determination, biophysical analysis (including analytical ultracentrifugation), mutagenesis, co-immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biophysical and mutational validation; multiple orthogonal methods\",\n      \"pmids\": [\"18495667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBXO7 isoform 1 displays predominantly diffuse nuclear localization in human cell lines and mouse primary neurons. An intact N-terminus is required for nuclear localization; PARK15-linked missense mutation (T22M) or N-terminal tagging causes cytoplasmic mislocalization. The N-terminus of wild-type (but not mutant) FBXO7 can confer nuclear localization to the cytoplasmic protein profilin. PARK15 patient cells show depletion of FBXO7 isoform 1.\",\n      \"method\": \"Immunofluorescence/localization studies, overexpression of wild-type and mutant constructs, fusion protein localization assay, patient cell analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with mutagenesis and functional fusion assay; single lab\",\n      \"pmids\": [\"21347293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fbxo7 knockdown in haematopoietic pro-B (Ba/F3) cells increases proliferation, decreases cell size, shortens G1, decreases p27 levels, and increases S-phase cyclins and Cdk2 activity. Fbxo7 protein levels inversely correlate with CD43 expression, suggesting regulation of B cell maturation. Homozygous Fbxo7(LacZ) mice show increased pro-B cell and pro-erythroblast populations.\",\n      \"method\": \"siRNA/shRNA knockdown, cell cycle analysis, flow cytometry, transgenic mouse model (LacZ insertion)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotypes plus in vivo mouse model; single lab\",\n      \"pmids\": [\"21652635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbxo7 physically interacts with PINK1 and Parkin and participates in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression show deficiencies in Parkin translocation to mitochondria, ubiquitination of mitofusin 1, and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescues loss of Parkin. PD-causing mutations in Fbxo7 interfere with this process.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with mitophagy assays (Parkin translocation, mitofusin 1 ubiquitination, mitochondrial clearance), Drosophila genetic rescue\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined mitophagy phenotypes, genetic epistasis in Drosophila; multiple orthogonal methods across two systems\",\n      \"pmids\": [\"23933751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the Fbxo7 FP domain at 2.0 Å resolution reveals an alpha/beta fold. The Fbxo7 FP domain uses an alpha/beta interface for inter-domain protein-protein interaction (distinct from the PI31 FP domain which uses alpha-alpha or beta-beta interfaces), features a larger contact surface area and more extensive hydrophobic interactions, and has the potential to bind two protein partners simultaneously.\",\n      \"method\": \"X-ray crystallography (2.0 Å resolution, SAD phasing)\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determined with SAD phasing to 2.0 Å; rigorous structural study\",\n      \"pmids\": [\"24419388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FBXO7 interacts with NRAGE and mediates K63-linked poly-ubiquitination of NRAGE in mammalian cells. FBXO7 overexpression accelerates NRAGE-TAK1-TAB1 complex formation and facilitates BMP receptor-NRAGE-TAK1-TAB1 complex assembly, upregulating NF-κB activity. BMP4 stimulation enhances NRAGE ubiquitination through FBXO7. This is a proteasome-independent ubiquitination.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assay (K63-linkage specific), siRNA knockdown, reporter assay (NF-κB)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid validated by Co-IP, K63 chain-specific ubiquitination assay, NF-κB reporter; single lab\",\n      \"pmids\": [\"24947323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fbxo7 stabilizes p27 protein levels during erythropoiesis. The M115I Fbxo7 variant (associated with SNP for smaller erythrocytes) binds p27 less efficiently and cells expressing Ile115 proliferate faster. Reduced Fbxo7 expression in erythroleukaemic cells fails to stabilize p27, impairs cell cycle exit, and blocks haemoglobin production. Fbxo7-deficient mice are anaemic with lower p27 levels and delayed mitophagy during terminal erythroid differentiation.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, cell cycle analysis, mouse model, haemoglobin assay, mitophagy assay\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — allelic binding assay, KD with phenotype, mouse model; single lab with multiple methods\",\n      \"pmids\": [\"26095538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCF(Fbxo7) ubiquitin ligase binds and ubiquitinates the proteasomal subunit PSMA2. FBXO7 is a proteasome-associated protein involved in proteasome assembly. FBXO7 knockout mice show reduced proteasome activity and early-onset motor deficits. Conditional deletion of FBXO7 in TH-positive or NEX-positive forebrain neurons causes motor defects.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome activity assay, conditional knockout mouse (Cre-lox), behavioral assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, in vitro ubiquitination, proteasome activity assay, and multiple conditional KO mouse lines with defined phenotypes; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27497298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fbxo7 deficiency leads to reduced cellular NAD+ levels, increased mitochondrial NADH redox index, impaired complex I activity in the electron transport chain, reduced mitochondrial membrane potential, reduced ATP, and increased cytosolic ROS. ROS activates PARP, and PARP inhibition restores NAD+, redox balance, and ATP pool, indicating PARP overactivation as a cause of decreased complex I-driven respiration in Fbxo7-deficient cells.\",\n      \"method\": \"Cellular metabolic assays (NAD+/NADH, oxygen consumption, mitochondrial membrane potential, ATP, ROS), PARP inhibitor rescue experiments, siRNA knockdown\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple metabolic assays with pharmacological rescue; single lab\",\n      \"pmids\": [\"27689878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCF(Fbxo7) ubiquitinates Gsk3β using K63 linkages and negatively regulates Gsk3β activity (rather than its levels or localization). SCF(Fbxo7) also ubiquitinates Tomm20; Tomm20 levels correlate positively with Fbxo7 expression (stabilizing effect). PD-associated Fbxo7 mutations do not impair Tomm20 ubiquitination.\",\n      \"method\": \"Protein array screen (high-throughput), in vitro ubiquitination assay, in vivo ubiquitination assay, ubiquitin chain restriction analysis, kinase activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro and in vivo ubiquitination assays with chain-type analysis, kinase activity measurement; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27503909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fbxo7 differentially regulates T cell development: Fbxo7-deficient immature thymocytes fail to expand due to lack of Cdk6 activity, while mature T cells show enhanced proliferation upon TCR engagement due to reduced p27 levels. These opposing effects are mediated through Fbxo7's distinct interactions with Cdk6 and p27 at different stages of T cell development.\",\n      \"method\": \"Transgenic mouse model (reduced Fbxo7 expression), flow cytometry, cell cycle analysis, Cdk6 activity assay, p27 western blot\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with mechanistic dissection via Cdk6 and p27 measurements; single lab\",\n      \"pmids\": [\"27915416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional deletion of Fbxo7 in midbrain dopamine neurons causes progressive loss of dopamine neurons and striatal dopamine levels. Mechanistically, there is increased expression of RPL23 (ribosomal stress sensor that inhibits MDM2), a corresponding activated p53 transcriptional signature biased toward pro-apoptotic genes, suggesting that FBXO7 normally suppresses the RPL23-MDM2-p53 axis to protect dopaminergic neurons.\",\n      \"method\": \"Conditional knockout mouse (dopamine neuron-specific), HPLC, immunohistochemistry, RNA-seq/transcriptional analysis, protein expression analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with pathway analysis; pathway placement is correlative (increased RPL23, activated p53 signature) without direct epistasis rescue\",\n      \"pmids\": [\"31144295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Male mice with reduced Fbxo7 expression are sterile. Despite successful meiosis and nuclear elongation, spermatids are phagocytosed by Sertoli cells during late spermiogenesis/cytoplasmic remodeling. PI31 levels are reduced in Fbxo7 mutant mice. The Drosophila ortholog (nutcracker) mutant shows the same sterility phenotype attributed to decreased DmPI31 and reduced proteasome activity, indicating conserved requirement for Fbxo7 at this developmental stage.\",\n      \"method\": \"Mouse model (hypomorphic/reduced expression), histology, electron microscopy, western blot (PI31 levels), Drosophila mutant analysis\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse and Drosophila models with histological and molecular analysis; conservation shown across species\",\n      \"pmids\": [\"31649556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FBXO7 targets PINK1 for ubiquitylation and proteasomal degradation, thereby mediating PINK1 cellular disposal and inducing mitochondrial injury. A small molecule (BC1464) identified by computational screening abrogates FBXO7-PINK1 association, increases PINK1 levels and activity, and limits mitochondrial damage, inflammation, and neuronal death.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, PINK1 stability/degradation assay, small molecule inhibitor screen, cell viability assay, murine lung inflammation model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, pharmacological rescue; single lab\",\n      \"pmids\": [\"32493843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fbxo7 and Pink1 reciprocally regulate each other's protein levels. Wild-type and PD familial mutant Fbxo7 stabilize the processed form of Pink1. The interaction of Fbxo7 with Bag2 further enhances Fbxo7's ability to stabilize Pink1. Pink1-mediated stabilization of Fbxo7 is observed specifically in substantia nigra pars compacta but not striatum or cerebral cortex.\",\n      \"method\": \"Co-immunoprecipitation, western blot (protein stability), regional brain fractionation, overexpression/knockdown studies\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and western blot protein stability assays; single lab, multiple cell and tissue contexts\",\n      \"pmids\": [\"33291077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SCF(Fbxo7) mediates proteasomal degradation of UXT-V2 (ubiquitously expressed transcript isoform 2) through K48- and K63-linked polyubiquitination, reducing UXT-V2 stability. The Ubl domain of Fbxo7 contributes to interaction with UXT-V2. FBXO7 knockdown promotes UXT-V2 accumulation, and overexpression of FBXO7-ΔF-box protects UXT-V2 from degradation and enhances NF-κB reporter activity. UXT-V2 colocalizes with Fbxo7 in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, cycloheximide chase assay, ubiquitin chain restriction analysis, siRNA knockdown, NF-κB reporter assay, co-localization microscopy\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of ubiquitination with chain-type analysis, stability assays, reporter assay; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33010352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p105 (NF-κB precursor) binds to FBXO7 and is ubiquitinated by it, but this leads to p105 accumulation rather than degradation (p105 is a pseudo-substrate of FBXO7). An inactive ΔF-box mutant of FBXO7 has the same effect on p105 accumulation, indicating ligase-independent stabilization. FBXO7 binding to p105 also increases p65 levels and promotes cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ΔF-box dominant-negative mutant, western blot, cell proliferation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, ubiquitination assay, and mutant analysis; single lab with multiple methods\",\n      \"pmids\": [\"32933748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO7 interacts with GET4 (a subunit of the BAG6 complex) directly, and this interaction is reduced in PD-associated FBXO7 variants. GET4 and UBL4A (other BAG6 complex subunits) are required for proper proteasome activity. GET4 is a non-proteolytic substrate of FBXO7-SCF. Binding of GET4 to BAG6 is enhanced by active FBXO7-SCF. The cytoplasmic localization of the BAG6 complex depends on FBXO7 E3 ubiquitin ligase activity.\",\n      \"method\": \"Co-immunoprecipitation, proteasome activity assay, ubiquitination assay, subcellular localization analysis, siRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, proteasome activity, and localization; single lab\",\n      \"pmids\": [\"34060591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO7 binds FOXO4 and negatively regulates intracellular FOXO4 levels through caspase 8-mediated proteolysis (not the ubiquitin-proteasome system or lysosome-autophagy pathway). In dopaminergic MN9D cells, 6-OHDA treatment reduces FOXO4 levels through FBXO7-mediated and caspase 8-mediated proteolysis.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay (caspase inhibitors, caspase 8 knockdown), western blot in neurotoxin-treated cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with pathway exclusion studies (proteasome inhibitor, lysosome inhibitor, caspase inhibitor rescue); single lab\",\n      \"pmids\": [\"34800438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO7 binds and stabilizes the co-transcriptional regulator EYA2 (by preventing its degradation by SCFFBXW7), stimulating mesenchymal gene expression and suppressing IFNα/β, chemokines CXCL9/10, and antigen presentation machinery in cancer cells. This axis is driven by AXL extracellular ligand GAS6. SCFFBXW7 antagonizes this by promoting EYA2 degradation.\",\n      \"method\": \"Co-immunoprecipitation, protein stability/ubiquitination assays, transcriptional reporter assays, siRNA knockdown, mouse tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, protein stability assays, functional gene expression data, and in vivo mouse models; multiple orthogonal methods\",\n      \"pmids\": [\"35182481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Fbxo7 promotes Cdk6-dependent phosphorylation of PFKP (platelet-type phosphofructokinase, gatekeeper of glycolysis) and also mediates Cdk6-independent ubiquitination of PFKP. Fbxo7-deficient T cells have reduced Cdk6 activity and increased glycolysis. Metabolomic analysis of activated CD4+ T cells confirms increased glycolytic flux in Fbxo7-deficient cells alongside altered nucleotide biosynthesis and arginine metabolism.\",\n      \"method\": \"Co-immunoprecipitation, substrate screen, kinase assay, ubiquitination assay, metabolomics, siRNA knockdown, T cell activation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — substrate identification with kinase assay and ubiquitination assay, metabolomics confirmation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35670764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of Fbxo7 in neurons (Nestin-Cre) causes juvenile motor dysfunction, decreased dopaminergic neuron numbers, fragmented mitochondria in dopaminergic and cortical neurons, and p62- and synuclein-positive Lewy body-like aggregates. The homeostatic level of p62, regulated by the ubiquitin-proteasome system, controls intracellular inclusion body formation.\",\n      \"method\": \"Conditional knockout mouse (Nestin-Cre), behavioral assays, immunohistochemistry, electron microscopy\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with multiple histological readouts; single lab\",\n      \"pmids\": [\"35701754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"siRNA and CRISPR/Cas9-mediated reduction of FBXO7 expression induces chromosome instability (CIN) in colonic epithelial cell contexts. FBXO7 knockout clones also exhibit hallmarks of cellular transformation (increased clonogenic and anchorage-independent growth), identifying FBXO7 as a CIN gene required to maintain genome stability.\",\n      \"method\": \"siRNA knockdown, CRISPR/Cas9 knockout, chromosome enumeration (CIN assay), clonogenic assay, anchorage-independent growth assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — short- and long-term loss-of-function with defined CIN phenotype; single lab with two orthogonal KD approaches\",\n      \"pmids\": [\"34791250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO7 ubiquitinates SIRT7 via SCF-dependent K48-linked polyubiquitination, promoting proteasomal degradation of SIRT7 and blocking SIRT7 deacetylase activity, leading to increased acetylation of histone H3 at K18 and K36 and repression of RPS20 gene transcription. H2O2 treatment triggers FBXO7-mediated SIRT7 degradation and cell death. The PD-linked FBXO7-R498X mutant with reduced SCF E3 ligase activity does not affect SIRT7 stability.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay (K48-linkage specific), cycloheximide chase, western blot (histone acetylation), gene reporter assay, H2O2 cell death assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo K48-specific ubiquitination assay with mechanistic downstream readouts (histone acetylation, transcription) and disease mutant comparison; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36646384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO7 ubiquitinates Rbfox2 at K249 via K63-linked ubiquitin chains following PRMT5-mediated arginine dimethylation at Arg341 and Arg441, leading to Rbfox2 stabilization (not degradation). FBXO7-stabilized Rbfox2 controls alternative splicing of mesenchymal genes including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion in FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, upregulating CD44, CD9, and ID1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K63-chain specific), mass spectrometry, alternative splicing analysis (RNA-seq), siRNA knockdown, mouse xenograft tumor model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ubiquitination site mapping by MS, K63-specific ubiquitination, splicing analysis, in vivo xenograft; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37822160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO7 is dispensable for PINK1/Parkin-dependent mitophagy in HeLa cells and induced neurons (iNeurons). FBXO7-/- cells show no defect in kinetics of phospho-ubiquitin accumulation, pUb puncta on mitochondria by super-resolution imaging, Parkin/autophagy machinery recruitment, mitophagic flux, or mitochondrial clearance quantified by global proteomics. Global proteomics of neurogenesis in FBXO7 absence reveals no obvious mitochondrial alterations.\",\n      \"method\": \"CRISPR/Cas9 knockout, super-resolution imaging, global proteomics, mitophagy flux assays, phospho-ubiquitin kinetics\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic, multi-endpoint negative result using genetic KO with super-resolution imaging and global proteomics in two independent cell systems; rigorous replication of key claims\",\n      \"pmids\": [\"37334901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO7 ubiquitinates INF2 (a factor that triggers mitochondrial division by recruiting DRP1) and promotes proteasomal degradation of INF2, thereby inhibiting INF2-DRP1-associated mitochondrial hyperfission and suppressing endometrial carcinoma cell proliferation and migration. ECa-associated FBXO7 mutants are defective in INF2 ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, overexpression, mitochondrial morphology analysis, mouse xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, mitochondrial morphology assay, in vivo tumor model; single lab\",\n      \"pmids\": [\"37344480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP7 (ubiquitin-specific protease 7) positively regulates FBXO7 stability through K48-linked deubiquitination, preventing proteasomal degradation of FBXO7. USP7 mitigates ER stress-induced cytotoxicity and apoptosis by stabilizing FBXO7.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay (K48-linkage specific), protein stability assay (cycloheximide chase), siRNA knockdown, cell viability/apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay with K48-chain specificity, stability assay, and functional rescue; single lab\",\n      \"pmids\": [\"37874827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO7 promotes K63-linked ubiquitination of PRMT1 at lysine 37, inducing proteasomal degradation of PRMT1. FBXO7-mediated PRMT1 downregulation impairs PRMT1-mediated arginine methylation and activation of PHGDH, resulting in impaired serine synthesis, ROS accumulation, and inhibition of hepatocellular carcinoma cell growth.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay (site mapping), protein stability assay, PHGDH methylation assay, serine synthesis assay, ROS assay, mouse tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination with site-specific mapping, downstream enzymatic activity assays, and in vivo tumor model; multiple orthogonal methods\",\n      \"pmids\": [\"38839752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A patient mutation (L250P) in the Fbxo7 dimerization (FP) domain selectively ablates Fbxo7-PI31 interaction and causes significant reduction in both Fbxo7 and PI31 protein levels. Patient fibroblasts show reduced proteasome activity and proteasome subunit levels. PI31 interacts with MiD49/51 fission adaptor proteins; PI31 facilitates SCF(Fbxo7)-mediated ubiquitination of MiD49. The L250P mutation reduces SCF(Fbxo7)-mediated ubiquitination of a subset of substrates. Patient cells show reduced mitochondrial function, reduced mitophagy, higher ROS, and reduced viability under stress.\",\n      \"method\": \"Patient cell biochemistry, co-immunoprecipitation, ubiquitination assay, proteasome activity assay, mitochondrial function assays, mitophagy assay, ROS assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient mutation providing natural allele-specific dissection, combined with multiple biochemical assays; multiple orthogonal methods providing mechanistic insight\",\n      \"pmids\": [\"38466799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of Fbxo7 in myelinating cells (oligodendrocytes and Schwann cells) in mice leads to motor impairment and axonal degeneration without affecting myelin biogenesis itself. Loss of Fbxo7 causes reduced proteasome activity in Schwann cells (but not cerebellar granule neurons), indicating cell-type specific sensitivity. CNS and PNS show inflammation; PNS shows fibrosis, macrophage infiltration, and edema.\",\n      \"method\": \"Conditional knockout mouse (Cnp1-Cre and Plp1-CreERT2), behavioral assays, histology, electron microscopy, proteasome activity assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent conditional KO lines with cell-type specific proteasome activity comparison; single lab\",\n      \"pmids\": [\"31085610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of Fbxo7 specifically in glutamatergic forebrain neurons (NEX-Cre) leads to changes in striatal dopamine, glutamatergic, GABAergic and dopaminergic pathways, astrogliosis, microgliosis, and alterations in synaptic membrane proteins (complement system, endocytosis and exocytosis pathways by quantitative proteomics), indicating a role of FBXO7 in corticostriatal projection integrity and synaptic function.\",\n      \"method\": \"Conditional knockout mouse (NEX-Cre), HPLC, histology, immunohistochemistry, synaptic membrane purification, quantitative mass spectrometry\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with proteomic analysis of synaptic membranes; single lab\",\n      \"pmids\": [\"37753846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FBXO7 physically interacts with IL-6 and acts as an E3 ubiquitin ligase targeting IL-6 for K48-linked ubiquitination specifically at lysine 114, suppressing IL-6-mediated activation of the JAK1/STAT3 signaling pathway. Conditional Fbxo7 knockout mice exhibit accelerated cartilage degradation, enhanced synovial inflammation, and increased cellular senescence.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-linkage specific, site-mapping by LC-MS/MS), conditional knockout mouse, histology, immunohistochemistry\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific ubiquitination mapped by MS, K48-chain specific assay, and conditional KO mouse; single lab\",\n      \"pmids\": [\"42102611\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO7 is a multifunctional F-box protein that acts as the substrate-recognition subunit of the SCF(FBXO7) E3 ubiquitin ligase complex—mediating degradative (K48-linked) or non-degradative (K63-linked) ubiquitination of diverse substrates including HURP, PRMT1, SIRT7, UXT-V2, INF2, IL-6, Gsk3β, Tomm20, MiD49, PFKP, NRAGE, and cIAP1—while also functioning in SCF-independent roles by selectively enhancing cyclin D/Cdk6 complex formation and activity, stabilizing p27, binding PI31 via its FP dimerization domain to regulate proteasome assembly and activity, interacting with PINK1 and Parkin to influence mitophagy (though its general requirement for PINK1/Parkin mitophagy is disputed by rigorous genetic studies), and stabilizing EYA2 to promote mesenchymal gene expression; loss of FBXO7 in neurons causes dopaminergic degeneration linked to the RPL23-MDM2-p53 apoptotic axis, reduced proteasome activity, and mitochondrial dysfunction, collectively explaining the early-onset parkinsonism (PARK15) caused by recessive FBXO7 mutations.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO7 is the substrate-recognition subunit of an SCF(FBXO7) E3 ubiquitin ligase that ubiquitinates a broad substrate set using both degradative K48-linked and non-degradative K63-linked chains, and it also performs ligase-independent functions in cell-cycle control and proteasome regulation [#0, #1, #12]. As an F-box adaptor it recruits and degrades targets such as HURP in a Cdk1-cyclin B phosphorylation-dependent manner [#0], and it directs context-specific outcomes: K48-linked degradation of SIRT7, PRMT1, INF2, UXT-V2, and IL-6 [#26, #31, #29, #18, #35], versus K63-linked, non-degradative ubiquitination that regulates Gsk3\\u03b2 activity, stabilizes Rbfox2, and stabilizes Tomm20 [#12, #27]. Independent of its ligase activity, FBXO7 selectively binds Cdk6 and D-type cyclins to enhance cyclin D/Cdk6 complex formation and kinase activity, and binds and stabilizes p27, coupling it to proliferation and differentiation decisions in haematopoietic, B-, and T-cell compartments [#1, #5, #9, #13]. Through its conserved N-terminal FP dimerization domain it homodimerizes and binds the proteasome inhibitor PI31, and SCF(FBXO7) ubiquitinates the proteasome subunit PSMA2, placing FBXO7 in proteasome assembly and activity control [#3, #7, #10]. In neurons, conditional loss causes dopaminergic and motor degeneration accompanied by activation of the RPL23-MDM2-p53 pro-apoptotic axis, reduced proteasome activity, mitochondrial dysfunction, and Lewy body-like aggregates, explaining the early-onset parkinsonism (PARK15) caused by recessive FBXO7 mutations, including FP-domain and N-terminal mutations that disrupt localization, PI31 binding, and substrate ubiquitination [#14, #10, #24, #4, #32]. FBXO7 interacts with PINK1/Parkin and influences mitophagy in some systems [#6, #16], but rigorous genetic knockout studies show FBXO7 is dispensable for PINK1/Parkin-dependent mitophagy in HeLa cells and induced neurons [#28].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that FBXO7 acts as a substrate-recognition adaptor defined its core biochemical identity within an SCF E3 ligase.\",\n      \"evidence\": \"siRNA knockdown, co-IP, ubiquitination and mutagenesis showing phosphorylation-dependent recruitment and degradation of HURP\",\n      \"pmids\": [\"15145941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the full substrate repertoire\", \"Physiological context of HURP degradation not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that FBXO7 binds Cdk6 and D-cyclins to enhance kinase activity revealed an SCF-independent, pro-proliferative function.\",\n      \"evidence\": \"Reciprocal Co-IP, kinase assay, Cdk6-dependent transformation and xenograft assays in fibroblasts\",\n      \"pmids\": [\"16096642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FBXO7 promotes complex assembly not structurally defined\", \"Relationship between ligase and Cdk6 roles unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the shared FP domain and the FBXO7-PI31 interaction connected FBXO7 to proteasome regulation beyond canonical ubiquitination.\",\n      \"evidence\": \"Crystal structure of PI31 FP domain, biophysics, mutagenesis and Co-IP showing FP-mediated dimerization and PI31 heterodimerization\",\n      \"pmids\": [\"18495667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of FBXO7-PI31 binding for proteasome activity not yet shown\", \"PI31 not a substrate\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Localization and B-cell studies linked FBXO7 N-terminal integrity to nuclear targeting and cell-cycle control during haematopoiesis.\",\n      \"evidence\": \"Mutant/fusion localization assays and patient cells; siRNA/shRNA knockdown with cell-cycle and mouse LacZ-insertion phenotypes\",\n      \"pmids\": [\"21347293\", \"21652635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between mislocalization and disease not defined\", \"Direct nuclear substrates not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Interaction with PINK1/Parkin and a high-resolution FP-domain structure positioned FBXO7 in mitophagy and refined its protein-interaction surfaces.\",\n      \"evidence\": \"Co-IP, mitophagy assays and Drosophila genetic rescue; 2.0 \\u00c5 crystal structure by SAD phasing\",\n      \"pmids\": [\"23933751\", \"24419388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"General requirement for FBXO7 in mitophagy later disputed\", \"Whether FBXO7-Parkin interaction is direct in vivo unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration of K63-linked, proteasome-independent ubiquitination of NRAGE established that FBXO7 can perform non-degradative signaling ubiquitination.\",\n      \"evidence\": \"Y2H, Co-IP, K63-specific ubiquitination assay and NF-\\u03baB reporter in mammalian cells\",\n      \"pmids\": [\"24947323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without in vitro reconstitution\", \"Physiological relevance of BMP/NF-\\u03baB axis in vivo not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Stabilization of p27 during erythropoiesis tied an allelic FBXO7 variant to erythrocyte phenotypes, linking FBXO7 to cell-cycle exit and differentiation.\",\n      \"evidence\": \"Co-IP, stability assays, allelic binding comparison, and anaemic Fbxo7-deficient mice\",\n      \"pmids\": [\"26095538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of p27 stabilization (ligase-dependent vs independent) not fully resolved\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of PSMA2 ubiquitination and KO-mouse motor deficits causally connected FBXO7 to proteasome assembly/activity and neurological phenotypes.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, proteasome activity assays and multiple conditional KO mouse lines\",\n      \"pmids\": [\"27497298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSMA2 ubiquitination affects assembly mechanistically not defined\", \"Link to specific neuron loss not yet mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Substrate-array and metabolic studies expanded FBXO7's reach to Gsk3\\u03b2 (K63, activity regulation), Tomm20 stabilization, and mitochondrial bioenergetics via NAD+/PARP.\",\n      \"evidence\": \"Protein-array screen, in vitro/in vivo chain-specific ubiquitination, kinase assays; metabolic assays with PARP-inhibitor rescue\",\n      \"pmids\": [\"27503909\", \"27689878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking FBXO7 loss to PARP overactivation not established\", \"Tomm20 stabilization mechanism unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cell-type-specific conditional deletions showed FBXO7 protects dopaminergic neurons via suppression of the RPL23-MDM2-p53 axis and supports myelinating-cell and germ-cell integrity.\",\n      \"evidence\": \"Dopamine-neuron, oligodendrocyte/Schwann-cell, and germline conditional KO/hypomorph mice with HPLC, histology, transcriptomics and proteasome assays\",\n      \"pmids\": [\"31144295\", \"31085610\", \"31649556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RPL23-p53 placement correlative, no epistasis rescue\", \"Proteasome-activity sensitivity is cell-type specific and mechanism unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies dissected FBXO7-PINK1 reciprocal regulation and added BAG6/GET4 and UXT-V2 as proteasome- and NF-\\u03baB-linked interactors/substrates.\",\n      \"evidence\": \"Co-IP, chain-specific ubiquitination, stability assays, small-molecule disruption, regional brain fractionation\",\n      \"pmids\": [\"32493843\", \"33291077\", \"33010352\", \"32933748\", \"34060591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing reports of FBXO7 degrading vs stabilizing PINK1 unreconciled\", \"Several interactions single-lab without reciprocal in vivo validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"FBXO7 was shown to drive cancer-relevant programs by stabilizing EYA2 and Rbfox2, by Cdk6/PFKP-linked glycolytic control, and by maintaining genome stability.\",\n      \"evidence\": \"Co-IP, stability/ubiquitination assays, splicing and metabolomic analyses, T-cell assays, CRISPR/siRNA CIN assays, and mouse tumor models\",\n      \"pmids\": [\"35182481\", \"35670764\", \"34791250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FBXO7 chooses stabilizing vs degradative outcomes for substrates not defined\", \"CIN mechanism not mapped to a specific substrate\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Rigorous knockout work established that FBXO7 is dispensable for PINK1/Parkin mitophagy, while parallel studies added SIRT7, Rbfox2, and INF2 as substrates linking FBXO7 to chromatin, splicing, and mitochondrial fission.\",\n      \"evidence\": \"CRISPR KO with super-resolution imaging and global proteomics (negative result); chain-specific ubiquitination, site-mapping, splicing and mitochondrial morphology assays\",\n      \"pmids\": [\"37334901\", \"36646384\", \"37822160\", \"37344480\", \"37874827\", \"37753846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of mitophagy-positive and mitophagy-negative findings unresolved\", \"In vivo relevance of individual cancer substrates varies by tissue\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Site-specific PRMT1 ubiquitination and a patient FP-domain mutation (L250P) connected FBXO7 catalytic and dimerization functions to serine metabolism and to proteasome/mitochondrial defects underlying disease.\",\n      \"evidence\": \"In vitro ubiquitination with site mapping, downstream enzymatic and metabolic assays, mouse tumor model; patient-cell biochemistry with allele-specific dissection\",\n      \"pmids\": [\"38839752\", \"38466799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether reduced substrate ubiquitination or proteasome dysfunction is the primary disease driver unresolved\", \"Full set of FP-domain-dependent substrates undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of IL-6 as a K48-linked substrate extended FBXO7 function to suppression of JAK1/STAT3 inflammatory signaling in cartilage homeostasis.\",\n      \"evidence\": \"Co-IP, MS-mapped K48-specific ubiquitination at K114, and conditional KO mice with osteoarthritis-like phenotypes\",\n      \"pmids\": [\"42102611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether IL-6 degradation occurs intracellularly or extracellularly not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what determines FBXO7's choice between degradative (K48) and non-degradative (K63) ubiquitination and between ligase-dependent and ligase-independent functions across its many substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for substrate/chain-type selection\", \"No structure of the full SCF(FBXO7) holoenzyme with substrate\", \"Reconciliation of conflicting mitophagy data outstanding\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 12, 18, 26, 27, 29, 31, 35]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 18, 26, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5, 9, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 10, 18, 26, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 5, 9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 24, 32]}\n    ],\n    \"complexes\": [\n      \"SCF(FBXO7) E3 ubiquitin ligase\",\n      \"BAG6 complex (via GET4)\"\n    ],\n    \"partners\": [\n      \"SKP1\",\n      \"PI31\",\n      \"CDK6\",\n      \"CDKN1B (p27)\",\n      \"PINK1\",\n      \"PRKN (Parkin)\",\n      \"PSMA2\",\n      \"USP7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}