Affinage

FBXO7

F-box only protein 7 · UniProt Q9Y3I1

Length
522 aa
Mass
58.5 kDa
Annotated
2026-06-09
79 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    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

    PMID:15145941

    Open questions at the time
    • Did not establish the full substrate repertoire
    • Physiological context of HURP degradation not defined
  2. 2005 High

    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

    PMID:16096642

    Open questions at the time
    • Mechanism by which FBXO7 promotes complex assembly not structurally defined
    • Relationship between ligase and Cdk6 roles unresolved
  3. 2008 High

    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

    PMID:18495667

    Open questions at the time
    • Functional consequence of FBXO7-PI31 binding for proteasome activity not yet shown
    • PI31 not a substrate
  4. 2011 Medium

    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

    PMID:21347293 PMID:21652635

    Open questions at the time
    • Mechanistic link between mislocalization and disease not defined
    • Direct nuclear substrates not identified
  5. 2013 High

    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

    PMID:23933751 PMID:24419388

    Open questions at the time
    • General requirement for FBXO7 in mitophagy later disputed
    • Whether FBXO7-Parkin interaction is direct in vivo unresolved
  6. 2014 Medium

    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

    PMID:24947323

    Open questions at the time
    • Single-lab study without in vitro reconstitution
    • Physiological relevance of BMP/NF-κB axis in vivo not shown
  7. 2015 Medium

    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

    PMID:26095538

    Open questions at the time
    • Mechanism of p27 stabilization (ligase-dependent vs independent) not fully resolved
    • Single-lab
  8. 2016 High

    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

    PMID:27497298

    Open questions at the time
    • How PSMA2 ubiquitination affects assembly mechanistically not defined
    • Link to specific neuron loss not yet mapped
  9. 2016 Medium

    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

    PMID:27503909 PMID:27689878

    Open questions at the time
    • Direct mechanism linking FBXO7 loss to PARP overactivation not established
    • Tomm20 stabilization mechanism unclear
  10. 2019 Medium

    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

    PMID:31085610 PMID:31144295 PMID:31649556

    Open questions at the time
    • RPL23-p53 placement correlative, no epistasis rescue
    • Proteasome-activity sensitivity is cell-type specific and mechanism unclear
  11. 2020 Medium

    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

    PMID:32493843 PMID:32933748 PMID:33010352 PMID:33291077 PMID:34060591

    Open questions at the time
    • Opposing reports of FBXO7 degrading vs stabilizing PINK1 unreconciled
    • Several interactions single-lab without reciprocal in vivo validation
  12. 2022 High

    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

    PMID:34791250 PMID:35182481 PMID:35670764

    Open questions at the time
    • How FBXO7 chooses stabilizing vs degradative outcomes for substrates not defined
    • CIN mechanism not mapped to a specific substrate
  13. 2023 High

    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

    PMID:36646384 PMID:37334901 PMID:37344480 PMID:37753846 PMID:37822160 PMID:37874827

    Open questions at the time
    • Reconciliation of mitophagy-positive and mitophagy-negative findings unresolved
    • In vivo relevance of individual cancer substrates varies by tissue
  14. 2024 High

    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

    PMID:38466799 PMID:38839752

    Open questions at the time
    • Whether reduced substrate ubiquitination or proteasome dysfunction is the primary disease driver unresolved
    • Full set of FP-domain-dependent substrates undefined
  15. 2026 Medium

    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

    PMID:42102611

    Open questions at the time
    • Single-lab study
    • Whether IL-6 degradation occurs intracellularly or extracellularly not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 3
Partners
CDK6CDKN1B (P27)PI31PINK1PRKN (PARKIN)PSMA2SKP1USP7
Complex memberships
BAG6 complex (via GET4)SCF(FBXO7) E3 ubiquitin ligase

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. siRNA knockdown, co-immunoprecipitation, ubiquitination assay, mutagenesis The Journal of biological chemistry High 15145941
2005 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. Co-immunoprecipitation (in vitro and in vivo), siRNA knockdown, kinase assay, E2F reporter assay, transformation assay, nude mouse xenograft The EMBO journal High 16096642
2006 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. Yeast two-hybrid screen, co-immunoprecipitation, co-localization by fluorescence microscopy, ubiquitination assay Biochemical and biophysical research communications Medium 16510124
2008 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). Crystal structure determination, biophysical analysis (including analytical ultracentrifugation), mutagenesis, co-immunoprecipitation, siRNA knockdown The Journal of biological chemistry High 18495667
2011 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. Immunofluorescence/localization studies, overexpression of wild-type and mutant constructs, fusion protein localization assay, patient cell analysis PloS one Medium 21347293
2011 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. siRNA/shRNA knockdown, cell cycle analysis, flow cytometry, transgenic mouse model (LacZ insertion) Journal of cell science Medium 21652635
2013 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. Co-immunoprecipitation, siRNA knockdown with mitophagy assays (Parkin translocation, mitofusin 1 ubiquitination, mitochondrial clearance), Drosophila genetic rescue Nature neuroscience High 23933751
2013 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. X-ray crystallography (2.0 Å resolution, SAD phasing) Acta crystallographica. Section D, Biological crystallography High 24419388
2014 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. Yeast two-hybrid screen, co-immunoprecipitation, ubiquitination assay (K63-linkage specific), siRNA knockdown, reporter assay (NF-κB) Cellular and molecular life sciences : CMLS Medium 24947323
2015 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. Co-immunoprecipitation, protein stability assay, cell cycle analysis, mouse model, haemoglobin assay, mitophagy assay The Journal of pathology Medium 26095538
2016 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. Co-immunoprecipitation, ubiquitination assay, proteasome activity assay, conditional knockout mouse (Cre-lox), behavioral assays The EMBO journal High 27497298
2016 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. Cellular metabolic assays (NAD+/NADH, oxygen consumption, mitochondrial membrane potential, ATP, ROS), PARP inhibitor rescue experiments, siRNA knockdown Cell death and differentiation Medium 27689878
2016 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. Protein array screen (high-throughput), in vitro ubiquitination assay, in vivo ubiquitination assay, 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. These opposing effects are mediated through Fbxo7's distinct interactions with Cdk6 and p27 at different stages of T cell development. Transgenic mouse model (reduced Fbxo7 expression), flow cytometry, cell cycle analysis, Cdk6 activity assay, 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 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. Conditional knockout mouse (dopamine neuron-specific), HPLC, immunohistochemistry, RNA-seq/transcriptional analysis, protein expression analysis The Journal of pathology Medium 31144295
2019 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. Mouse model (hypomorphic/reduced expression), histology, electron microscopy, western blot (PI31 levels), Drosophila mutant analysis Frontiers in physiology Medium 31649556
2020 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. Co-immunoprecipitation, ubiquitination assay, PINK1 stability/degradation assay, small molecule inhibitor screen, cell viability assay, murine lung inflammation model JCI insight Medium 32493843
2020 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. Co-immunoprecipitation, western blot (protein stability), regional brain fractionation, overexpression/knockdown studies Aging Medium 33291077
2020 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. 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 Biochimica et biophysica acta. General subjects High 33010352
2020 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. Co-immunoprecipitation, ubiquitination assay, ΔF-box dominant-negative mutant, western blot, cell proliferation assay Biochemical and biophysical research communications Medium 32933748
2021 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. Co-immunoprecipitation, proteasome activity assay, ubiquitination assay, subcellular localization analysis, siRNA knockdown The Biochemical journal Medium 34060591
2021 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. Co-immunoprecipitation, protein stability assay (caspase inhibitors, caspase 8 knockdown), western blot in neurotoxin-treated cells The Journal of biological chemistry Medium 34800438
2022 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. Co-immunoprecipitation, protein stability/ubiquitination assays, transcriptional reporter assays, siRNA knockdown, mouse tumor models Molecular cell High 35182481
2022 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. Co-immunoprecipitation, substrate screen, kinase assay, ubiquitination assay, metabolomics, siRNA knockdown, T cell activation assay The Journal of cell biology High 35670764
2022 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. Conditional knockout mouse (Nestin-Cre), behavioral assays, immunohistochemistry, electron microscopy Molecular brain Medium 35701754
2022 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. siRNA knockdown, CRISPR/Cas9 knockout, chromosome enumeration (CIN assay), clonogenic assay, anchorage-independent growth assay Human molecular genetics Medium 34791250
2023 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. Co-immunoprecipitation, in vivo ubiquitination assay (K48-linkage specific), cycloheximide chase, western blot (histone acetylation), gene reporter assay, H2O2 cell death assay The Journal of biological chemistry High 36646384
2023 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. Co-immunoprecipitation, ubiquitination assay (K63-chain specific), mass spectrometry, alternative splicing analysis (RNA-seq), siRNA knockdown, mouse xenograft tumor model Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 37822160
2023 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. CRISPR/Cas9 knockout, super-resolution imaging, global proteomics, mitophagy flux assays, phospho-ubiquitin kinetics EMBO reports High 37334901
2023 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. Co-immunoprecipitation, ubiquitination assay, protein stability assay, siRNA knockdown, overexpression, mitochondrial morphology analysis, mouse xenograft Cell death & disease Medium 37344480
2023 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. Co-immunoprecipitation, deubiquitination assay (K48-linkage specific), protein stability assay (cycloheximide chase), siRNA knockdown, cell viability/apoptosis assay PloS one Medium 37874827
2024 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. 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 Nature communications High 38839752
2024 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. Patient cell biochemistry, co-immunoprecipitation, ubiquitination assay, proteasome activity assay, mitochondrial function assays, mitophagy assay, ROS assay The FEBS journal High 38466799
2019 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. Conditional knockout mouse (Cnp1-Cre and Plp1-CreERT2), behavioral assays, histology, electron microscopy, proteasome activity assay The Journal of neuroscience Medium 31085610
2023 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. Conditional knockout mouse (NEX-Cre), HPLC, histology, immunohistochemistry, synaptic membrane purification, quantitative mass spectrometry Journal of neurochemistry Medium 37753846
2026 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. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific, site-mapping by LC-MS/MS), conditional knockout mouse, histology, immunohistochemistry International immunopharmacology Medium 42102611

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 259 19038853
2013 The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nature neuroscience 258 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 116 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 81 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 76 18495667
2024 FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature communications 62 38839752
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
2016 Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice. The EMBO journal 56 27497298
2020 Chemical inhibition of FBXO7 reduces inflammation and confers neuroprotection by stabilizing the mitochondrial kinase PINK1. JCI insight 53 32493843
2016 Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation. Cell death and differentiation 51 27689878
2016 FBXO7 mutations in Parkinson's disease and multiple system atrophy. Neurobiology of aging 44 26882974
2016 Gsk3β and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. The Biochemical journal 42 27503909
2018 Pathophysiological mechanisms linking F-box only protein 7 (FBXO7) and Parkinson's disease (PD). Mutation research. Reviews in mutation research 41 30454685
2011 Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15). PloS one 40 21347293
2013 FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson disease and multiple system atrophy. Journal of neuropathology and experimental neurology 38 23656991
2014 A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism. Parkinsonism & related disorders 37 25085748
2011 Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells. Journal of cell science 35 21652635
2012 Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish. PloS one 32 23133663
2017 Mechanistic contributions of FBXO7 to Parkinson disease. Journal of neurochemistry 29 29134665
2014 FBXO7-R498X mutation: phenotypic variability from chorea to early onset parkinsonism within a family. Parkinsonism & related disorders 29 25169713
2023 PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems. EMBO reports 27 37334901
2014 The F-box protein FBXO7 positively regulates bone morphogenetic protein-mediated signaling through Lys-63-specific ubiquitination of neurotrophin receptor-interacting MAGE (NRAGE). Cellular and molecular life sciences : CMLS 26 24947323
2020 Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect. Annals of clinical and translational neurology 23 32767480
2019 Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway. The Journal of pathology 23 31144295
2022 A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells. Molecular cell 22 35182481
2015 Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression. The Journal of pathology 22 26095538
2011 Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. PloS one 21 21695055
2006 Fbxo7 gets proactive with cyclin D/cdk6. Cell cycle (Georgetown, Tex.) 19 16410730
2023 FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative Splicing. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 37822160
2013 Mutational analysis of FBXO7 gene in Parkinson's disease in a Taiwanese population. Neurobiology of aging 18 23352116
2012 Lack of association between three single nucleotide polymorphisms in the PARK9, PARK15, and BST1 genes and Parkinson's disease in the northern Han Chinese population. Chinese medical journal 18 22490479
2017 Structure and Function of Fbxo7/PARK15 in Parkinson's Disease. Current protein & peptide science 17 26965690
2022 Impaired mitochondrial accumulation and Lewy pathology in neuron-specific FBXO7-deficient mice. Molecular brain 16 35701754
2022 The characteristics of FBXO7 and its role in human diseases. Gene 16 36261086
2020 Fbxo7 and Pink1 play a reciprocal role in regulating their protein levels. Aging 16 33291077
2019 A Conserved Requirement for Fbxo7 During Male Germ Cell Cytoplasmic Remodeling. Frontiers in physiology 16 31649556
2023 E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide. The Journal of biological chemistry 13 36646384
2016 Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27. Cellular and molecular life sciences : CMLS 12 27915416
2014 FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease. PloS one 12 25029497
2022 Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells. The Journal of cell biology 11 35670764
2020 The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-κB signaling pathway. Biochimica et biophysica acta. General subjects 11 33010352
2019 Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy. The Journal of neuroscience : the official journal of the Society for Neuroscience 11 31085610
2018 Genetic analysis of ATP13A2, PLA2G6 and FBXO7 in a cohort of Chinese patients with early-onset Parkinson's disease. Scientific reports 11 30232368
2017 Deficiency of Parkinson's disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation. Cell death and differentiation 11 29027992
2010 FBXO7 gene mutations may be rare in Chinese early-onset Parkinsonism patients. Neuroscience letters 11 20603184
2024 Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria. The FEBS journal 10 38466799
2023 FBXO7, a tumor suppressor in endometrial carcinoma, suppresses INF2-associated mitochondrial division. Cell death & disease 10 37344480
2023 USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7. PloS one 10 37874827
2022 The F-box protein, FBXO7, is required to maintain chromosome stability in humans. Human molecular genetics 10 34791250
2020 The p105 NF-ĸB precursor is a pseudo substrate of the ubiquitin ligase FBXO7, and its binding to the ligase stabilizes it and results in stimulated cell proliferation. Biochemical and biophysical research communications 10 32933748
2021 FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity. The Journal of biological chemistry 9 34800438
2013 Structure of the FP domain of Fbxo7 reveals a novel mode of protein-protein interaction. Acta crystallographica. Section D, Biological crystallography 8 24419388
2020 Compound heterozygous variants of the FBXO7 gene resulting in infantile-onset Parkinsonian-pyramidal syndrome in siblings of a Chinese family. Journal of clinical laboratory analysis 7 32274857
2020 Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson's disease. Parkinsonism & related disorders 7 33002721
2016 Familial atypical parkinsonism with rare variant in VPS35 and FBXO7 genes: A case report. Medicine 7 27861377
2014 The FP domains of PI31 and Fbxo7 have the same protein fold but very different modes of protein-protein interaction. Journal of biomolecular structure & dynamics 7 25266262
2024 A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function. The FEBS journal 6 38708447
2021 The parkinsonism-associated protein FBXO7 cooperates with the BAG6 complex in proteasome function and controls the subcellular localization of the complex. The Biochemical journal 5 34060591
2019 FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele. PloS one 5 30840666
2016 The FBXO7 homologue nutcracker and binding partner PI31 in Drosophila melanogaster models of Parkinson's disease. Genome 5 27936908
2013 Systematic mutational analysis of FBXO7 in a Parkinson's disease population from southern Spain. Neurobiology of aging 5 24112787
2023 Serum extracellular vesicles with NSD1 and FBXO7 mRNA as novel biomarkers for gastric cancer. Clinical biochemistry 4 37742869
2022 Nearly Abolished Dopamine Transporter Uptake in a Patient With a Novel FBXO7 Mutation. Journal of movement disorders 4 35880381
2021 Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells. Biochemical and biophysical research communications 4 33774278
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 3 41507145
2021 A novel FBXO7-R345P mutation in a Chinese family with autosomal recessive parkinsonian-pyramidal syndrome. Parkinsonism & related disorders 3 34144229
2016 Medicinal herbs Oenanthe javanica (Blume) DC., Casuarina equisetifolia L. and Sorghum bicolor (L.) Moench protect human cells from MPP+ damage via inducing FBXO7 expression. Phytomedicine : international journal of phytotherapy and phytopharmacology 3 27765362
2009 Correlation of FBX dosimeter and micronucleus assay in radiation dosimetry of gamma chambers. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 3 19392656
2013 Expression, purification and crystallization of the FP domain of the human F-box protein Fbxo7. Acta crystallographica. Section F, Structural biology and crystallization communications 2 24100556
2023 Loss of the parkinsonism-associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to abnormal motor behavior and synaptic defects. Journal of neurochemistry 1 37753846
2026 CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR. ACS chemical neuroscience 0 41640382
2026 rAAV Fbxo7 gene therapy rescues the progressive nigrostriatal pathology in a mouse model of juvenile parkinsonism. Acta neuropathologica communications 0 41992302
2026 FBXO7 protects against osteoarthritis by promoting IL-6 ubiquitination and inhibiting JAK1/STAT3 signaling. International immunopharmacology 0 42102611
2025 FBXO7 Pathogenic Variants in Early-Onset Parkinsonism: Insights from a Neuroimaging Perspective and Review of the Literature. Movement disorders clinical practice 0 40740144
2025 CHEK1 is a synthetic lethal interactor of FBXO7 in colonic epithelial cells. Molecular therapy. Oncology 0 40896366
2024 Correction: USP7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of FBXO7. PloS one 0 38265984

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