Affinage

FBXO9

F-box only protein 9 · UniProt Q9UK97

Length
447 aa
Mass
52.3 kDa
Annotated
2026-06-09
9 papers in source corpus 9 papers cited in narrative 9 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

FBXO9 is the substrate-recognition subunit of an SCF (SKP1–Cullin1–RBX1) E3 ubiquitin ligase that selects diverse phosphorylation- and degron-defined substrates for K48-linked polyubiquitination and proteasomal degradation, functioning as a context-dependent regulator of differentiation, proteasome homeostasis, and tumor biology (PMID:31684170, PMID:32029586, PMID:40902979). In hematopoietic cells FBXO9 restrains proteasome activity, and its loss accelerates AML in vivo, establishing a tumor-suppressive role tied to proteostasis control (PMID:31684170). Its substrate repertoire spans developmental and oncogenic programs: it binds Neurog2 through its F-box motif to drive neural crest progenitors toward glial fate downstream of Sox10 (PMID:32029586), targets the pluripotency factor DPPA5 to oppose reprogramming (PMID:38227647), and degrades the V-ATPase catalytic subunit ATP6V1A—promoting its HSPA8-dependent cytoplasmic sequestration to block V-ATPase assembly, vesicular acidification, and Wnt-driven metastasis (PMID:38486234). FBXO9 recognizes YAP via a conserved phosphodegron that requires GSK-3β-mediated phosphorylation at Ser338/Thr342, with Akt modulating the cascade, and ubiquitinates YAP at K76 for degradation (PMID:40902979). It additionally directs degradation of FBXW7 within a ZNF143-driven axis (PMID:35847937), PD-L1 to limit tumor immune evasion (PMID:41646985), and p53, where it lowers p53 stability (PMID:35003915). A conserved neuronal requirement for the Drosophila homologue supports an ancestral role for this F-box protein in neural tissue (PMID:27173356).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2016 Low

    Before biochemical substrates were known, conservation analysis asked whether this F-box protein had an ancestral physiological role, establishing a conserved neuronal requirement.

    Evidence UAS-EP overexpression and RNAi knockdown of the Drosophila homologue CG5961 in dopaminergic neurons with lifespan analysis

    PMID:27173356

    Open questions at the time
    • Phenotypic readout only with no direct biochemical mechanism
    • No substrate identified in the ortholog
    • Relevance to mammalian FBXO9 function not established
  2. 2019 High

    Defined FBXO9 as the substrate-recognition subunit of an SCF E3 ligase and showed it normally restrains proteasome activity, linking its loss to aggressive leukemia.

    Evidence CRISPR/Cas9 conditional knockout in an inv(16) AML mouse model, quantitative mass spectrometry, in vitro proteasome activity and bortezomib sensitivity assays

    PMID:31684170

    Open questions at the time
    • Substrate(s) responsible for proteasome restraint not fully resolved
    • Mechanism connecting FBXO9 loss to elevated proteasome activity not defined
  3. 2020 High

    Identified Neurog2 as a direct degradation substrate and placed FBXO9 downstream of Sox10 in a developmental fate decision, showing ubiquitin-mediated control of neural crest cell fate.

    Evidence Reciprocal Co-IP, ubiquitination assay, Sox10 epistasis, and gain/loss-of-function in avian trunk neural crest with fate-choice readout

    PMID:32029586

    Open questions at the time
    • Degron on Neurog2 not mapped
    • No in vitro reconstitution of the ubiquitination reaction
  4. 2021 Medium

    Extended FBXO9 substrates to p53, proposing it lowers p53 stability and linking zoledronic acid to p53 stabilization and osteoclast ferroptosis.

    Evidence Co-IP, knockdown/overexpression rescue, CCK-8 viability and ferroptosis marker measurements

    PMID:35003915

    Open questions at the time
    • No in vitro ubiquitination reconstitution or degron mutagenesis
    • Single lab without independent replication
    • Direct vs indirect effect on p53 not distinguished
  5. 2022 Medium

    Placed FBXO9 within a transcriptional regulatory axis by identifying ZNF143 as an upstream activator and FBXW7 as a degradation target, connecting FBXO9 to HCC proliferation and metastasis.

    Evidence In vitro/in vivo loss- and gain-of-function, Co-IP, ubiquitination assay, ChIP/reporter assay for ZNF143

    PMID:35847937

    Open questions at the time
    • No structural validation of FBXW7 recognition
    • Not independently replicated
    • Degron on FBXW7 unmapped
  6. 2024 High

    Defined a non-canonical degradation outcome by showing FBXO9 ubiquitinates ATP6V1A to drive HSPA8-dependent cytoplasmic sequestration, inhibiting V-ATPase assembly and Wnt-driven metastasis.

    Evidence MS-based interactome, reciprocal Co-IP, CRISPR/shRNA, migration/sphere assays, in vivo metastasis model and V-ATPase inhibitor treatment

    PMID:38486234

    Open questions at the time
    • Mechanism by which ubiquitination promotes HSPA8 binding not defined
    • Ubiquitin linkage type not specified
  7. 2024 Medium

    Identified DPPA5 as a substrate from a reprogramming screen, showing FBXO9 opposes pluripotency induction by degrading a pluripotency-associated protein.

    Evidence RNAi screen during cellular reprogramming with FBXO9 silencing and DPPA5 proteasomal degradation readout

    PMID:38227647

    Open questions at the time
    • No reconstitution confirming direct ubiquitination of DPPA5
    • Degron not mapped
    • Single lab
  8. 2025 High

    Established the most detailed substrate-recognition mechanism: a GSK-3β/Akt-primed YAP phosphodegron and K48-linked ubiquitination at K76, defining kinase-gated degron logic for FBXO9.

    Evidence Co-IP, K48-linkage-specific ubiquitination assay, mutagenesis of YAP K76 and phosphosites, pharmacological Akt/GSK-3β inhibition, chemosensitivity assays

    PMID:40902979

    Open questions at the time
    • Structural basis of degron engagement not resolved
    • In vivo relevance of the YAP axis not established in this study
  9. 2026 Medium

    Linked FBXO9 to anti-tumor immunity by showing it degrades PD-L1 and impedes its maturation, impairing immune evasion in pancreatic cancer.

    Evidence Co-IP, ubiquitination assay, in vivo overexpression tumor model, cytotoxic T cell activation readout

    PMID:41646985

    Open questions at the time
    • No structural validation or degron mapping on PD-L1
    • Not independently replicated
    • Mechanism of maturation interference vs degradation not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FBXO9 selects among its many substrates in a given cell type, and whether common degron features or upstream signals coordinate this context-dependent specificity, remains unresolved.
  • No structural model of FBXO9 substrate engagement
  • Determinants of tissue-specific substrate choice unknown
  • No unified degron consensus across substrates established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Complex memberships
SCF (SKP1-Cullin1-RBX1) E3 ubiquitin ligase

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 FBXO9 interacts with p53 and promotes its ubiquitination and degradation, thereby decreasing p53 protein stability; zoledronic acid suppresses FBXO9 expression, stabilizing p53 and inducing osteoclast ferroptosis. Co-immunoprecipitation, knockdown/overexpression functional assays, CCK-8 viability assay, ferroptosis marker measurement (Fe2+, ROS, MDA, GPX4, GSH) PeerJ Medium 35003915
2019 FBXO9 is the substrate recognition component of an SCF E3 ubiquitin ligase; its loss in AML leads to increased proteasome activity and more aggressive leukemia in an inv(16) mouse model, indicating FBXO9 normally restrains proteasome activity. CRISPR/Cas9 conditional knockout mouse model, quantitative mass spectrometry of primary tumors, in vitro proteasome activity assay, bortezomib sensitivity assay Cancers High 31684170
2020 Fbxo9, acting downstream of Sox10, functions as a substrate receptor of an SCF-type ubiquitin ligase that binds Neurog2 through its F-box motif and promotes Neurog2 ubiquitination and proteasomal destabilization, thereby directing neural crest progenitors toward glial rather than neuronal fate. Co-immunoprecipitation (Fbxo9–Neurog2 interaction), overexpression and knockdown in avian trunk neural crest, epistasis analysis with Sox10, transcriptional profiling, ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 32029586
2024 FBXO9, as part of the SKP1-cullin-1-RBX1 ubiquitin ligase complex, ubiquitinates the V-ATPase catalytic subunit ATP6V1A; this ubiquitination promotes ATP6V1A interaction with the cytoplasmic chaperone HSPA8 and its sequestration in the cytoplasm, thereby inhibiting functional V-ATPase assembly, reducing vesicular acidification, and suppressing pro-metastatic Wnt signaling in lung cancer cells. Mass spectrometry-based protein interaction studies, co-immunoprecipitation, immunoblot, CRISPR-Cas9 knockout, shRNA knockdown, migration/clonogenic/tumor sphere assays, in vivo mouse metastasis model, V-ATPase inhibitor treatment Experimental hematology & oncology High 38486234
2022 FBXO9 targets FBXW7 for ubiquitination and degradation; ZNF143 acts as a direct upstream transcription factor of FBXO9, forming a ZNF143-FBXO9-FBXW7 regulatory axis that promotes HCC cell proliferation and metastasis. Loss- and gain-of-function experiments in vitro and in vivo, co-immunoprecipitation, ubiquitination assay, ChIP or reporter assay for ZNF143 as transcriptional regulator, drug sensitivity assay Frontiers in oncology Medium 35847937
2025 The SCF-FBXO9-CRL1 E3 ligase complex recognizes YAP through a conserved degron motif and facilitates K48-linked polyubiquitination at lysine K76, promoting proteasomal degradation; GSK-3β-mediated phosphorylation of YAP at Ser338 and Thr342 is required for FBXO9 recognition, and Akt kinase modulates this axis by controlling GSK-3β phosphorylation status. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), site-directed mutagenesis of YAP K76 and phosphosites, pharmacological inhibition of Akt/GSK-3β, chemosensitivity assays in cancer models The Journal of biological chemistry High 40902979
2024 FBXO9 targets DPPA5 (a pluripotency-associated protein) for ubiquitylation and proteasomal degradation; FBXO9 silencing decreases DPPA5 degradation and facilitates induction of cellular reprogramming to pluripotency. RNAi screen during cellular reprogramming, FBXO9 silencing with functional pluripotency readouts, proteasomal degradation assay for DPPA5 Stem cells (Dayton, Ohio) Medium 38227647
2026 FBXO9 directly binds PD-L1 protein and promotes its ubiquitination and degradation, thereby impeding PD-L1 maturation and impairing tumor immune evasion in pancreatic cancer; FBXO9 overexpression suppresses tumor growth and promotes cytotoxic T cell activation in vivo. Co-immunoprecipitation (FBXO9–PD-L1 interaction), ubiquitination assay, overexpression in vivo tumor model, cytotoxic T cell activation readout Frontiers in immunology Medium 41646985
2016 The Drosophila FBXO9 homologue CG5961 is required for normal neuronal tissue formation; altered expression of CG5961 in dopaminergic neurons reduces lifespan, suggesting conserved neuronal function for this F-box protein family member. Targeted UAS-EP overexpression and RNAi knockdown in Drosophila dopaminergic neurons and eye, lifespan analysis, protein domain conservation analysis Genetics and molecular research Low 27173356

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Zoledronic acid promotes osteoclasts ferroptosis by inhibiting FBXO9-mediated p53 ubiquitination and degradation. PeerJ 37 35003915
2019 Loss of FBXO9 Enhances Proteasome Activity and Promotes Aggressiveness in Acute Myeloid Leukemia. Cancers 22 31684170
2020 Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization. Proceedings of the National Academy of Sciences of the United States of America 16 32029586
2024 Ubiquitin ligase subunit FBXO9 inhibits V-ATPase assembly and impedes lung cancer metastasis. Experimental hematology & oncology 12 38486234
2022 FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma. Frontiers in oncology 12 35847937
2025 FBXO9 mediated the ubiquitination and degradation of YAP in a GSK-3β-dependent manner. The Journal of biological chemistry 2 40902979
2024 Ubiquitin E3 Ligase FBXO9 Regulates Pluripotency by Targeting DPPA5 for Ubiquitylation and Degradation. Stem cells (Dayton, Ohio) 1 38227647
2016 Altered expression of CG5961, a putative Drosophila melanogaster homologue of FBXO9, provides a new model of Parkinson disease. Genetics and molecular research : GMR 1 27173356
2026 FBXO9 promotes anti-tumor immunity via degradation of PD-L1 in pancreatic cancer. Frontiers in immunology 0 41646985

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