Affinage

FBXO22

F-box only protein 22 · UniProt Q8NEZ5

Length
403 aa
Mass
44.5 kDa
Annotated
2026-06-09
65 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXO22 is the substrate-recognition F-box subunit of an SKP1-CUL1-FBXO22 (SCF) E3 ubiquitin ligase that controls diverse cellular programs by targeting specific proteins for ubiquitin-dependent degradation (PMID:21768309, PMID:29945959, PMID:31138683). A recurring theme is its control of chromatin-modifying enzymes: it degrades the histone demethylases KDM4A, KDM4B and KDM5A, thereby setting H3K9/H3K36 and H3K4me3 marks and downstream transcription (PMID:21768309, PMID:36112263), and ubiquitinates KDM4A-associated methylated p53 to drive the late phase of cellular senescence (PMID:26868148). Through KDM4B turnover FBXO22 governs the TP53-TFEB autophagy axis (PMID:33706682), SERM/tamoxifen responsiveness of estrogen-receptor-positive breast cancer (PMID:30418174), and trophoblast stem-cell identity via degradation of the CoREST complex (PMID:42240618). Substrate selection frequently depends on signal-induced modification: FBXO22 recognizes a conserved phosphodegron and degrades ERK-phosphorylated BAG3 (PMID:34215846), degrades GSK3β-phosphorylated SNAIL to restrain EMT and metastasis (PMID:29945959), and the amino-acid-sensing kinase GCN2 phosphorylates FBXO22 itself to drive K27-linked ubiquitination and inhibition of mTOR during starvation (PMID:37979583). Its broad substrate roster—including p21, p57Kip2, HDM2, nuclear PTEN (at K221), PD-L1, LKB1, BACH1, RPS5 and others—places it at nodes regulating cell cycle, EMT, mTOR signaling, oxidative-stress and antiviral responses (PMID:30808376, PMID:32249768, PMID:31138683, PMID:34795058, PMID:31217475, PMID:36774506, PMID:39809956). Beyond degradation, FBXO22 binds serine racemase non-catalytically to promote D-serine synthesis by altering its localization (PMID:25336657). Loss-of-function variants in FBXO22 cause a human syndrome of prenatal growth restriction and neurodevelopmental delay, with patient fibroblasts accumulating KDM4B (PMID:40215970). The C-terminal domain harbors reactive cysteines (Cys326, Cys227/228) that aldehyde- and electrophile-bearing small molecules covalently engage to recruit SCF(FBXO22) for targeted degradation of neo-substrates (PMID:38926334, PMID:38965383, PMID:42026065).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2011 High

    Established FBXO22 as a functional SCF substrate-receptor by showing it degrades the histone demethylase KDM4A and thereby tunes histone methylation and transcription.

    Evidence RNAi, overexpression, co-IP with FIST/JmjN-JmjC domain mapping, histone and transcriptional readouts in human cells

    PMID:21768309

    Open questions at the time
    • Did not establish ubiquitin chain linkage type
    • Generality beyond KDM4A unknown at the time
  2. 2012 Medium

    Revealed that a bacterial pathogen exploits the FBXO22/Skp1 interface, the first hint that FBXO22 assembly can be hijacked to alter signaling.

    Evidence Domain mapping, siRNA, NFκB reporter assays and Salmonella infection model with the effector GogB

    PMID:22761574

    Open questions at the time
    • Whether GogB blocks endogenous FBXO22 substrate turnover not shown
    • No structural definition of the GogB F-box mimic interface
  3. 2014 Medium

    Uncovered a non-canonical, non-degradative function: FBXO22 binds serine racemase as a free (non-SCF) species to control its localization and promote D-serine synthesis.

    Evidence Co-IP, in vivo ubiquitination and half-life assays, subcellular fractionation, D-serine measurement

    PMID:25336657

    Open questions at the time
    • Mechanism of localization control unresolved
    • Physiological relevance in neurons not tested
  4. 2016 High

    Connected FBXO22 to senescence and tumor suppression by showing it degrades KDM4A-bound methylated p53, with an in vivo growth phenotype in knockout mice.

    Evidence Co-IP, catalytic KDM4A mutant, ubiquitination assays, Fbxo22-knockout mouse model and senescence readouts

    PMID:26868148

    Open questions at the time
    • How methylation status of p53 is read by the complex not fully defined
    • Tissue-specific consequences of p53 accumulation unresolved
  5. 2018 High

    Defined FBXO22 as a context-dependent tumor suppressor through phosphorylation-gated degradation of SNAIL and as the determinant of SERM antagonism via KDM4B degradation on tamoxifen-bound ER.

    Evidence Co-IP, ubiquitination assays, patient-derived W52R mutant, ChIP, live-cell imaging, in vitro/in vivo metastasis and xenograft models

    PMID:29945959 PMID:30418174

    Open questions at the time
    • Reconciling tumor-suppressive versus tumor-promoting roles across tissues
    • Determinants of substrate switching not defined
  6. 2019 Medium

    Expanded the substrate roster to cell-cycle and oncogenic regulators (p21, HDM2, LKB1), including a non-degradative K63-linked mode that inhibits LKB1 kinase activity.

    Evidence Co-IP, CHX chase, linkage-specific ubiquitination, kinase assays, proteome screen, xenograft and 4T1 metastasis models

    PMID:30808376 PMID:31138683 PMID:31217475

    Open questions at the time
    • What dictates K48 versus K63 chain output is unknown
    • Apparently opposing effects on p21 versus HDM2 not mechanistically reconciled
  7. 2020 High

    Demonstrated compartment- and site-specific substrate targeting by showing FBXO22 ubiquitinates only nuclear PTEN at K221.

    Evidence Co-IP, lysine-mutant ubiquitination assays, nuclear/cytoplasmic fractionation, functional assays

    PMID:32249768

    Open questions at the time
    • How nuclear restriction of activity is achieved unclear
    • Upstream signals controlling nuclear PTEN turnover unknown
  8. 2021 High

    Connected FBXO22 to immune evasion, autophagy and chaperone biology, and defined a phosphodegron consensus, establishing signal-gated recognition (CDK5-PD-L1, TP53-TFEB autophagy, ERK-BAG3).

    Evidence Phosphoproteomics, co-IP, ubiquitination assays, phosphomutants, ChIP-seq, knockout/overexpressing mice, drug-sensitization assays

    PMID:33706682 PMID:34182063 PMID:34215846 PMID:34795058

    Open questions at the time
    • Whether all substrates share the XXPpSPXPXX degron unresolved
    • Kinases that license each substrate not comprehensively mapped
  9. 2022 Medium

    Broadened the cell-cycle and tumor-pathway substrate set (p57Kip2, KDM5A-p16 axis, LATS2/Hippo), reinforcing roles in proliferation and metastasis.

    Evidence Co-IP, ubiquitination/half-life assays, flow cytometry, RNA-seq, xenograft and rescue experiments

    PMID:36112263 PMID:36127346 PMID:36515852

    Open questions at the time
    • Single-lab findings without reciprocal validation for some substrates
    • Tissue selectivity of substrate choice unexplained
  10. 2023 High

    Established in vivo genetic substrate dependency in leukemia (BACH1) and added GAK as a substrate, linking FBXO22 to LSC self-renewal.

    Evidence Conditional/global Fbxo22 knockout mice, AP-MS, BACH1 heterozygous rescue, serial transplantation, proteomics

    PMID:36774506 PMID:37442264

    Open questions at the time
    • Why BACH1 degradation is pro-leukemogenic versus tumor-suppressive elsewhere unresolved
  11. 2024 High

    Placed FBXO22 in nutrient and growth-factor signaling via two distinct mTOR-directed mechanisms (GCN2-driven K27-linked ubiquitination at mTOR K2066, and degradation of pS2448-mTOR), and defined antiviral and angiogenic roles.

    Evidence Linkage- and site-specific ubiquitination, GCN2 phosphorylation cascade, tissue-specific knockout mice, AOM/DSS and viral models, reconstituted heme-dependent BACH1 assay

    PMID:37979583 PMID:38673728 PMID:39223933 PMID:39485803 PMID:39809956

    Open questions at the time
    • How FBXO22 distinguishes mTOR modification states to choose degradative versus inhibitory ubiquitination unclear
    • Heme cofactor requirement generalizability beyond BACH1 untested
  12. 2024 High

    Identified FBXO22 as a recruitable E3 for targeted protein degradation through covalent engagement of reactive cysteines by aldehyde- and electrophile-bearing degraders.

    Evidence Intact-protein MS, CRISPR activation screen, cysteine mutagenesis (Cys326, Cys227/228), degradation assays across FKBP12/NSD2/XIAP/BRD4

    PMID:38926334 PMID:38965383 PMID:38965384

    Open questions at the time
    • Endogenous role of these cysteines unknown
    • Determinants of neo-substrate selectivity incompletely defined
  13. 2025 High

    Provided a structural mechanism for covalent degrader engagement and human disease validation, and identified regulators that disassemble the SCF(FBXO22)-BACH1 complex.

    Evidence Cryo-EM of SCF-FBXO22-NSD2, patient exome sequencing with fibroblast KDM4B readout, SDCBP PDZ1 disassembly, additional substrates (TRIM48, CoREST, KLF10), chemical-biology warhead characterization

    PMID:40215970 PMID:40263598 PMID:41096745 PMID:41292500 PMID:41314902 PMID:42026065 PMID:42240618

    Open questions at the time
    • Full endogenous substrate degron map still incomplete
    • How accessory proteins gate substrate access across tissues unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how FBXO22 selects among its many substrates and chooses degradative (K48) versus non-degradative (K63/K27) or non-catalytic outcomes in a tissue- and signal-specific manner.
  • No unified model for substrate-specificity switching
  • Limited structural data on endogenous substrate engagement surfaces
  • Reconciliation of context-dependent tumor-suppressor versus oncogenic roles lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 5 GO:0031386 protein tag activity 5 GO:0060090 molecular adaptor activity 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 3 R-HSA-9612973 Autophagy 1
Partners
BACH1CUL1KDM4AKDM4BMTORSDCBPSKP1SNAIL
Complex memberships
SCF(FBXO22) (SKP1-CUL1-FBXO22) E3 ubiquitin ligase

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 FBXO22 forms an SCF(FBXO22) ubiquitin ligase complex that targets the histone demethylase KDM4A for proteasomal degradation; FBXO22 recognizes KDM4A via its FIST (intracellular signal transduction) domain interacting with KDM4A's catalytic JmjN/JmjC domains. Modulation of FBXO22 levels alters KDM4A abundance and consequently changes histone H3K9 and H3K36 methylation levels and transcription of the KDM4A target gene ASCL2. RNA interference, overexpression, co-immunoprecipitation, domain mapping, chromatin and transcriptional readouts Molecular and cellular biology High 21768309
2016 SCF(FBXO22) forms a complex with the lysine demethylase KDM4A to ubiquitinate and degrade methylated p53, thereby regulating the late phase of cellular senescence including induction of p16 and senescence-associated secretory phenotypes (SASP). A catalytic KDM4A mutant stabilizes p53 and enhances p53 interaction with PHF20 in the presence of FBXO22. Fbxo22-knockout mice accumulate p53 and are approximately half the size of heterozygous littermates. Co-immunoprecipitation, ectopic expression of catalytic mutant, Fbxo22-knockout mouse model, ubiquitination assays Nature communications High 26868148
2015 FBXO22 interacts with the tumor suppressor transcription factor KLF4, as well as Cullin1 and SKP1 (forming an SCF complex), and mediates KLF4 polyubiquitination and proteasomal degradation, thereby promoting hepatocellular carcinoma cell proliferation. Affinity purification and mass spectrometry, co-immunoprecipitation, ubiquitination assay, KD/OE proliferation assays in vitro and xenograft in vivo Oncotarget Medium 26087183
2018 FBXO22 targets the EMT master regulator SNAIL for ubiquitin-mediated proteasomal degradation in a GSK3β phosphorylation-dependent manner to suppress breast cancer EMT and metastasis. A patient-derived W52R mutation in the F-box domain impairs FBXO22 binding to SKP1-Cullin1, blocks SNAIL degradation, and abrogates anti-metastatic activity. Co-immunoprecipitation, ubiquitination assay, mutagenesis (W52R), rescue experiments with SNAIL re-expression, in vitro migration/invasion assays, in vivo metastasis model Cancer research High 29945959
2018 SCF(Fbxo22) ubiquitylates KDM4B that is complexed with tamoxifen-bound estrogen receptor α (ER), causing KDM4B degradation which releases steroid receptor coactivator (SRC) from ER. This mechanism determines the antagonistic activity of SERMs (e.g., tamoxifen) in breast cancer; depletion of Fbxo22 results in ER-dependent transcriptional activation via AF1 even in the presence of SERMs, and Fbxo22-depleted ER-positive breast cancers fail to respond to tamoxifen both in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, live-cell imaging of SRC/KDM4B on ER, ChIP on ER-SRC-bound enhancers/promoters, KD/OE with in vitro and xenograft in vivo assays The Journal of clinical investigation High 30418174
2019 FBXO22 interacts with p21 (CDKN1A) and promotes its ubiquitination and proteasomal degradation, thereby promoting hepatocellular carcinoma cell proliferation; FBXO22 knockdown decreases p21 ubiquitylation and its overexpression enhances it. Co-immunoprecipitation, CHX chase, MG132 inhibition, ubiquitination assay, KD/OE in vitro and xenograft in vivo Journal of experimental & clinical cancer research Medium 30808376
2019 FBXO22 interacts with and mediates K63-linked (non-degradative) polyubiquitination of LKB1, inhibiting its kinase activity and thereby suppressing LKB1-AMPK-mTOR signaling to promote non-small cell lung cancer cell growth. Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, kinase activity assay, KD/OE in vitro and xenograft in vivo Cell death & disease Medium 31217475
2019 SCF(FBXO22) targets HDM2 (human MDM2 homolog) for ubiquitin-dependent proteasomal degradation; FBXO22 was identified as the dominant HDM2 E3 ligase from the human proteome. FBXO22 knockdown increases HDM2 levels and drives breast cancer cell invasiveness and metastasis. Unbiased biochemical proteome screen, co-immunoprecipitation, protein decay rate analysis, ubiquitination assay, siRNA knockdown, 4T1 mouse tumor metastasis model Proceedings of the National Academy of Sciences of the United States of America High 31138683
2020 FBXO22 specifically ubiquitylates nuclear (but not cytoplasmic) PTEN at lysine 221, promoting its degradation. This compartment-specific ubiquitination is responsible for selective loss of nuclear PTEN in cancer. Co-immunoprecipitation, ubiquitination assay with lysine mutants, nuclear/cytoplasmic fractionation, in vitro and in vivo functional assays Nature communications High 32249768
2017 FBXO22 recognizes the intracellular domain (ICD) of the transmembrane glycoprotein CD147, mediating its polyubiquitination and proteasomal degradation; deletion of CD147-ICD prolongs CD147 half-life and abrogates FBXO22 binding. Mass spectrometry and Western blot (interaction identification), CHX chase, ubiquitination assay, FBXO22 knockdown International journal of molecular sciences Medium 28117675
2021 FBXO22 is activated by phosphorylation and promotes PD-L1 ubiquitination and proteasomal degradation in non-small cell lung cancer cells. CDK5 phosphorylates and thereby inhibits FBXO22, leading to increased PD-L1 levels; CDK5 inhibition increases FBXO22 and decreases PD-L1, sensitizing cancer cells to DNA damage (ionizing radiation and cisplatin). Co-immunoprecipitation, ubiquitination assay, CDK5 inhibition/knockdown, sensitization assays with IR and cisplatin Proceedings of the National Academy of Sciences of the United States of America Medium 34795058
2021 FBXO22 recognizes a conserved phosphodegron motif (XXPpSPXPXX) in substrates for SCF(FBXO22)-mediated ubiquitination and degradation. BAG3, an HSP70 co-chaperone, is a bona fide FBXO22 substrate; FBXO22 mediates BAG3 ubiquitination and degradation requiring ERK-dependent phosphorylation of BAG3 at S377, defining an ERK-FBXO22-BAG3 axis in tumorigenesis. Quantitative phosphoproteomics, co-immunoprecipitation, ubiquitination assay, phosphomutant (S377A), in vitro and in vivo functional assays Cell death and differentiation High 34215846
2021 FBXO22 ubiquitylates KDM4B complexed with MYC-NCOR1 suppressors at the TFEB promoter, promoting KDM4B degradation and thereby inducing TFEB transcription and upregulation of autophagy-related genes. This TP53-FBXO22-TFEB axis controls basal autophagy. Mitogen-induced AKT1 activation counteracts this by phosphorylating KDM4B, which inhibits FBXO22-mediated ubiquitination. Fbxo22-null mice die within 10 hours of birth with lowered basal autophagy. Co-immunoprecipitation, ubiquitination assay, ChIP-seq, Fbxo22-knockout mice, MEF autophagy assays, FBXO22-overexpressing mice Autophagy High 33706682
2014 FBXO22 interacts with serine racemase (SR) and is required for optimal D-serine synthesis in cells. Unlike classical SCF substrates, SR interacts preferentially with free (non-SCF-associated) FBXO22 species. FBXO22 does not target SR for proteasomal degradation but instead affects SR subcellular localization, preventing SR association with intracellular membranes to enhance D-serine synthesis. Co-immunoprecipitation, in vivo ubiquitination assay, SR half-life determination, subcellular fractionation, D-serine measurement The Journal of biological chemistry Medium 25336657
2012 The Salmonella effector GogB interacts with the human SCF E3 ubiquitin ligase via binding to Skp1 and FBXO22 using a eukaryotic-like F-box motif in its C-terminal domain. GogB-mediated engagement of FBXO22/Skp1 inhibits IκB degradation and NFκB activation in macrophages, dampening inflammatory responses during infection. Domain mapping, functional knockdown (siRNA), NFκB reporter assays, infection model PLoS pathogens Medium 22761574
2022 FBXO22 physically interacts with the CDK inhibitor p57Kip2 and mediates its ubiquitination and proteasomal degradation, promoting G1/S cell cycle progression in cervical cancer cells. Co-immunoprecipitation, ubiquitination assay, protein half-life assay, flow cytometry (cell cycle), KD/OE functional assays, xenograft in vivo Cell death & disease Medium 36127346
2022 FBXO22 ubiquitinates and degrades KDM5A (a histone H3K4me3 demethylase), reducing KDM5A-mediated H3K4me3 demethylation, which in turn upregulates p16 expression, inducing DNA damage and reducing tumorigenesis and metastasis in triple-negative breast cancer. RNA-sequencing, co-immunoprecipitation, ubiquitination assay, KD/OE experiments in vitro and in vivo Cell biology and toxicology Medium 36112263
2023 FBXO22 promotes degradation of BACH1 (a pro-metastatic/anti-proliferative transcription factor) in MLL-rearranged AML cells, thereby facilitating leukemogenesis and LSC self-renewal. Conditional Fbxo22 deletion in hematopoietic cells abrogates MLL-AF9-induced leukemogenesis, and heterozygous BACH1 deletion reverses the delayed leukemogenesis of Fbxo22-deficient mice. Conditional and global Fbxo22 knockout mice, immunoprecipitation/LC-MS, Western blot, rescue experiments with BACH1 overexpression, serial transplantation LSC assays Journal of hematology & oncology High 36774506
2023 Amino acid depletion causes accumulation of uncharged tRNAs, activating GCN2 kinase to phosphorylate FBXO22, which then accumulates in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner, inhibiting mTORC1 kinase activity by preventing substrate recruitment. Mutation of mTOR K2066 abolishes this ubiquitination and renders mTOR insensitive to amino acid starvation. Co-immunoprecipitation, ubiquitination assay specifying K27 linkage, kinase activity assay, K2066 mutation, subcellular fractionation, GCN2 phosphorylation of FBXO22 demonstrated in vitro and in vivo Cell metabolism High 37979583
2024 FBXO22 targets the serine 2448-phosphorylated form of mTOR (pS2448-mTOR) for ubiquitin-dependent proteasomal degradation. Using intestinal epithelium-specific and systemic Fbxo22 knockout mouse models, FBXO22 was shown to suppress colorectal inflammatory responses and colorectal carcinogenesis by degrading pS2448-mTOR, dampening downstream S6K1 and 4E-BP1 phosphorylation. Systemic and tissue-specific gene knockout mouse models, co-immunoprecipitation, phosphopeptide binding assay, ubiquitination assay, AOM/DSS colorectal cancer model, rapamycin rescue Proceedings of the National Academy of Sciences of the United States of America High 39485803
2024 Small molecules bearing alkylamine groups (which are metabolized to reactive aldehydes) covalently and reversibly engage Cys326 of FBXO22's C-terminal domain to recruit the SCF(FBXO22) complex for targeted protein degradation. This mechanism is conserved across multiple alkylamine-tethered degraders targeting different proteins (FKBP12, NSD2, XIAP). Intact protein MS (covalent adduct), co-immunoprecipitation, ubiquitination assay, mutagenesis (C326), metabolic conversion analysis Nature communications High 38926334
2024 FBXO22 can be covalently engaged at Cys227 and/or Cys228 (in addition to Cys326) by electrophilic PROTAC compounds bearing an SLF warhead (22-SLF), enabling FBXO22-dependent degradation of FKBP12 and BRD4. This was identified via a CRISPR-based transcriptional activation screen for E3 ligases supporting heterobifunctional compound-mediated target degradation. CRISPR activation screen, mechanistic follow-up with cysteine mutagenesis, degradation assays across cancer cell lines Nature chemical biology Medium 38965383
2024 Alkylamine-containing degrader UNC8732 is metabolized to an aldehyde that covalently engages Cys326 of FBXO22 to recruit SCF(FBXO22) complex for NSD2 degradation in acute lymphoblastic leukemia cells harboring the NSD2 E1099K gain-of-function mutation, leading to growth suppression and reversal of drug resistance. Biochemical characterization of covalent adduct, co-immunoprecipitation, ubiquitination assays, AML cellular degradation assays, growth/apoptosis assays Nature chemical biology High 38965384
2025 Cryo-EM structure of the full SKP1-CUL1-F-box (SCF)-FBXO22 complex bound to NSD2 via an aldehyde-based degrader reveals a conformational change in the FBXO22 loop surrounding Cys326, further exposing the cysteine for covalent engagement. NSD2 binds to a different surface of FBXO22 than the endogenous substrate BACH1, allowing concurrent ternary complex formation with both. Cryo-EM structure determination, biochemical reconstitution, medicinal chemistry (benzaldehyde non-prodrug degraders), concurrent BACH1/NSD2 complex formation Nature communications High 42026065
2025 FBXO22 ubiquitinates RPS5 (40S ribosomal protein S5) at Lys85 via K48-linked ubiquitin chains in the cytoplasm, promoting its degradation. Reduced RPS5 activates the PI3K/AKT signaling pathway, elevating HIF-1α and VEGF-A levels to promote hepatocellular carcinoma angiogenesis and metastasis. Co-immunoprecipitation, ubiquitination assay with lysine-specific (K85) and linkage-specific (K48) analysis, subcellular fractionation, KD/OE in vitro and in vivo Cancer gene therapy Medium 39809956
2024 FBXO22 mediates ubiquitination and degradation of KLF4 in macrophages, thereby promoting NGF transcription (normally repressed by KLF4) and activating the NGF/TRKA signaling pathway to drive prostate cancer bone metastasis and macrophage M2 polarization. Transcriptome sequencing, FBXO22 knockdown in mice, flow cytometry (macrophage polarization), co-culture assays, ubiquitination assays The American journal of pathology Medium 37301536
2024 FBXO22 degrades SARS-CoV-2 NSP5 (main protease) via K48-linked polyubiquitination at lysine residues 5 and 90. FBXO22 physically interacts with NSP5; FBXO22 knockdown increases NSP5 stability and enhances viral immune evasion. Co-immunoprecipitation, ubiquitination assay specifying K48 linkage and sites (K5, K90), FBXO22 knockdown, viral load measurement Journal of medical virology Medium 39223933
2021 FBXO22 ubiquitinates and promotes proteasomal degradation of PHLPP1 (a phosphatase that dephosphorylates AKT). In a rotenone-induced Parkinson's disease model, FBXO22 overexpression reduces PHLPP1 levels to activate AKT-mTOR signaling and reduce neuronal apoptosis; PHLPP1 overexpression partially reverses FBXO22-mediated neuroprotection. Co-immunoprecipitation, ubiquitination assay, FBXO22 overexpression in SH-SY5Y cells and rat PD model, rescue with PHLPP1 overexpression Toxicology letters Medium 34182063
2022 FBXO22 promotes pancreatic cancer cell growth by directly interacting with and destabilizing LATS2, a critical kinase of the Hippo tumor suppressor pathway, thereby deactivating the Hippo pathway. Co-immunoprecipitation, Western blotting, KD/OE functional assays in vitro and xenograft, LATS2 rescue experiment Digestive diseases and sciences Medium 36515852
2024 FBXO22 promotes Rad51 gene transcription by increasing levels of the transcription factor FOXM1 at the Rad51 promoter, inducing radioresistance in lung cancer. FBXO22 knockdown reduces FOXM1 at the Rad51 promoter and increases radiosensitivity. KD experiments, ChIP assay (FOXM1 at Rad51 promoter), clonogenic survival assays, in vivo tumor models with radiation Cell death & disease Medium 38296976
2025 FBXO22 identifies and ubiquitinates TRIM48 for K48-linked proteasomal degradation via the SCF(FBXO22) complex. FBXO22 deficiency leads to TRIM48 accumulation, enhanced oxidative stress-induced ASK1 activation, and increased cell death; additional TRIM48 knockdown reverses this phenotype. Co-immunoprecipitation, CHX chase, K48-specific ubiquitination assay, siRNA knockdown epistasis (FBXO22 KD + TRIM48 KD), ASK1 activation assays International journal of molecular sciences Medium 41096745
2025 FBXO22 ubiquitinates and destabilizes the CoREST histone-modifying complex in the nuclei of cytotrophoblasts, coordinating with HDAC1 and LSD1 to regulate H3K27 acetylation and H3K9 dimethylation, and thereby maintaining trophoblast stem cell identity and preventing premature differentiation into syncytiotrophoblasts. Loss-of-function experiments, co-immunoprecipitation, ubiquitination assay, ChIP for histone marks, human trophoblast stem cell differentiation assays, placental samples from recurrent pregnancy loss patients Nucleic acids research Medium 42240618
2025 Loss-of-function variants in FBXO22 cause a human pleiotropic syndrome characterized by prenatal-onset growth restriction and neurodevelopmental delay. Patient-derived fibroblasts with frameshift FBXO22 mutations lack FBXO22 protein and show increased levels of the known substrate KDM4B, confirming that FBXO22-mediated KDM4B turnover regulates histone H3K9 methylation in vivo in humans. Exome/genome sequencing, patient-derived fibroblasts, FBXO22 protein detection, KDM4B level measurement, epigenome (long-read sequencing) analysis American journal of human genetics Medium 40215970
2025 SDCBP (Syntenin-1) disassembles the SCF(FBXO22)-BACH1 complex via its PDZ1 domain, preventing K48-linked polyubiquitination and proteasomal degradation of BACH1 in triple-negative breast cancer cells. This provides an alternative heme/HO-1-independent mechanism for BACH1 stabilization. Co-immunoprecipitation, ubiquitination assay (K48-specific), PDZ domain deletion mutagenesis, KD experiments, in vivo tumor models The EMBO journal Medium 40263598
2024 In a reconstitution assay using highly purified components, FBXO22 polyubiquitinates BACH1 only in the presence of heme, establishing heme as a co-factor required for FBXO22-mediated BACH1 degradation. This is a negative finding for heme-independent FBXO22-BACH1 ubiquitination. Highly purified in vitro reconstitution ubiquitination assay International journal of molecular sciences High 38673728
2023 FBXO22 mediates ubiquitination and degradation of GAK (Cyclin G Associated Kinase) in cervical cancer cells, and this proteasome-dependent degradation requires direct FBXO22-GAK interaction, as identified by proteomics and confirmed by co-immunoprecipitation and ubiquitination assays. Proteomics, co-immunoprecipitation, protein half-life assay, cellular ubiquitination assay, KD/OE experiments Experimental cell research Medium 37442264
2024 Compound G-6599 (a monovalent SMARCA2/A4 bromodomain-binding ligand) recruits FBXO22 via covalent conjugation to a cysteine residue on FBXO22, promoting ternary complex formation between SMARCA2 and FBXO22 and inducing SMARCA2/A4 degradation through the ubiquitin-proteasome pathway. Unlike other FBXO22 degraders, G-6599 does not require metabolic biotransformation. Biochemical covalent adduct characterization, co-immunoprecipitation (ternary complex), proteasome inhibitor rescue, mutagenesis of FBXO22 cysteine Nature communications Medium 41184243
2025 FBXO22 ubiquitinates and promotes proteasomal degradation of KLF10 in pancreatic cancer cells; KLF10 normally suppresses cancer growth via TGF-β signaling, and FBXO22-mediated KLF10 degradation facilitates pancreatic cancer proliferation and invasion. Mass spectrometry (substrate identification), co-immunoprecipitation, ubiquitination assay, KD/OE functional assays, xenograft in vivo Pancreatology Medium 41314902
2026 FBXO22 interacts with c-Cbl and promotes its K48-linked ubiquitination and proteasomal degradation. Overexpression of FBXO22 reduces c-Cbl levels, induces apoptosis, promotes differentiation, and inhibits leukemia cell proliferation; c-Cbl overexpression rescues these effects, placing c-Cbl as a key FBXO22 substrate in leukemia. Co-immunoprecipitation, ubiquitination assay, KD/OE of FBXO22 and c-Cbl, rescue experiments, in vivo leukemia mouse model Scientific reports Medium 41748789
2025 2-Pyridinecarboxaldehyde (2-PCA) functions as a novel electrophilic warhead that forms a reversible thioacetal with Cys326 of FBXO22, enabling FBXO22 recruitment for targeted protein degradation. Hexane-1,6-diamine acts as a minimal FBXO22 self-degrader, while shorter diamine analogs (C4-C5) do not induce FBXO22 degradation. Chemical biology characterization, covalent adduct analysis, mutagenesis (Cys326), degradation assays (BRD4, CDK12) Journal of the American Chemical Society Medium 41292500
2025 BPC157 peptide engages FBXO22 via its proline residue at position 3, forming a protein complex that suppresses FBXO22-mediated ubiquitination and degradation of BACH1, leading to BACH1 stabilization and enhanced endothelial cell proliferation and tube formation (angiogenesis). Co-immunoprecipitation, ubiquitination assay, mutagenesis of BPC157 Pro3, BACH1 stability assay, tube formation and proliferation assays Cell communication and signaling Low 41606641
2024 FBXO22 deficiency in mice does not affect spermatogenesis or male fertility; conditional and global Fbxo22 knockout mice showed no differences in semen quality, fertility, or testicular histology compared to controls. Conditional knockout (cKO) and global knockout (KO) mouse models, CASA (computer-assisted sperm analysis), histological and immunostaining analysis American journal of translational research Medium 38883371

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 FBXO22 Possesses Both Protumorigenic and Antimetastatic Roles in Breast Cancer Progression. Cancer research 98 29945959
2016 SCF(Fbxo22)-KDM4A targets methylated p53 for degradation and regulates senescence. Nature communications 97 26868148
2019 FBXO22 promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21. Journal of experimental & clinical cancer research : CR 93 30808376
2011 SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation. Molecular and cellular biology 85 21768309
2021 The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 80 34795058
2020 FBXO22 degrades nuclear PTEN to promote tumorigenesis. Nature communications 79 32249768
2012 GogB is an anti-inflammatory effector that limits tissue damage during Salmonella infection through interaction with human FBXO22 and Skp1. PLoS pathogens 74 22761574
2023 The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency. Cell metabolism 51 37979583
2015 F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression. Oncotarget 51 26087183
2019 FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth. Cell death & disease 49 31217475
2024 Recruitment of FBXO22 for targeted degradation of NSD2. Nature chemical biology 48 38965384
2018 Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. The Journal of clinical investigation 47 30418174
2024 A CRISPR activation screen identifies FBXO22 supporting targeted protein degradation. Nature chemical biology 43 38965383
2019 SCFFBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis. Proceedings of the National Academy of Sciences of the United States of America 41 31138683
2020 Emerging role of FBXO22 in carcinogenesis. Cell death discovery 39 32793396
2019 Knockdown of FBXO22 inhibits melanoma cell migration, invasion and angiogenesis via the HIF-1α/VEGF pathway. Investigational new drugs 39 30887251
2024 Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation. Nature communications 36 38926334
2021 Global identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis. Cell death and differentiation 36 34215846
2020 Long noncoding RNA SNHG14 promotes osteosarcoma progression via miR-433-3p/FBXO22 axis. Biochemical and biophysical research communications 36 31948764
2020 Circular RNA circ_0006282 Contributes to the Progression of Gastric Cancer by Sponging miR-155 to Upregulate the Expression of FBXO22. OncoTargets and therapy 34 32099403
2019 FBXO22 Suppresses Metastasis in Human Renal Cell Carcinoma via Inhibiting MMP-9-Mediated Migration and Invasion and VEGF-Mediated Angiogenesis. International journal of biological sciences 33 30745851
2017 F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells. International journal of molecular sciences 32 28117675
2022 Fbxo22 promotes cervical cancer progression via targeting p57Kip2 for ubiquitination and degradation. Cell death & disease 30 36127346
2020 FBXO22, an epigenetic multiplayer coordinating senescence, hormone signaling, and metastasis. Cancer science 26 32536008
2023 FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia. Journal of hematology & oncology 22 36774506
2021 TP53/p53-FBXO22-TFEB controls basal autophagy to govern hormesis. Autophagy 20 33706682
2022 Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation. Cell biology and toxicology 19 36112263
2023 FBXO22 Mediates the NGF/TRKA Signaling Pathway in Bone Metastases in Prostate Cancer. The American journal of pathology 15 37301536
2021 FBXO22 Promotes Growth and Metastasis and Inhibits Autophagy in Epithelial Ovarian Cancers via the MAPK/ERK Pathway. Frontiers in pharmacology 15 34950036
2014 FBXO22 protein is required for optimal synthesis of the N-methyl-D-aspartate (NMDA) receptor coagonist D-serine. The Journal of biological chemistry 14 25336657
2025 FBXO22 promotes HCC angiogenesis and metastasis via RPS5/AKT/HIF-1α/VEGF-A signaling axis. Cancer gene therapy 13 39809956
2024 Targeting FBXO22 enhances radiosensitivity in non-small cell lung cancer by inhibiting the FOXM1/Rad51 axis. Cell death & disease 13 38296976
2021 FBXO22, ubiquitination degradation of PHLPP1, ameliorates rotenone induced neurotoxicity by activating AKT pathway. Toxicology letters 12 34182063
2025 Rational design of potent small-molecule SMARCA2/A4 degraders acting via the recruitment of FBXO22. Nature communications 11 41184243
2024 E3 ligase FBXO22 is not significant for spermatogenesis and male fertility in mice. American journal of translational research 9 38883371
2023 ELK4 Promotes Cell Cycle Progression and Stem Cell-like Characteristics in HPV-associated Cervical Cancer by Regulating the FBXO22/PTEN Axis. Balkan medical journal 9 37519006
2024 FBXO22 promotes glioblastoma malignant progression by mediating VHL ubiquitination and degradation. Cell death discovery 8 38519492
2024 TANK Binding Kinase 1 Promotes BACH1 Degradation through Both Phosphorylation-Dependent and -Independent Mechanisms without Relying on Heme and FBXO22. International journal of molecular sciences 6 38673728
2024 E3 ubiquitin ligase FBXO22 inhibits SARS-CoV-2 replication via promoting proteasome-dependent degradation of NSP5. Journal of medical virology 6 39223933
2023 FBXO22 inhibits proliferation and metastasis of cervical cancer cells by mediating ubiquitination-dependent degradation of GAK. Experimental cell research 6 37442264
2022 FBXO22 Accelerates Pancreatic Cancer Growth by Deactivation of the Hippo Pathway via Destabilizing LATS2. Digestive diseases and sciences 6 36515852
2024 FBXO22 promotes osteosarcoma progression via regulation of FOXO1 for ubiquitination and degradation. Journal of cellular and molecular medicine 5 39153212
2023 Recruitment of FBXO22 for Targeted Degradation of NSD2. bioRxiv : the preprint server for biology 5 37961297
2025 Prominin-2/FBXO22/BACH1 axis protects bone marrow mesenchymal stem cells against TBHP-induced ferroptosis and ameliorates intervertebral disc degeneration. Stem cell research & therapy 4 40598356
2024 FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR. Proceedings of the National Academy of Sciences of the United States of America 4 39485803
2024 Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3. Respiratory research 4 39487426
2023 A CRISPR activation screen identifies FBXO22 as an E3 ligase supporting targeted protein degradation. bioRxiv : the preprint server for biology 4 37745578
2022 Aberrant expression of FBXO22 is associated with propofol-induced synaptic plasticity and cognitive dysfunction in adult mice. Frontiers in aging neuroscience 4 36425318
2025 Ribosomal protein L6 suppresses hepatocellular carcinoma by modulating FBXO22-mediated p53 degradation. Cellular signalling 2 39842528
2024 Potential role of Fbxo22 in resistance to endocrine therapy in breast cancer with invasive lobular carcinoma. Breast cancer research and treatment 2 38180699
2024 FBXO22 is a potential therapeutic target for recurrent chondrosarcoma. Journal of bone oncology 2 38742151
2026 BPC157 drives angiogenesis through FBXO22-dependent stabilization of BACH1. Cell communication and signaling : CCS 1 41606641
2025 FBXO22 deficiency defines a pleiotropic syndrome of growth restriction and multi-system anomalies associated with a unique epigenetic signature. American journal of human genetics 1 40215970
2025 SDCBP/Syntenin-1 stabilizes BACH1 by disassembling the SCFFBXO22-BACH1 complex in triple-negative breast cancer. The EMBO journal 1 40263598
2025 FBXO22 Suppresses Oxidative Stress-Induced ASK1 Activation and Cell Death via Ubiquitination-Dependent Degradation of TRIM48. International journal of molecular sciences 1 41096745
2025 FBXO22-mediated ubiquitination of KLF10 promoting pancreatic cancer proliferation and invasion. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 1 41314902
2025 FBXO22 promotes hepatocellular carcinoma progression via paracrine myo‑inositol‑induced M2‑type polarization of macrophages. International journal of molecular medicine 1 41347800
2022 Erratum: FBXO22 Suppresses Metastasis in Human Renal Cell Carcinoma via Inhibiting MMP-9-Mediated Migration and Invasion and VEGF-Mediated Angiogenesis. International journal of biological sciences 1 35173537
2026 FBXO22 targets ubiquitination and degradation of c-Cbl in leukemia. Scientific reports 0 41748789
2026 Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22. Nature communications 0 42026065
2026 Reduced FBXO22 skews human trophoblast fate equilibrium toward syncytialization via polyubiquitinating the CoREST complex. Nucleic acids research 0 42240618
2025 Development of Degraders and 2-pyridinecarboxyaldehyde (2-PCA) as a recruitment Ligand for FBXO22. bioRxiv : the preprint server for biology 0 40894587
2025 Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22. bioRxiv : the preprint server for biology 0 40909644
2025 FBXO22 regulates proliferation, migration, and invasion of esophageal cancer cells via the WNT/β-catenin signaling pathway. American journal of translational research 0 40950282
2025 Development of FBXO22 Degraders and the Recruitment Ligand 2-Pyridinecarboxyaldehyde (2-PCA). Journal of the American Chemical Society 0 41292500

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