Affinage

FBXO10

F-box only protein 10 · UniProt Q9UK96

Length
956 aa
Mass
105.2 kDa
Annotated
2026-06-09
12 papers in source corpus 11 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXO10 is a substrate-recognition F-box subunit of the SCF (SKP1/CUL1/F-box) E3 ubiquitin ligase that controls the abundance of diverse substrates and, through compartment-specific targeting, couples ubiquitination to apoptosis, B-cell receptor signaling, mitochondrial proteostasis, and ferroptosis (PMID:27157620, PMID:31570756, PMID:39306844, PMID:38659932). Its substrate engagement is governed by where the ligase is positioned: BCR stimulation triggers reversible palmitoylation that relocalizes SCF-FBXO10 from cytosol to the plasma membrane, where it ubiquitylates and degrades HGAL through recognition of a single conserved residue (H91), dampening BCR-induced calcium influx in a negative-feedback loop (PMID:31570756); geranylgeranylation at C953, read out by the prenyl-binding chaperone PDE6δ together with HSP90, traffics FBXO10 to the outer mitochondrial membrane where it degrades PGAM5 to sustain mitochondrial membrane potential, ATP production, and myogenic differentiation (PMID:39306844, PMID:38659932). Across cell types FBXO10 directs proteasomal or lysosomal turnover of additional substrates including BCL2 in mantle cell lymphoma (PMID:27157620), RAGE following PKCζ phosphorylation (PMID:28515150, PMID:34492157), ACSL4 (constraining ferroptotic lipid peroxidation independently of GPX4/SLC7A11) (PMID:40616744), and RAS (suppressing RAS/ERK-driven Golgi stress and neuronal apoptosis) (PMID:41999223). FBXO10 transcription is itself induced through a PKC–c-Fos/AP1 axis acting on its promoter and is repressed by EZH2-deposited H3K27me3 (PMID:24008983, PMID:41999223). A well-controlled CRISPR knock-in mouse study found that FBXO10 loss does not elevate B-cell BCL2 or alter BCL2-regulated lymphocyte subsets, indicating it is not the sole non-redundant BCL2 ligase in vivo (PMID:33914737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2013 Medium

    Established how FBXO10 expression is controlled, defining an inducible signaling input rather than a constitutive ligase.

    Evidence Promoter-luciferase reporters, PKC inhibitors, and endogenous mRNA/protein induction by TPA in Jurkat T cells

    PMID:24008983

    Open questions at the time
    • Does not connect transcriptional induction to a specific substrate or physiological outcome
    • AP1/c-Fos regulation shown in T-cell line only
  2. 2016 Medium

    Defined the first FBXO10 substrate by linking its E3 ligase activity to BCL2 turnover in a disease context.

    Evidence Protein/expression analysis across MCL patient tissue and cell lines with FBXO10 knockdown and BCL2 stability readout

    PMID:27157620

    Open questions at the time
    • No reconstituted FBXO10-mediated BCL2 ubiquitination
    • Correlative/knockdown evidence rather than direct enzymatic assay
  3. 2017 Medium

    Showed FBXO10 directs a substrate to a non-proteasomal fate and is gated by upstream phosphorylation, expanding its mechanistic repertoire.

    Evidence Reciprocal Co-IP of FBXO10/RAGE, K374 ubiquitination site mapping, PKCζ manipulation, and RAGE stability assays

    PMID:28515150

    Open questions at the time
    • Monoubiquitination versus polyubiquitination determinants not resolved
    • Single lab; lysosomal routing mechanism not defined
  4. 2019 High

    Revealed that lipid-modification-driven relocalization, not phosphorylation, dictates FBXO10 substrate access at the membrane and feeds back on BCR signaling.

    Evidence Palmitoylation assay, subcellular fractionation, H91 mutagenesis, ubiquitination assay, and calcium/phospho-effector readouts

    PMID:31570756

    Open questions at the time
    • Palmitoyltransferase responsible for FBXO10 modification not identified
    • Generality of phosphorylation-independent recognition to other substrates untested
  5. 2021 Medium

    Tested the BCL2-ligase model in vivo and found FBXO10 is not the non-redundant BCL2 E3 in mouse B cells, qualifying the lymphoma model.

    Evidence Two independent CRISPR/Cas9 knock-in Fbxo10 alleles with BCL2 Western blot and lymphocyte flow cytometry

    PMID:33914737

    Open questions at the time
    • Does not exclude redundant ligases masking a BCL2 phenotype
    • Species/context differences from human MCL unaddressed
  6. 2021 Medium

    Extended the RAGE axis to neuroinflammatory control, linking FBXO10 substrate degradation to microglial polarization in vivo.

    Evidence FBXO10 overexpression/RAGE knockdown in BV2 cells with ubiquitination, cytokine ELISA, and a CUS mouse model

    PMID:34492157

    Open questions at the time
    • Direct FBXO10–RAGE binding in microglia not re-demonstrated
    • p38/NF-κB effects could be indirect
  7. 2024 High

    Defined a second lipid-modification route—geranylgeranylation with a dedicated chaperone system—that targets FBXO10 to mitochondria for a specific substrate and physiological output.

    Evidence C953S mutagenesis, PDE6δ/HSP90 Co-IP, LFQ-MS substrate identification, PGAM5 ubiquitination, and mitochondrial/differentiation assays

    PMID:38659932 PMID:39306844

    Open questions at the time
    • How prenylation versus palmitoylation is selected in a given cell is unknown
    • Structural basis of PGAM5 recognition undefined
  8. 2025 Medium

    Connected FBXO10 to ferroptosis control by degrading ACSL4 through a pathway parallel to canonical GPX4/SLC7A11 axes.

    Evidence Co-IP/colocalization, FBXO10 silencing with ACSL4 ubiquitination/stability, ferroptosis markers, and xenograft

    PMID:40616744

    Open questions at the time
    • Ubiquitin linkage type on ACSL4 not specified
    • Single lab; no reconstitution
  9. 2025 Low

    Reported an atypical activity—K63-linked ubiquitination that stabilizes rather than degrades a substrate—broadening FBXO10's possible output modes.

    Evidence Co-IP of FBXO10/FRMPD1, K63-linkage assay, silencing/overexpression with FRMPD1 levels and rescue in HCC cells

    PMID:40699790

    Open questions at the time
    • Not independently confirmed and lacks structural/reconstitution support
    • Stabilizing K63 chains are unusual for an SCF/F-box ligase and need orthogonal validation
  10. 2026 Medium

    Linked FBXO10 to RAS turnover and placed it under epigenetic repression, integrating its activity into RAS/ERK-driven Golgi stress.

    Evidence FBXO10/RAS Co-IP, RAS ubiquitination assay, H3K27me3 ChIP at the FBXO10 promoter, and rescue in H2O2-treated neuronal lines

    PMID:41999223

    Open questions at the time
    • Which RAS isoform is targeted not resolved
    • EZH2 repression shown by ChIP/manipulation but direct promoter occupancy mechanism limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown what unifies FBXO10 substrate selection across compartments and whether a common structural determinant or chaperone code governs its palmitoylation-versus-prenylation choice and degradative-versus-stabilizing outputs.
  • No structure of FBXO10 with any substrate
  • No unifying rule for ubiquitin linkage choice
  • Cross-substrate competition and tissue-specific dominance untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 3 GO:0060089 molecular transducer activity 1
Localization
GO:0005739 mitochondrion 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 1
Complex memberships
SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 FBXO10 functions as an E3 ubiquitin ligase subunit that targets BCL2 for protein degradation in mantle cell lymphoma; loss of FBXO10 expression leads to BCL2 protein accumulation due to impaired ubiquitin-proteasome degradation. Protein expression analysis in MCL patient tissue microarray and cell lines; RNA-seq with BTK shRNA knockdown; BCL2 protein level assessment after FBXO10 loss Oncogene Medium 27157620
2017 FBXO10 directly associates with RAGE (receptor for advanced glycation end products) to mediate its monoubiquitination at K374 and lysosomal degradation; PKCζ phosphorylates RAGE to promote this FBXO10-mediated degradation; FBXO10 depletion stabilizes RAGE and prevents ODN2006-mediated degradation. Co-immunoprecipitation of FBXO10 and RAGE; FBXO10 knockdown with RAGE protein stability assay; PKCζ overexpression/knockdown; identification of ubiquitination site K374 FASEB journal Medium 28515150
2019 BCR stimulation induces rapid and reversible palmitoylation of the SCF-FBXO10 E3 ligase complex, causing FBXO10 relocalization from cytosol to the cell membrane, where it targets HGAL for ubiquitylation and degradation; FBXO10 recognition of HGAL is phosphorylation-independent and requires a single conserved HGAL residue H91; HGAL degradation via FBXO10 decreases BCR-induced calcium influx and phosphorylation of proximal BCR effectors, creating a negative autoregulatory feedback loop. Palmitoylation assay, subcellular fractionation/localization, ubiquitination assay, site-directed mutagenesis (H91), calcium influx measurements, phosphorylation assays of BCR effectors Leukemia High 31570756
2021 FBXO10 promotes ubiquitination and degradation of RAGE in BV2 microglia cells; FBXO10 overexpression reduces RAGE accumulation, inhibits p38 MAPK and NF-κB signaling, and promotes M2 microglial polarization, while FBXO10 loss leads to RAGE stabilization and M1-skewed neuroinflammation. FBXO10 overexpression and RAGE knockdown in BV2 cells; ubiquitination assay; cytokine ELISA; in vivo CUS mouse model with viral FBXO10 overexpression; immunofluorescence for microglial phenotype CNS neuroscience & therapeutics Medium 34492157
2024 FBXO10 undergoes geranylgeranyl lipid modification at cysteine 953 (C953), which is required for its trafficking to the outer mitochondrial membrane (OMM); this trafficking is orchestrated by interaction with PDE6δ (prenyl group-binding protein) and HSP90 chaperone; at the OMM, FBXO10 targets PGAM5 for polyubiquitylation and proteasomal degradation; the geranylgeranylation-deficient C953S mutant redistributes away from the OMM, fails to degrade PGAM5, and causes impaired mitochondrial ATP production, decreased membrane potential, increased fragmentation, and impaired myogenic differentiation. Geranylgeranylation site identification and C953S mutagenesis; subcellular fractionation and live-cell imaging; co-immunoprecipitation with PDE6δ and HSP90; comparative quantitative mass spectrometry (LFQ-MS/MS) of enriched mitochondria for substrate identification; PGAM5 ubiquitination assay; mitochondrial function assays (ATP, membrane potential); iPSC and murine myoblast differentiation assays Cell reports High 38659932 39306844
2021 CRISPR/Cas9-engineered Fbxo10 loss-of-function mutations (D54K missense in FBOX domain and frameshift truncation) in mice did not increase BCL2 protein levels in B cells, nor did they increase mature B cell, germinal center B cell, or other BCL2-regulated lymphocyte subset numbers — indicating that FBXO10 does not regulate BCL2 as a sole non-redundant E3 ligase in mouse B lymphocytes. CRISPR/Cas9 knock-in mice with two distinct Fbxo10 mutations; Western blot for BCL2 protein; flow cytometry for lymphocyte subsets PloS one Medium 33914737
2025 FBXO10 directly interacts with ACSL4 and mediates its ubiquitination and proteasomal degradation; FBXO10 silencing stabilizes ACSL4 and potentiates ferroptosis through amplified lipid peroxidation and Fe2+ accumulation in esophageal squamous cell carcinoma cells; this axis operates independently of the GPX4/SLC7A11 pathway. Co-immunoprecipitation and immunofluorescence colocalization of FBXO10 and ACSL4; FBXO10 silencing with ACSL4 ubiquitination and protein stability assay; ferroptosis markers (lipid peroxidation, Fe2+); in vivo xenograft with FBXO10 knockdown Journal of molecular histology Medium 40616744
2025 FBXO10 directly interacts with FRMPD1 and mediates its K63-linked polyubiquitination, leading to FRMPD1 stabilization (not degradation); this post-translational stabilization of FRMPD1 promotes hepatocellular carcinoma cell proliferation. Co-immunoprecipitation of FBXO10 and FRMPD1; K63-linkage ubiquitination assay; FBXO10 silencing and overexpression with FRMPD1 protein level measurement; FRMPD1 rescue experiment Current issues in molecular biology Low 40699790
2026 FBXO10 promotes ubiquitin-dependent degradation of RAS, thereby inactivating the RAS/ERK axis and suppressing Golgi stress and neuronal apoptosis; EZH2 represses FBXO10 expression by promoting H3K27me3 modification at the FBXO10 promoter, thus indirectly activating RAS/ERK-driven Golgi stress. Co-immunoprecipitation of FBXO10 and RAS; RAS ubiquitination assay; ChIP for H3K27me3 at FBXO10 promoter; FBXO10 knockdown/overexpression in H2O2-treated neuronal cell lines (HT-22, NSC34); Western blot for RAS, ERK, Golgi markers FASEB journal Medium 41999223
2013 FBXO10/Fbxo10 transcription is activated via a PKC-dependent pathway: TPA activates PKCµ (an atypical PKC isoform), which signals through c-Fos/AP1 transcription factor binding to AP1-specific DNA elements in the Fbxo10 promoter; TPA induces endogenous FBXO10 mRNA and protein in Jurkat T cells with peak expression at 1.5–2.5 h. Luciferase reporter assays with Fbxo10 promoter constructs; PKC inhibitors; c-Fos identification as AP1 mediator; endogenous FBXO10 mRNA/protein induction by TPA in Jurkat cells Molecular carcinogenesis Medium 24008983

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma. Oncogene 60 27157620
2012 Human MCS5A1 candidate breast cancer susceptibility gene FBXO10 is induced by cellular stress and correlated with lens epithelium-derived growth factor (LEDGF). Molecular carcinogenesis 22 23138933
2017 Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 28515150
2019 Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. Leukemia 15 31570756
2021 FBXO10 prevents chronic unpredictable stress-induced behavioral despair and cognitive impairment through promoting RAGE degradation. CNS neuroscience & therapeutics 9 34492157
2024 Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function. Cell reports 8 39306844
2021 Loss-of-function of Fbxo10, encoding a post-translational regulator of BCL2 in lymphomas, has no discernible effect on BCL2 or B lymphocyte accumulation in mice. PloS one 5 33914737
2025 FBXO10 inhibits ferroptosis and promotes the progression of esophageal squamous cell carcinoma by post-translational mediation of ACSL4 degradation. Journal of molecular histology 4 40616744
2013 Differential 12-O-Tetradecanoylphorbol-13-acetate-induced activation of rat mammary carcinoma susceptibility Fbxo10 variant promoters via a PKC-AP1 pathway. Molecular carcinogenesis 4 24008983
2024 Geranylgeranylated-SCFFBXO10 Regulates Selective Outer Mitochondrial Membrane Proteostasis and Function. bioRxiv : the preprint server for biology 1 38659932
2026 H3K27me3 Modified FBXO10 Promotes Golgi Stress to Accelerate Traumatic Brain Injury via Activation of the RAS/ERK Axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41999223
2025 FBXO10 Drives Hepatocellular Carcinoma Proliferation via K63-Linked Ubiquitination and Stabilization of FRMPD1. Current issues in molecular biology 0 40699790

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