Affinage

FBXO7

F-box only protein 7 · UniProt Q9Y3I1

Length
522 aa
Mass
58.5 kDa
Annotated
2026-04-28
79 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXO7 is a multifunctional F-box protein that operates as the substrate-recognition subunit of the SCF(FBXO7) E3 ubiquitin ligase complex and additionally serves SCF-independent scaffolding roles in cell cycle control, proteasome assembly, and mitochondrial quality control. As an E3 ligase, FBXO7 targets a broad substrate repertoire—including HURP, PRMT1, SIRT7, UXT-V2, INF2, MiD49, Gsk3β, PFKP, and Rbfox2—for K48- or K63-linked ubiquitination, thereby governing substrate degradation, kinase inhibition, alternative splicing, or protein stabilization depending on chain topology (PMID:15145941, PMID:36646384, PMID:33010352, PMID:37344480, PMID:27503909, PMID:37822160, PMID:38839752). Independent of its ligase activity, FBXO7 stabilizes cyclin D/Cdk6 complexes and p27 to regulate G1-phase progression in hematopoietic and immune cells, and heterodimerizes with the proteasome regulator PI31 through a conserved FP domain to promote proteasome assembly and activity—functions critical for spermiogenesis, neuronal survival, and erythropoiesis (PMID:16096642, PMID:21652635, PMID:18495667, PMID:27497298, PMID:31649556). Loss of FBXO7 in dopaminergic neurons causes progressive neurodegeneration through the RPL23–MDM2–p53 pro-apoptotic axis, proteasome impairment with Lewy body-like inclusions, and mitochondrial fragmentation, consistent with FBXO7 (PARK15) mutations causing autosomal-recessive early-onset parkinsonism (PMID:31144295, PMID:35701754, PMID:38466799).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    Establishing FBXO7 as a bona fide substrate-recognition subunit of an SCF E3 ligase answered the fundamental question of whether this orphan F-box protein had catalytic ubiquitin ligase function, identifying HURP as its first substrate in a phosphorylation-dependent manner.

    Evidence Co-IP, ubiquitination assay, and mutagenesis of Cdk1-cyclin B phosphorylation sites and Fbxo7 proline-rich region in human cells

    PMID:15145941

    Open questions at the time
    • No in vivo physiological role for HURP degradation demonstrated
    • Other substrates unknown at this point
    • Structural basis of HURP recognition not resolved
  2. 2005 High

    Discovery that FBXO7 stabilizes cyclin D/Cdk6 complexes and transforms fibroblasts in a Cdk6-dependent manner revealed an SCF-independent oncogenic scaffolding function, establishing FBXO7 as a cell cycle regulator beyond its E3 ligase role.

    Evidence Co-IP, in vitro binding, Cdk6 knockdown rescue of transformation, nude mouse tumor assays

    PMID:16096642

    Open questions at the time
    • Mechanism by which FBXO7 enhances Cdk6 activity without ubiquitination unknown
    • Relevance to human cancers not established
  3. 2008 High

    Structural and biochemical characterization of the conserved FP domain resolved how FBXO7 heterodimerizes with PI31 and homodimerizes, establishing a protein interaction module distinct from the F-box and substrate-binding domains.

    Evidence Crystal structure of PI31 FP domain, biophysical analysis, mutagenesis ablating interaction in human cells

    PMID:18495667

    Open questions at the time
    • Functional consequence of FP-mediated interactions not yet linked to proteasome biology
    • FBXO7 FP domain structure itself not yet solved
  4. 2011 High

    Identification of p27 as a direct FBXO7 binding partner that is stabilized (not degraded) by FBXO7 revealed a second SCF-independent cell cycle regulatory mechanism, with in vivo validation from Fbxo7-deficient mice showing hematopoietic expansion defects.

    Evidence siRNA knockdown, cell cycle analysis, transgenic Fbxo7(LacZ) mouse model with flow cytometry

    PMID:21652635

    Open questions at the time
    • Mechanism of p27 stabilization (direct protection from other E3 ligases?) not defined
    • Whether Cdk6 and p27 functions are coordinated in the same cells unclear
  5. 2013 High

    Two key advances: the crystal structure of the FBXO7 FP domain was solved at 2.0 Å revealing an asymmetric homodimerization mode, and FBXO7 was linked to PINK1/Parkin-dependent mitophagy with genetic rescue in Drosophila, connecting FBXO7 to mitochondrial quality control and Parkinson's disease pathogenesis.

    Evidence X-ray crystallography (FP domain); Co-IP with PINK1/Parkin, mitophagy assays, Drosophila genetic epistasis

    PMID:23933751 PMID:24419388

    Open questions at the time
    • The mitophagy role was later challenged by rigorous CRISPR KO studies (PMID:37334901)
    • Whether FBXO7 acts upstream or in parallel to Parkin remained ambiguous
  6. 2015 High

    Demonstration that FBXO7 stabilizes p27 during terminal erythropoiesis and that Fbxo7-deficient mice are anemic with impaired cell cycle exit and delayed mitophagy unified the p27-stabilization and mitochondrial functions in a physiological differentiation program.

    Evidence Mouse genetic model, SNP binding efficiency assay, erythroid differentiation assays, mitophagy measurement

    PMID:26095538

    Open questions at the time
    • Direct ubiquitination target mediating erythroid mitophagy not identified
    • Whether p27 and mitophagy defects are independent or linked unclear
  7. 2016 High

    Multiple studies converged to establish FBXO7 as a proteasome assembly factor (ubiquitinating PSMA2), a regulator of mitochondrial respiration (Complex I/NAD+ axis), and a K63-linked ubiquitin ligase for Gsk3β and Tomm20, vastly expanding the substrate repertoire and linking FBXO7 loss to motor deficits in conditional knockout mice.

    Evidence Conditional KO mice (whole-body/neuron-specific), proteasome activity assays, in vitro ubiquitination with chain linkage analysis, mitochondrial function assays with PARP inhibitor rescue

    PMID:27497298 PMID:27503909 PMID:27689878

    Open questions at the time
    • Whether proteasome and mitochondrial phenotypes are mechanistically linked or parallel unknown
    • Relative contribution of each substrate to motor phenotype not dissected
  8. 2016 Medium

    Opposing cell cycle roles of FBXO7 at different T cell developmental stages—Cdk6-dependent expansion in immature thymocytes versus p27-dependent restraint in mature T cells—clarified how a single protein exerts context-dependent proliferative control.

    Evidence Murine hypomorphic Fbxo7 model, thymocyte and mature T cell proliferation assays, Cdk6/p27 Western blots

    PMID:27915416

    Open questions at the time
    • Molecular switch determining which activity dominates at each stage unknown
    • Hypomorphic model may not fully recapitulate null phenotype
  9. 2019 Medium

    Conditional dopaminergic neuron deletion of Fbxo7 established the RPL23–MDM2–p53 pro-apoptotic axis as the molecular mechanism of dopaminergic neurodegeneration, and separately, Fbxo7's role in PI31-dependent proteasome function during spermiogenesis was shown to be essential for male fertility.

    Evidence Conditional KO mice (DAT-Cre for neurons, transgenic for spermatids), gene expression profiling, histology, proteasome activity assays

    PMID:31144295 PMID:31649556

    Open questions at the time
    • Whether RPL23 upregulation is a direct or indirect consequence of FBXO7 loss not resolved
    • PI31 regulation mechanism (direct ubiquitination vs. stabilization) in spermatids not defined
  10. 2020 High

    The relationship between FBXO7 and PINK1 was refined: FBXO7 both ubiquitinates PINK1 for degradation (targetable by the small molecule BC1464) and reciprocally stabilizes processed PINK1 in a brain-region-specific manner, revealing a complex regulatory circuit rather than simple linear pathway.

    Evidence Reciprocal Co-IP, ubiquitination assays, pharmacological disruption of FBXO7-PINK1, brain-region-specific Western blots

    PMID:32493843 PMID:33291077

    Open questions at the time
    • How FBXO7 switches between degradative and stabilizing modes toward PINK1 unclear
    • BC1464 selectivity and in vivo neuronal efficacy not fully characterized
  11. 2020 Medium

    Identification of UXT-V2 and p105/NF-κB as substrates linked FBXO7 to NF-κB signaling through both conventional degradation (UXT-V2) and an unconventional pseudo-substrate stabilization mechanism (p105), demonstrating that FBXO7 binding can have non-degradative outcomes even for proteasomal substrates.

    Evidence In vitro/in vivo ubiquitination with chain linkage analysis, ΔF-Box mutant analysis, NF-κB reporter assays

    PMID:32933748 PMID:33010352

    Open questions at the time
    • Physiological context of p105 pseudo-substrate relationship not defined
    • Whether UXT-V2 and p105 regulation are coordinated unknown
  12. 2021 Medium

    Discovery that FBXO7 associates with the BAG6 chaperone complex via GET4 and controls its cytoplasmic localization connected FBXO7's proteasome-assembly function to a known protein quality control pathway, with PD-associated variants showing reduced GET4 binding.

    Evidence Co-IP, siRNA knockdown, proteasome activity assay, subcellular localization microscopy, PD mutant analysis

    PMID:34060591

    Open questions at the time
    • Whether BAG6 complex mediates FBXO7's proteasome assembly role or represents a parallel function unclear
    • Single-lab finding awaits independent confirmation
  13. 2022 High

    Multiple new substrates and functions were established: FBXO7 ubiquitinates PFKP to regulate glycolysis in T cells (linking it to metabolic control), stabilizes EYA2 to promote mesenchymal gene programs and immune evasion in tumors, and loss of FBXO7 induces chromosome instability, broadening its roles to metabolism, transcription, and genome integrity.

    Evidence Ubiquitination/phosphorylation assays for PFKP, metabolomics in CD4+ T cells; Co-IP and transcriptomics for EYA2 with mouse tumor models; CRISPR KO with CIN imaging assays

    PMID:34791250 PMID:35182481 PMID:35670764

    Open questions at the time
    • Mechanism linking FBXO7 loss to CIN (direct substrate or indirect?) not identified
    • Whether PFKP ubiquitination is degradative or regulatory not fully resolved
  14. 2022 Medium

    Neuron-specific FBXO7 knockout mice developed Lewy body-like inclusions containing p62 and α-synuclein, directly linking proteasome impairment from FBXO7 loss to protein aggregation pathology characteristic of Parkinson's disease.

    Evidence Conditional KO mice (Nestin-Cre), immunofluorescence, electron microscopy, behavioral analysis

    PMID:35701754

    Open questions at the time
    • Whether inclusions are primary drivers of neurodegeneration or secondary to other dysfunction unknown
    • Relationship to RPL23-MDM2-p53 axis not integrated
  15. 2023 High

    A rigorous CRISPR knockout study with quantitative proteomics found FBXO7 dispensable for PINK1/Parkin-dependent mitophagy in neurons and HeLa cells, directly contradicting the 2013 finding and redefining the mitochondrial role of FBXO7 as likely independent of canonical Parkin-mediated mitophagy.

    Evidence CRISPR KO in induced neurons and HeLa cells, pUb kinetics, super-resolution imaging, global quantitative proteomics

    PMID:37334901

    Open questions at the time
    • Whether FBXO7 contributes to alternative (Parkin-independent) mitophagy pathways remains open
    • Cell type-specific differences may explain discrepancy with earlier findings
  16. 2023 High

    New substrates SIRT7 (K48-linked degradation affecting histone acetylation), Rbfox2 (K63-linked stabilization controlling alternative splicing of mesenchymal genes), and INF2 (degradation controlling mitochondrial fission via DRP1) further expanded the functional reach of FBXO7 into chromatin regulation, RNA splicing, and mitochondrial dynamics.

    Evidence In vitro ubiquitination with linkage and site specificity, histone acetylation readouts, RNA splicing analysis, mitochondrial morphology in xenograft models

    PMID:36646384 PMID:37344480 PMID:37822160

    Open questions at the time
    • Integration of these diverse substrate functions into a unified cellular logic remains unclear
    • Whether these substrates are context/tissue-specific not fully explored
  17. 2024 High

    FBXO7 was shown to ubiquitinate PRMT1 at K37 for degradation (suppressing serine synthesis via PHGDH), and a patient mutation (L250P) in the FP domain was shown to ablate PI31 interaction, reduce proteasome activity, impair mitochondrial function, and reduce cellular stress tolerance, providing direct human genetic evidence linking the FP domain–PI31 axis to disease.

    Evidence In vitro ubiquitination with site-specific mutagenesis for PRMT1; patient fibroblast characterization with proteasome and mitochondrial assays for L250P

    PMID:38466799 PMID:38839752

    Open questions at the time
    • Whether L250P patients develop parkinsonism or a distinct syndrome not fully characterized
    • Structural basis of L250P disruption of PI31 binding not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how does FBXO7 select among its many substrates in different cellular contexts; whether FBXO7's mitochondrial functions operate through Parkin-independent mechanisms; and how its proteasome-assembly, cell cycle, and ubiquitin ligase activities are coordinately regulated to prevent neurodegeneration.
  • No structural model of full-length FBXO7 or SCF(FBXO7)–substrate complexes exists
  • Substrate selectivity determinants in different tissues/cell types uncharacterized
  • Whether proteasome and mitochondrial dysfunction are causally linked in neurodegeneration is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 8 GO:0140096 catalytic activity, acting on a protein 8 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-1640170 Cell Cycle 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
CDK6CDKN1BEYA2GET4PI31PINK1PRKNSKP1
Complex memberships
BAG6 complexSCF(FBXO7)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Fbxo7 functions as the substrate-recognition subunit of 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 HURP degradation. Mutation of Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbxo7 abolishes the Fbxo7-HURP interaction. siRNA knockdown, co-immunoprecipitation, ubiquitination assay, mutagenesis The Journal of biological chemistry High 15145941
2005 Fbxo7 selectively interacts with Cdk6 (but not Cdk4 or Cdk2) and D-type cyclins, enhancing cyclin D/Cdk6 complex formation and activity. Fbxo7 overexpression transforms murine fibroblasts in a Cdk6-dependent manner; Cdk6 knockdown reverses transformed phenotypes. Co-immunoprecipitation, in vitro binding, siRNA knockdown, cell transformation assay, nude mouse tumor formation The EMBO journal High 16096642
2006 Fbxo7 interacts with cIAP1 (inhibitor of apoptosis protein 1) in human cells and promotes cIAP1 ubiquitination when co-expressed, suggesting SCF(Fbxo7)-mediated ubiquitination of cIAP1. Fbxo7 and cIAP1 co-localize in the cytoplasm, nucleus, and at Golgi-like structures. Yeast two-hybrid screen, co-immunoprecipitation, co-localization microscopy, ubiquitination assay Biochemical and biophysical research communications Medium 16510124
2008 Fbxo7 and the proteasome inhibitor PI31 share a conserved N-terminal FP (Fbxo7/PI31) domain that mediates heterodimerization between Fbxo7·Skp1 and PI31, as well as homodimerization of each protein. Crystal structure of the PI31 FP domain reveals a novel alpha/beta fold; equivalent mutations in Fbxo7 ablate PI31 interaction and Fbxo7 homodimerization. PI31 is not a substrate for SCF(Fbxo7) degradation. Crystal structure determination, biophysical analysis, mutagenesis, co-immunoprecipitation, siRNA knockdown The Journal of biological chemistry High 18495667
2011 Fbxo7 directly binds p27 and stabilizes p27 protein levels. Reduction of Fbxo7 in haematopoietic Ba/F3 cells decreased p27 levels, increased S-phase cyclins and Cdk2 activity, shortened G1 phase and increased proliferation. Homozygous Fbxo7(LacZ) mice showed increased pro-B cell and pro-erythroblast populations consistent with an anti-proliferative/pro-maturation role. siRNA knockdown, flow cytometry, transgenic mouse model (LacZ insertion), cell cycle analysis, Western blot Journal of cell science High 21652635
2011 Wild-type 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, as N-terminal PARK15 missense mutations or N-terminal tags cause cytoplasmic mislocalization. PARK15 mutations reduce FBXO7 protein stability. Subcellular fractionation, immunofluorescence, overexpression of tagged constructs, patient cell lines PloS one Medium 21347293
2013 Fbxo7 participates in mitophagy through direct physical interaction with PINK1 and Parkin. Cells with reduced Fbxo7 expression show deficiencies in Parkin translocation to mitochondria, ubiquitination of mitofusin 1, and mitophagic flux. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting functional epistasis. PD-causing mutations in Fbxo7 interfered with this process. Co-immunoprecipitation, siRNA knockdown, mitophagy assay, Drosophila genetic epistasis, ubiquitination assay Nature neuroscience High 23933751
2013 The crystal structure of the Fbxo7 FP domain at 2.0 Å resolution reveals an α/β-fold. The Fbxo7 FP domain mediates homodimerization via an αβ interface (α-helical surface of one protomer with β-sheet surface of the other), distinct from the PI31 FP domain interaction mode, and the Fbxo7 FP domain can potentially bind two partners simultaneously. X-ray crystallography at 2.0 Å resolution Acta crystallographica. Section D, Biological crystallography High 24419388
2014 FBXO7 interacts with NRAGE (neurotrophin receptor-interacting MAGE protein) and mediates Lys-63-linked poly-ubiquitination of NRAGE in a proteasome-independent manner. FBXO7 overexpression accelerates NRAGE-TAK1-TAB1 complex formation and positively regulates BMP4-mediated NF-κB signaling. BMP4 stimulation enhances NRAGE ubiquitination through FBXO7. Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assay (K63-specific), siRNA knockdown, NF-κB reporter assay Cellular and molecular life sciences : CMLS Medium 24947323
2015 Fbxo7 stabilizes p27 during erythropoiesis. The M115I SNP reduces Fbxo7 binding efficiency to p27, accelerating cell proliferation. Erythroleukaemic cells with reduced Fbxo7 fail to stabilize p27, exit the cell cycle, or produce haemoglobin. Fbxo7-deficient mice are anaemic with lower p27 levels, increased late-stage erythroblasts with >2N DNA content, and delayed mitophagy during terminal differentiation. Protein binding assay (SNP allele comparison), siRNA knockdown, mouse genetic model, flow cytometry, Western blot, mitophagy assay The Journal of pathology High 26095538
2016 FBXO7-SCF E3 ligase ubiquitinates the proteasomal subunit PSMA2 and FBXO7 is a proteasome-associated protein involved in proteasome assembly. FBXO7 knockout mice exhibit reduced proteasome activity and early-onset motor deficits. Neuron-specific (NEX-Cre and TH-positive) deletion of FBXO7 in mice causes motor defects. Co-immunoprecipitation, ubiquitination assay, conditional knockout mice, proteasome activity assay, behavioral analysis The EMBO journal High 27497298
2016 Fbxo7 deficiency causes reduced cellular NAD+ levels, increased mitochondrial NADH redox index, impaired Complex I activity of the electron transport chain, reduced mitochondrial membrane potential, reduced ATP, and increased cytosolic ROS. ROS activates PARP in Fbxo7-deficient cells; PARP inhibition restores NAD+ content and Complex I-driven respiration. siRNA knockdown, mitochondrial function assays (NADH redox, oxygen consumption), PARP inhibition, NAD+/NADH measurement Cell death and differentiation Medium 27689878
2016 SCF(Fbxo7) ubiquitinates Gsk3β using K63-linked ubiquitin chains and negatively regulates Gsk3β kinase activity (without affecting its levels or localization). SCF(Fbxo7) also ubiquitinates Tomm20 (mitochondrial outer membrane translocase), and Tomm20 levels positively correlate with Fbxo7 expression, indicating a stabilizing effect. Protein array high-throughput screen, in vitro ubiquitination assay, co-immunoprecipitation, ubiquitin chain restriction analysis, kinase activity assay The Biochemical journal High 27503909
2016 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. This establishes opposing cell cycle regulation by Fbxo7 via Cdk6 and p27 at different stages of T cell development. Murine hypomorphic Fbxo7 model, flow cytometry, thymocyte proliferation assay, Cdk6 and p27 Western blot Cellular and molecular life sciences : CMLS Medium 27915416
2019 Conditional deletion of Fbxo7 in midbrain dopamine neurons causes progressive loss of dopamine neurons and locomotor defects, mediated mechanistically by increased expression of RPL23, which inhibits MDM2 (the negative regulator of p53), leading to p53 activation and a pro-apoptotic transcriptional signature in dopaminergic neurons. Conditional knockout mice, HPLC dopamine measurement, immunohistochemistry, gene expression profiling, Western blot The Journal of pathology Medium 31144295
2019 Fbxo7 is required for male germ cell cytoplasmic remodeling during spermiogenesis; reduced Fbxo7 expression in mice causes male sterility with spermatid death during cytoplasmic remodeling. Fbxo7 regulates PI31 protein levels, and PI31 reduction correlates with proteasome defects in spermatids. The requirement for Fbxo7 at this stage is conserved with the Drosophila ortholog nutcracker. Transgenic mouse model, histology, proteasome activity assay, Western blot for PI31 Frontiers in physiology Medium 31649556
2020 FBXO7 targets PINK1 for ubiquitylation and degradation, thereby reducing cellular PINK1 levels. A small molecule (BC1464) identified by computational screening disrupts FBXO7-PINK1 association, increasing PINK1 levels and activity, reducing mitochondrial injury and inflammation, and conferring neuroprotection. Co-immunoprecipitation, ubiquitination assay, small molecule screening, cellular PINK1 levels measurement, mitophagy assay, in vivo lung inflammation model JCI insight High 32493843
2020 SCF(Fbxo7) mediates proteasomal degradation of UXT-V2 (ubiquitously expressed transcript isoform 2) through K48- and K63-linked polyubiquitination, inhibiting NF-κB signaling. The Ubl domain of Fbxo7 contributes to UXT-V2 interaction. FBXO7 knockdown promotes UXT-V2 accumulation and enhances NF-κB reporter activity. Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, ubiquitin chain restriction analysis, cycloheximide chase, siRNA knockdown, NF-κB reporter assay Biochimica et biophysica acta. General subjects High 33010352
2020 p105 NF-κB precursor binds FBXO7 and is ubiquitinated by FBXO7, but this leads to p105 accumulation rather than degradation (pseudo-substrate relationship). Both active FBXO7 and a ΔF-Box inactive mutant cause p105 and p65 accumulation and increased cell proliferation, indicating binding rather than ubiquitination activity drives this effect. Co-immunoprecipitation, ubiquitination assay, ΔF-Box mutant analysis, cell proliferation assay Biochemical and biophysical research communications Medium 32933748
2020 Fbxo7 and Pink1 reciprocally regulate each other's protein levels. Wild-type and PD mutant forms of Fbxo7 stabilize the processed form of Pink1. Fbxo7 interaction with Bag2 further facilitates its ability to stabilize Pink1. Fbxo7 stabilization by Pink1 is specifically observed in substantia nigra pars compacta but not striatum or cerebral cortex. Co-immunoprecipitation, Western blot in multiple brain regions, overexpression studies Aging Medium 33291077
2021 FBXO7-SCF associates with the BAG6 complex (subunits BAG6, GET4, UBL4A). GET4 is a direct interactor of FBXO7 and is a non-proteolytic substrate of SCF(Fbxo7). GET4 and UBL4A are required for proteasome activity. FBXO7 PD-associated variants show reduced GET4 binding and reduced proteasome activity. FBXO7-SCF E3 ligase activity determines cytoplasmic localization of the BAG6 complex. Co-immunoprecipitation, siRNA knockdown, proteasome activity assay, subcellular localization by microscopy, mutant analysis The Biochemical journal Medium 34060591
2021 FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4, negatively regulating FOXO4 levels independently of the ubiquitin-proteasome system and lysosome-autophagy pathway. Treatment with 6-OHDA reduces FOXO4 levels through FBXO7/caspase 8-mediated proteolysis in dopaminergic neurons. Co-immunoprecipitation, caspase 8 inhibitor treatment, caspase 8 knockdown, 6-OHDA neuronal cell death model, Western blot The Journal of biological chemistry Medium 34800438
2022 FBXO7 promotes Cdk6-independent ubiquitination of PFKP (the gatekeeper enzyme of glycolysis) and Cdk6-dependent phosphorylation of PFKP. Fbxo7-deficient CD4+ T cells show increased glycolysis and altered nucleotide/arginine metabolism. Fbxo7 expression is glucose-responsive at the mRNA and protein level. Substrate screen, co-immunoprecipitation, ubiquitination assay, phosphorylation assay, metabolomics, siRNA knockdown, glycolysis measurement The Journal of cell biology High 35670764
2022 FBXO7 binds and stabilizes EYA2 (SIX1 co-transcriptional regulator), promoting mesenchymal gene expression and suppressing IFNα/β, CXCL9/10, and antigen presentation machinery driven by AXL ligand GAS6. The ubiquitin ligase SCFFBXW7 antagonizes this pathway by promoting EYA2 degradation, establishing a FBXO7/EYA2-SCFFBXW7 axis. Co-immunoprecipitation, siRNA knockdown, gene expression profiling, mouse tumor models, T/NK cell infiltration analysis Molecular cell High 35182481
2022 Reduced FBXO7 expression induces chromosome instability (CIN) in colonic epithelial cells, and FBXO7 knockout cells exhibit hallmarks of cellular transformation (increased clonogenic and anchorage-independent growth), establishing FBXO7 as a CIN gene required for genome stability. siRNA knockdown, CRISPR/Cas9 knockout, quantitative imaging microscopy for CIN, clonogenic assay, anchorage-independent growth assay Human molecular genetics Medium 34791250
2022 Neuron-specific FBXO7 conditional knockout mice (Nestin-Cre) exhibit motor dysfunction, reduced dopaminergic neurons, fragmented mitochondria in dopaminergic and cortical neurons, and p62- and synuclein-positive Lewy body-like aggregates in neurons. Loss of FBXO7 impairs the ubiquitin-proteasome system, resulting in p62 accumulation that drives inclusion body formation. Conditional knockout mouse (Nestin-Cre), histology, immunofluorescence, electron microscopy, behavioral analysis Molecular brain Medium 35701754
2023 FBXO7 ubiquitinates SIRT7 via K48-linked polyubiquitination through the SCF complex, leading to proteasomal degradation of SIRT7. FBXO7-mediated SIRT7 degradation blocks SIRT7 deacetylase activity, increasing H3K18 and H3K36 acetylation and repressing RPS20 transcription. Hydrogen peroxide treatment triggers FBXO7-mediated SIRT7 degradation and cell death. The PD-linked R498X mutant FBXO7 lacks this activity. Co-immunoprecipitation, in vitro ubiquitination assay (K48-specific), cycloheximide chase, histone acetylation analysis, gene reporter assay, hydrogen peroxide cytotoxicity assay, disease mutant analysis The Journal of biological chemistry High 36646384
2023 FBXO7 ubiquitinates Rbfox2 at Lys249 through K63-linked ubiquitin chains (after PRMT5-dependent arginine dimethylation of Rbfox2 at Arg341/441), stabilizing Rbfox2. FBXO7-stabilized Rbfox2 controls alternative splicing of mesenchymal genes including FoxM1, Mta1, and Postn, promoting FoxM1 exon Va inclusion and MEK1-dependent nuclear translocation, driving GBM mesenchymal transformation. Co-immunoprecipitation, ubiquitination assay (K63-specific), RNA splicing analysis, siRNA knockdown, mouse xenograft model Advanced science High 37822160
2023 FBXO7/PARK15 is dispensable for PINK1/Parkin-dependent mitophagy in induced neurons and HeLa cells. FBXO7-/- cells show no defect in pUb accumulation kinetics, Parkin recruitment, autophagy machinery recruitment, mitophagic flux, or mitochondrial clearance by global proteomics. CRISPR knockout, super-resolution imaging, global quantitative proteomics, mitophagic flux assay, pUb accumulation kinetics EMBO reports High 37334901
2023 USP7 (ubiquitin-specific protease 7) acts as a deubiquitinase for FBXO7, removing K48-linked ubiquitin from FBXO7 and stabilizing it. USP7 mitigates ER stress-induced cytotoxicity and apoptosis by preventing proteasomal degradation of FBXO7. Co-immunoprecipitation, deubiquitination assay (K48-specific), cycloheximide chase, ER stress induction, cell viability assay PloS one Medium 37874827
2023 FBXO7 ubiquitinates and promotes proteasomal degradation of INF2 (a mitochondrial fission factor that recruits DRP1), suppressing INF2-DRP1-mediated mitochondrial hyper-division. ECa-associated FBXO7 mutants are defective in INF2 ubiquitination, allowing mitochondrial hyper-division that promotes tumor cell proliferation and migration. Co-immunoprecipitation, ubiquitination assay, protein stability assay, mitochondrial morphology analysis, siRNA knockdown, mouse xenograft model Cell death & disease High 37344480
2023 Loss of FBXO7 in glutamatergic forebrain neurons leads to increased striatal dopamine concentrations, changes in glutamatergic/GABAergic/dopaminergic pathway markers, astro- and microgliosis, and alterations in synaptic membrane proteins (complement system, endocytosis/exocytosis pathways) by quantitative mass spectrometry, establishing FBXO7 as essential for corticostriatal projection integrity. Conditional knockout mice (NEX-Cre), HPLC, histology, quantitative synaptic membrane proteomics by mass spectrometry Journal of neurochemistry Medium 37753846
2024 FBXO7 binds PRMT1 and promotes its K37 ubiquitination and proteasomal degradation (acting as SCF E3 ligase). FBXO7-mediated PRMT1 downregulation impairs PHGDH arginine methylation and activation, reducing serine synthesis, increasing ROS, and inhibiting HCC cell growth. Co-immunoprecipitation, in vitro ubiquitination assay (site-specific mutagenesis identifying K37), PHGDH methylation assay, ROS measurement, cell growth assay, patient tissue correlation Nature communications High 38839752
2024 An Fbxo7 L250P mutation in the FP dimerization domain selectively ablates Fbxo7-PI31 interaction, reduces Fbxo7 and PI31 protein levels, reduces proteasome activity and subunit levels in patient fibroblasts. PI31 interacts with MiD49/51 mitochondrial fission adaptors and facilitates SCF(Fbxo7)-mediated ubiquitination of MiD49. Patient cells show reduced mitochondrial function, reduced mitophagy, higher ROS, and decreased viability under stress. Patient cell characterization, co-immunoprecipitation, ubiquitination assay, proteasome activity assay, mitochondrial function assay, ROS measurement The FEBS journal High 38466799

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 256 19038853
2013 The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nature neuroscience 255 23933751
2010 Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Movement disorders : official journal of the Movement Disorder Society 188 20669327
2011 Phylogenetic comparison of F-Box (FBX) gene superfamily within the plant kingdom reveals divergent evolutionary histories indicative of genomic drift. PloS one 114 21297981
2004 Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region. The Journal of biological chemistry 98 15145941
2013 Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins. Open biology 79 24107298
2005 Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6. The EMBO journal 78 16096642
2008 Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor. The Journal of biological chemistry 74 18495667
2012 A comprehensive analysis of interaction and localization of Arabidopsis SKP1-like (ASK) and F-box (FBX) proteins. PloS one 69 23166809
2006 The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein cIAP1 and promotes cIAP1 ubiquitination. Biochemical and biophysical research communications 57 16510124
2024 FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature communications 55 38839752
2016 Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice. The EMBO journal 55 27497298
2020 Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1. JCI insight 51 32493843
2016 Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation. Cell death and differentiation 49 27689878
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2011 Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells. Journal of cell science 35 21652635
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2026 HSP90AA1 restrains clear cell renal cell carcinoma progression by promoting CADM1 expression and suppressing the PI3K-AKT pathway through interaction with FBXO7. Cell death discovery 0 41507145
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