{"gene":"FBXO22","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"RNA interference, overexpression, co-immunoprecipitation, domain mapping, chromatin and transcriptional readouts","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding mapped to specific domains, multiple orthogonal functional readouts (protein levels, histone marks, gene expression), replicated by subsequent studies","pmids":["21768309"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, ectopic expression of catalytic mutant, Fbxo22-knockout mouse model, ubiquitination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical, genetic mouse model, cellular senescence assays), published in Nature Communications with in vivo validation","pmids":["26868148"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Affinity purification and mass spectrometry, co-immunoprecipitation, ubiquitination assay, KD/OE proliferation assays in vitro and xenograft in vivo","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS identification plus co-IP and functional rescue, single lab","pmids":["26087183"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, mutagenesis (W52R), rescue experiments with SNAIL re-expression, in vitro migration/invasion assays, in vivo metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including patient-derived mutagenesis, in vitro and in vivo validation, rescue experiments","pmids":["29945959"],"is_preprint":false},{"year":2018,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including ChIP, live-cell imaging, in vitro and in vivo functional validation, single lab","pmids":["30418174"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, CHX chase, MG132 inhibition, ubiquitination assay, KD/OE in vitro and xenograft in vivo","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (co-IP, CHX chase, ubiquitination), single lab","pmids":["30808376"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, kinase activity assay, KD/OE in vitro and xenograft in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — linkage-specific ubiquitination plus kinase activity assay and in vivo validation, single lab","pmids":["31217475"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Unbiased biochemical proteome screen, co-immunoprecipitation, protein decay rate analysis, ubiquitination assay, siRNA knockdown, 4T1 mouse tumor metastasis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteome identification, multiple orthogonal biochemical validations, in vivo metastasis model","pmids":["31138683"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay with lysine mutants, nuclear/cytoplasmic fractionation, in vitro and in vivo functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific mutagenesis (K221) identifying ubiquitination site, subcellular fractionation distinguishing nuclear vs cytoplasmic substrate, multiple orthogonal methods","pmids":["32249768"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Mass spectrometry and Western blot (interaction identification), CHX chase, ubiquitination assay, FBXO22 knockdown","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping (ICD deletion), MS identification, ubiquitination assay, single lab","pmids":["28117675"],"is_preprint":false},{"year":2021,"finding":"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).","method":"Co-immunoprecipitation, ubiquitination assay, CDK5 inhibition/knockdown, sensitization assays with IR and cisplatin","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and functional assays, pathway epistasis via CDK5 inhibition, single lab","pmids":["34795058"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Quantitative phosphoproteomics, co-immunoprecipitation, ubiquitination assay, phosphomutant (S377A), in vitro and in vivo functional assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — system-wide phosphoproteomics plus biochemical verification including phosphomutant rescue, in vivo validation, multiple orthogonal methods","pmids":["34215846"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP-seq, Fbxo22-knockout mice, MEF autophagy assays, FBXO22-overexpressing mice","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, biochemical, genetic mouse models), in vivo lethality phenotype, single lab with comprehensive methodology","pmids":["33706682"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, SR half-life determination, subcellular fractionation, D-serine measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical approaches (co-IP, ubiquitination assay, localization fractionation, metabolite measurement), single lab","pmids":["25336657"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Domain mapping, functional knockdown (siRNA), NFκB reporter assays, infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping plus functional knockdown, epistasis via Skp1/FBXO22 requirement demonstrated, single lab","pmids":["22761574"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, protein half-life assay, flow cytometry (cell cycle), KD/OE functional assays, xenograft in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical and cellular methods, single lab","pmids":["36127346"],"is_preprint":false},{"year":2022,"finding":"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.","method":"RNA-sequencing, co-immunoprecipitation, ubiquitination assay, KD/OE experiments in vitro and in vivo","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain (ubiquitination → demethylase levels → histone marks → p16) with multiple experimental validations, single lab","pmids":["36112263"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Conditional and global Fbxo22 knockout mice, immunoprecipitation/LC-MS, Western blot, rescue experiments with BACH1 overexpression, serial transplantation LSC assays","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in vivo (knockout mice + heterozygous Bach1 rescue), AP-MS, multiple orthogonal methods","pmids":["36774506"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay specifying K27 linkage, kinase activity assay, K2066 mutation, subcellular fractionation, GCN2 phosphorylation of FBXO22 demonstrated in vitro and in vivo","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — site-specific ubiquitination mutagenesis (K2066), GCN2-FBXO22 phosphorylation cascade validated, multiple orthogonal methods, published in Cell Metabolism","pmids":["37979583"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Systemic and tissue-specific gene knockout mouse models, co-immunoprecipitation, phosphopeptide binding assay, ubiquitination assay, AOM/DSS colorectal cancer model, rapamycin rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two genetic mouse models, phospho-specific substrate recognition, reconstituted ubiquitination, in vivo pharmacological rescue, multiple orthogonal methods","pmids":["39485803"],"is_preprint":false},{"year":2024,"finding":"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).","method":"Intact protein MS (covalent adduct), co-immunoprecipitation, ubiquitination assay, mutagenesis (C326), metabolic conversion analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — covalent mechanism confirmed by intact protein MS, critical cysteine identified by mutagenesis, replicated across multiple degrader compounds and substrates","pmids":["38926334"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR activation screen, mechanistic follow-up with cysteine mutagenesis, degradation assays across cancer cell lines","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus cysteine mutagenesis, single lab, distinct cysteine residues from Cys326","pmids":["38965383"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Biochemical characterization of covalent adduct, co-immunoprecipitation, ubiquitination assays, AML cellular degradation assays, growth/apoptosis assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — covalent mechanism characterized, Cys326 identified, cellular functional validation, complemented by structural study (cryo-EM, PMID 42026065)","pmids":["38965384"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Cryo-EM structure determination, biochemical reconstitution, medicinal chemistry (benzaldehyde non-prodrug degraders), concurrent BACH1/NSD2 complex formation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of full SCF complex, biochemical reconstitution, identifies conformational mechanism, replicated by two independent groups","pmids":["42026065"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay with lysine-specific (K85) and linkage-specific (K48) analysis, subcellular fractionation, KD/OE in vitro and in vivo","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific and linkage-specific ubiquitination, pathway validation, single lab","pmids":["39809956"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Transcriptome sequencing, FBXO22 knockdown in mice, flow cytometry (macrophage polarization), co-culture assays, ubiquitination assays","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown in vivo plus biochemical ubiquitination assay and rescue experiments, single lab","pmids":["37301536"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay specifying K48 linkage and sites (K5, K90), FBXO22 knockdown, viral load measurement","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific (K5, K90) and K48-specific ubiquitination confirmed, interaction and functional viral assays, single lab","pmids":["39223933"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, FBXO22 overexpression in SH-SY5Y cells and rat PD model, rescue with PHLPP1 overexpression","journal":"Toxicology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination, functional rescue, in vivo rat model, single lab","pmids":["34182063"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, Western blotting, KD/OE functional assays in vitro and xenograft, LATS2 rescue experiment","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and functional epistasis via LATS2 rescue, single lab","pmids":["36515852"],"is_preprint":false},{"year":2024,"finding":"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.","method":"KD experiments, ChIP assay (FOXM1 at Rad51 promoter), clonogenic survival assays, in vivo tumor models with radiation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates transcriptional mechanism, functional radioresistance assays in vitro and in vivo, single lab","pmids":["38296976"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, CHX chase, K48-specific ubiquitination assay, siRNA knockdown epistasis (FBXO22 KD + TRIM48 KD), ASK1 activation assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical validations plus genetic epistasis (double knockdown rescue), single lab","pmids":["41096745"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear-specific mechanism with histone mark validation and functional differentiation assays, single lab","pmids":["42240618"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Exome/genome sequencing, patient-derived fibroblasts, FBXO22 protein detection, KDM4B level measurement, epigenome (long-read sequencing) analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic validation of substrate relationship (KDM4B) using patient fibroblasts, replicated across 16 cases/14 families, but substrate mechanism previously established","pmids":["40215970"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay (K48-specific), PDZ domain deletion mutagenesis, KD experiments, in vivo tumor models","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific disassembly mechanism, K48-specific ubiquitination, functional in vivo validation, single lab","pmids":["40263598"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Highly purified in vitro reconstitution ubiquitination assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro assay with purified components is gold standard, single lab but clean biochemical result","pmids":["38673728"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Proteomics, co-immunoprecipitation, protein half-life assay, cellular ubiquitination assay, KD/OE experiments","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics identification plus multiple biochemical validations, single lab","pmids":["37442264"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Biochemical covalent adduct characterization, co-immunoprecipitation (ternary complex), proteasome inhibitor rescue, mutagenesis of FBXO22 cysteine","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — covalent mechanism confirmed, ternary complex validated, single lab","pmids":["41184243"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Mass spectrometry (substrate identification), co-immunoprecipitation, ubiquitination assay, KD/OE functional assays, xenograft in vivo","journal":"Pancreatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification plus biochemical and in vivo functional validation, single lab","pmids":["41314902"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assay, KD/OE of FBXO22 and c-Cbl, rescue experiments, in vivo leukemia mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal rescue experiments, in vivo validation, single lab","pmids":["41748789"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Chemical biology characterization, covalent adduct analysis, mutagenesis (Cys326), degradation assays (BRD4, CDK12)","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — chemical mechanism validated with site-specific mutagenesis and adduct analysis, single lab","pmids":["41292500"],"is_preprint":false},{"year":2025,"finding":"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).","method":"Co-immunoprecipitation, ubiquitination assay, mutagenesis of BPC157 Pro3, BACH1 stability assay, tube formation and proliferation assays","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single paper, mechanism of BPC157-FBXO22 interaction not fully characterized structurally, modest experimental depth in abstract","pmids":["41606641"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Conditional knockout (cKO) and global knockout (KO) mouse models, CASA (computer-assisted sperm analysis), histological and immunostaining analysis","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two genetic mouse models (cKO and KO), comprehensive phenotypic assessment; this is a confirmed negative finding","pmids":["38883371"],"is_preprint":false}],"current_model":"FBXO22 is the substrate-recognition F-box subunit of the SKP1-CUL1-FBXO22 (SCF) E3 ubiquitin ligase complex that mediates proteasomal degradation of a broad and growing roster of substrates—including KDM4A, KDM4B, KDM5A, methylated p53, p21, SNAIL, HDM2, KLF4, LKB1, CD147, PTEN (nuclear-specific, at K221), PD-L1, BAG3 (via an ERK-phosphorylated degron), mTOR (pS2448 form), mTOR (K27-linked, amino-acid-sensing branch via GCN2 phosphorylation of FBXO22), BACH1 (heme-dependent), p57Kip2, LATS2, RPS5 (K48-linked, at K85), TRIM48, CoREST complex, KLF10, c-Cbl, and others—thereby regulating senescence, epigenetic histone marks, cell cycle, EMT/metastasis, autophagy, amino acid sensing, antiviral defense, trophoblast differentiation, and SERM/hormonal signaling; in addition to its canonical ubiquitin ligase role, FBXO22 can interact with serine racemase in a non-degradative manner to promote D-serine synthesis, and its Cys326 (and Cys227/228) residues are exploitable by covalent aldehyde-bearing small molecules to recruit the SCF(FBXO22) complex for targeted protein degradation of neo-substrates."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2011,"claim":"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","pmids":["21768309"],"confidence":"High","gaps":["Did not establish ubiquitin chain linkage type","Generality beyond KDM4A unknown at the time"]},{"year":2012,"claim":"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","pmids":["22761574"],"confidence":"Medium","gaps":["Whether GogB blocks endogenous FBXO22 substrate turnover not shown","No structural definition of the GogB F-box mimic interface"]},{"year":2014,"claim":"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","pmids":["25336657"],"confidence":"Medium","gaps":["Mechanism of localization control unresolved","Physiological relevance in neurons not tested"]},{"year":2016,"claim":"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","pmids":["26868148"],"confidence":"High","gaps":["How methylation status of p53 is read by the complex not fully defined","Tissue-specific consequences of p53 accumulation unresolved"]},{"year":2018,"claim":"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","pmids":["29945959","30418174"],"confidence":"High","gaps":["Reconciling tumor-suppressive versus tumor-promoting roles across tissues","Determinants of substrate switching not defined"]},{"year":2019,"claim":"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","pmids":["30808376","31138683","31217475"],"confidence":"Medium","gaps":["What dictates K48 versus K63 chain output is unknown","Apparently opposing effects on p21 versus HDM2 not mechanistically reconciled"]},{"year":2020,"claim":"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","pmids":["32249768"],"confidence":"High","gaps":["How nuclear restriction of activity is achieved unclear","Upstream signals controlling nuclear PTEN turnover unknown"]},{"year":2021,"claim":"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","pmids":["34795058","33706682","34215846","34182063"],"confidence":"High","gaps":["Whether all substrates share the XXPpSPXPXX degron unresolved","Kinases that license each substrate not comprehensively mapped"]},{"year":2022,"claim":"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","pmids":["36127346","36112263","36515852"],"confidence":"Medium","gaps":["Single-lab findings without reciprocal validation for some substrates","Tissue selectivity of substrate choice unexplained"]},{"year":2023,"claim":"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","pmids":["36774506","37442264"],"confidence":"High","gaps":["Why BACH1 degradation is pro-leukemogenic versus tumor-suppressive elsewhere unresolved"]},{"year":2024,"claim":"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","pmids":["37979583","39485803","39223933","39809956","38673728"],"confidence":"High","gaps":["How FBXO22 distinguishes mTOR modification states to choose degradative versus inhibitory ubiquitination unclear","Heme cofactor requirement generalizability beyond BACH1 untested"]},{"year":2024,"claim":"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","pmids":["38926334","38965383","38965384"],"confidence":"High","gaps":["Endogenous role of these cysteines unknown","Determinants of neo-substrate selectivity incompletely defined"]},{"year":2025,"claim":"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","pmids":["42026065","40215970","40263598","41096745","42240618","41314902","41292500"],"confidence":"High","gaps":["Full endogenous substrate degron map still incomplete","How accessory proteins gate substrate access across tissues unresolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,7,8,11,18,30]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,3,7,17,24]},{"term_id":"GO:0031386","term_label":"protein tag activity","supporting_discovery_ids":[0,6,18,24,30]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,7,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,16,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,24]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,7,8,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,5,15,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,16,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,18,19,28]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7,17,32]}],"complexes":["SCF(FBXO22) (SKP1-CUL1-FBXO22) E3 ubiquitin ligase"],"partners":["SKP1","CUL1","KDM4A","KDM4B","SNAIL","BACH1","MTOR","SDCBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NEZ5","full_name":"F-box only protein 22","aliases":["F-box protein FBX22p44"],"length_aa":403,"mass_kda":44.5,"function":"Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex that is implicated in the control of various cellular processes such as cell cycle control, transcriptional regulation, DNA damage repair, and apoptosis. Promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin (ACTN2) and filamin-C (FLNC), essential for maintenance of normal contractile function. Acts as a key regulator of histone methylation marks namely H3K9 and H3K36 methylation through the regulation of histone demethylase KDM4A protein levels (PubMed:21768309). In complex with KDM4A, also regulates the abundance of TP53 by targeting methylated TP53 for degradation at the late senescent stage (PubMed:26868148). Under oxidative stress, promotes the ubiquitination and degradation of BACH1. Mechanistically, reactive oxygen species (ROS) covalently modify cysteine residues on the bZIP domain of BACH1, leading to its release from chromatin and making it accessible to FBXO22 (PubMed:39504958). Upon amino acid depletion, mediates 'Lys-27'-linked ubiquitination of MTOR and thereby inhibits substrate recruitment to mTORC1 (PubMed:37979583). Also inhibits SARS-CoV-2 replication by inducing NSP5 degradation (PubMed:39223933)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q8NEZ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO22","classification":"Not Classified","n_dependent_lines":23,"n_total_lines":1208,"dependency_fraction":0.01903973509933775},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO22","total_profiled":1310},"omim":[{"mim_id":"621184","title":"TAYOUN-MAAWALI SYNDROME; TYMAS","url":"https://www.omim.org/entry/621184"},{"mim_id":"609764","title":"LYSINE DEMETHYLASE 4A; KDM4A","url":"https://www.omim.org/entry/609764"},{"mim_id":"609096","title":"F-BOX ONLY PROTEIN 22; FBXO22","url":"https://www.omim.org/entry/609096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXO22"},"hgnc":{"alias_symbol":["FBX22","FISTC1"],"prev_symbol":[]},"alphafold":{"accession":"Q8NEZ5","domains":[{"cath_id":"-","chopping":"68-399","consensus_level":"high","plddt":87.7673,"start":68,"end":399},{"cath_id":"1.20.1280","chopping":"23-63","consensus_level":"high","plddt":91.1288,"start":23,"end":63}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ5-F1-predicted_aligned_error_v6.png","plddt_mean":86.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO22","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO22"},"sequence":{"accession":"Q8NEZ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NEZ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NEZ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ5"}},"corpus_meta":[{"pmid":"29945959","id":"PMC_29945959","title":"FBXO22 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Modulation of FBXO22 levels alters KDM4A abundance and consequently changes histone H3K9 and H3K36 methylation levels and transcription of the KDM4A target gene ASCL2.\",\n      \"method\": \"RNA interference, overexpression, co-immunoprecipitation, domain mapping, chromatin and transcriptional readouts\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding mapped to specific domains, multiple orthogonal functional readouts (protein levels, histone marks, gene expression), replicated by subsequent studies\",\n      \"pmids\": [\"21768309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression of catalytic mutant, Fbxo22-knockout mouse model, ubiquitination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical, genetic mouse model, cellular senescence assays), published in Nature Communications with in vivo validation\",\n      \"pmids\": [\"26868148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity purification and mass spectrometry, co-immunoprecipitation, ubiquitination assay, KD/OE proliferation assays in vitro and xenograft in vivo\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS identification plus co-IP and functional rescue, single lab\",\n      \"pmids\": [\"26087183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mutagenesis (W52R), rescue experiments with SNAIL re-expression, in vitro migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including patient-derived mutagenesis, in vitro and in vivo validation, rescue experiments\",\n      \"pmids\": [\"29945959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including ChIP, live-cell imaging, in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"30418174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CHX chase, MG132 inhibition, ubiquitination assay, KD/OE in vitro and xenograft in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (co-IP, CHX chase, ubiquitination), single lab\",\n      \"pmids\": [\"30808376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay specifying K63 linkage, kinase activity assay, KD/OE in vitro and xenograft in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — linkage-specific ubiquitination plus kinase activity assay and in vivo validation, single lab\",\n      \"pmids\": [\"31217475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Unbiased biochemical proteome screen, co-immunoprecipitation, protein decay rate analysis, ubiquitination assay, siRNA knockdown, 4T1 mouse tumor metastasis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteome identification, multiple orthogonal biochemical validations, in vivo metastasis model\",\n      \"pmids\": [\"31138683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with lysine mutants, nuclear/cytoplasmic fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific mutagenesis (K221) identifying ubiquitination site, subcellular fractionation distinguishing nuclear vs cytoplasmic substrate, multiple orthogonal methods\",\n      \"pmids\": [\"32249768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry and Western blot (interaction identification), CHX chase, ubiquitination assay, FBXO22 knockdown\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping (ICD deletion), MS identification, ubiquitination assay, single lab\",\n      \"pmids\": [\"28117675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, CDK5 inhibition/knockdown, sensitization assays with IR and cisplatin\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and functional assays, pathway epistasis via CDK5 inhibition, single lab\",\n      \"pmids\": [\"34795058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative phosphoproteomics, co-immunoprecipitation, ubiquitination assay, phosphomutant (S377A), in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — system-wide phosphoproteomics plus biochemical verification including phosphomutant rescue, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"34215846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP-seq, Fbxo22-knockout mice, MEF autophagy assays, FBXO22-overexpressing mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, biochemical, genetic mouse models), in vivo lethality phenotype, single lab with comprehensive methodology\",\n      \"pmids\": [\"33706682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, SR half-life determination, subcellular fractionation, D-serine measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical approaches (co-IP, ubiquitination assay, localization fractionation, metabolite measurement), single lab\",\n      \"pmids\": [\"25336657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Domain mapping, functional knockdown (siRNA), NFκB reporter assays, infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping plus functional knockdown, epistasis via Skp1/FBXO22 requirement demonstrated, single lab\",\n      \"pmids\": [\"22761574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein half-life assay, flow cytometry (cell cycle), KD/OE functional assays, xenograft in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical and cellular methods, single lab\",\n      \"pmids\": [\"36127346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-sequencing, co-immunoprecipitation, ubiquitination assay, KD/OE experiments in vitro and in vivo\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain (ubiquitination → demethylase levels → histone marks → p16) with multiple experimental validations, single lab\",\n      \"pmids\": [\"36112263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional and global Fbxo22 knockout mice, immunoprecipitation/LC-MS, Western blot, rescue experiments with BACH1 overexpression, serial transplantation LSC assays\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in vivo (knockout mice + heterozygous Bach1 rescue), AP-MS, multiple orthogonal methods\",\n      \"pmids\": [\"36774506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay specifying K27 linkage, kinase activity assay, K2066 mutation, subcellular fractionation, GCN2 phosphorylation of FBXO22 demonstrated in vitro and in vivo\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — site-specific ubiquitination mutagenesis (K2066), GCN2-FBXO22 phosphorylation cascade validated, multiple orthogonal methods, published in Cell Metabolism\",\n      \"pmids\": [\"37979583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Systemic and tissue-specific gene knockout mouse models, co-immunoprecipitation, phosphopeptide binding assay, ubiquitination assay, AOM/DSS colorectal cancer model, rapamycin rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two genetic mouse models, phospho-specific substrate recognition, reconstituted ubiquitination, in vivo pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39485803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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).\",\n      \"method\": \"Intact protein MS (covalent adduct), co-immunoprecipitation, ubiquitination assay, mutagenesis (C326), metabolic conversion analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — covalent mechanism confirmed by intact protein MS, critical cysteine identified by mutagenesis, replicated across multiple degrader compounds and substrates\",\n      \"pmids\": [\"38926334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR activation screen, mechanistic follow-up with cysteine mutagenesis, degradation assays across cancer cell lines\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus cysteine mutagenesis, single lab, distinct cysteine residues from Cys326\",\n      \"pmids\": [\"38965383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical characterization of covalent adduct, co-immunoprecipitation, ubiquitination assays, AML cellular degradation assays, growth/apoptosis assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — covalent mechanism characterized, Cys326 identified, cellular functional validation, complemented by structural study (cryo-EM, PMID 42026065)\",\n      \"pmids\": [\"38965384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, biochemical reconstitution, medicinal chemistry (benzaldehyde non-prodrug degraders), concurrent BACH1/NSD2 complex formation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of full SCF complex, biochemical reconstitution, identifies conformational mechanism, replicated by two independent groups\",\n      \"pmids\": [\"42026065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay with lysine-specific (K85) and linkage-specific (K48) analysis, subcellular fractionation, KD/OE in vitro and in vivo\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific and linkage-specific ubiquitination, pathway validation, single lab\",\n      \"pmids\": [\"39809956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptome sequencing, FBXO22 knockdown in mice, flow cytometry (macrophage polarization), co-culture assays, ubiquitination assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown in vivo plus biochemical ubiquitination assay and rescue experiments, single lab\",\n      \"pmids\": [\"37301536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay specifying K48 linkage and sites (K5, K90), FBXO22 knockdown, viral load measurement\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific (K5, K90) and K48-specific ubiquitination confirmed, interaction and functional viral assays, single lab\",\n      \"pmids\": [\"39223933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBXO22 overexpression in SH-SY5Y cells and rat PD model, rescue with PHLPP1 overexpression\",\n      \"journal\": \"Toxicology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination, functional rescue, in vivo rat model, single lab\",\n      \"pmids\": [\"34182063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, KD/OE functional assays in vitro and xenograft, LATS2 rescue experiment\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and functional epistasis via LATS2 rescue, single lab\",\n      \"pmids\": [\"36515852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"KD experiments, ChIP assay (FOXM1 at Rad51 promoter), clonogenic survival assays, in vivo tumor models with radiation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates transcriptional mechanism, functional radioresistance assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"38296976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, CHX chase, K48-specific ubiquitination assay, siRNA knockdown epistasis (FBXO22 KD + TRIM48 KD), ASK1 activation assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical validations plus genetic epistasis (double knockdown rescue), single lab\",\n      \"pmids\": [\"41096745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear-specific mechanism with histone mark validation and functional differentiation assays, single lab\",\n      \"pmids\": [\"42240618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Exome/genome sequencing, patient-derived fibroblasts, FBXO22 protein detection, KDM4B level measurement, epigenome (long-read sequencing) analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic validation of substrate relationship (KDM4B) using patient fibroblasts, replicated across 16 cases/14 families, but substrate mechanism previously established\",\n      \"pmids\": [\"40215970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48-specific), PDZ domain deletion mutagenesis, KD experiments, in vivo tumor models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific disassembly mechanism, K48-specific ubiquitination, functional in vivo validation, single lab\",\n      \"pmids\": [\"40263598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Highly purified in vitro reconstitution ubiquitination assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro assay with purified components is gold standard, single lab but clean biochemical result\",\n      \"pmids\": [\"38673728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, protein half-life assay, cellular ubiquitination assay, KD/OE experiments\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics identification plus multiple biochemical validations, single lab\",\n      \"pmids\": [\"37442264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical covalent adduct characterization, co-immunoprecipitation (ternary complex), proteasome inhibitor rescue, mutagenesis of FBXO22 cysteine\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — covalent mechanism confirmed, ternary complex validated, single lab\",\n      \"pmids\": [\"41184243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry (substrate identification), co-immunoprecipitation, ubiquitination assay, KD/OE functional assays, xenograft in vivo\",\n      \"journal\": \"Pancreatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification plus biochemical and in vivo functional validation, single lab\",\n      \"pmids\": [\"41314902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KD/OE of FBXO22 and c-Cbl, rescue experiments, in vivo leukemia mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"41748789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Chemical biology characterization, covalent adduct analysis, mutagenesis (Cys326), degradation assays (BRD4, CDK12)\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chemical mechanism validated with site-specific mutagenesis and adduct analysis, single lab\",\n      \"pmids\": [\"41292500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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).\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mutagenesis of BPC157 Pro3, BACH1 stability assay, tube formation and proliferation assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single paper, mechanism of BPC157-FBXO22 interaction not fully characterized structurally, modest experimental depth in abstract\",\n      \"pmids\": [\"41606641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout (cKO) and global knockout (KO) mouse models, CASA (computer-assisted sperm analysis), histological and immunostaining analysis\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two genetic mouse models (cKO and KO), comprehensive phenotypic assessment; this is a confirmed negative finding\",\n      \"pmids\": [\"38883371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO22 is the substrate-recognition F-box subunit of the SKP1-CUL1-FBXO22 (SCF) E3 ubiquitin ligase complex that mediates proteasomal degradation of a broad and growing roster of substrates—including KDM4A, KDM4B, KDM5A, methylated p53, p21, SNAIL, HDM2, KLF4, LKB1, CD147, PTEN (nuclear-specific, at K221), PD-L1, BAG3 (via an ERK-phosphorylated degron), mTOR (pS2448 form), mTOR (K27-linked, amino-acid-sensing branch via GCN2 phosphorylation of FBXO22), BACH1 (heme-dependent), p57Kip2, LATS2, RPS5 (K48-linked, at K85), TRIM48, CoREST complex, KLF10, c-Cbl, and others—thereby regulating senescence, epigenetic histone marks, cell cycle, EMT/metastasis, autophagy, amino acid sensing, antiviral defense, trophoblast differentiation, and SERM/hormonal signaling; in addition to its canonical ubiquitin ligase role, FBXO22 can interact with serine racemase in a non-degradative manner to promote D-serine synthesis, and its Cys326 (and Cys227/228) residues are exploitable by covalent aldehyde-bearing small molecules to recruit the SCF(FBXO22) complex for targeted protein degradation of neo-substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #3, #7]. 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 [#0, #16], and ubiquitinates KDM4A-associated methylated p53 to drive the late phase of cellular senescence [#1]. Through KDM4B turnover FBXO22 governs the TP53-TFEB autophagy axis [#12], SERM/tamoxifen responsiveness of estrogen-receptor-positive breast cancer [#4], and trophoblast stem-cell identity via degradation of the CoREST complex [#31]. Substrate selection frequently depends on signal-induced modification: FBXO22 recognizes a conserved phosphodegron and degrades ERK-phosphorylated BAG3 [#11], degrades GSK3\\u03b2-phosphorylated SNAIL to restrain EMT and metastasis [#3], and the amino-acid-sensing kinase GCN2 phosphorylates FBXO22 itself to drive K27-linked ubiquitination and inhibition of mTOR during starvation [#18]. Its broad substrate roster\\u2014including p21, p57Kip2, HDM2, nuclear PTEN (at K221), PD-L1, LKB1, BACH1, RPS5 and others\\u2014places it at nodes regulating cell cycle, EMT, mTOR signaling, oxidative-stress and antiviral responses [#5, #8, #7, #10, #6, #17, #24]. Beyond degradation, FBXO22 binds serine racemase non-catalytically to promote D-serine synthesis by altering its localization [#13]. Loss-of-function variants in FBXO22 cause a human syndrome of prenatal growth restriction and neurodevelopmental delay, with patient fibroblasts accumulating KDM4B [#32]. 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 [#20, #21, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established FBXO22 as a functional SCF substrate-receptor by showing it degrades the histone demethylase KDM4A and thereby tunes histone methylation and transcription.\",\n      \"evidence\": \"RNAi, overexpression, co-IP with FIST/JmjN-JmjC domain mapping, histone and transcriptional readouts in human cells\",\n      \"pmids\": [\"21768309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish ubiquitin chain linkage type\", \"Generality beyond KDM4A unknown at the time\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed that a bacterial pathogen exploits the FBXO22/Skp1 interface, the first hint that FBXO22 assembly can be hijacked to alter signaling.\",\n      \"evidence\": \"Domain mapping, siRNA, NF\\u03baB reporter assays and Salmonella infection model with the effector GogB\",\n      \"pmids\": [\"22761574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GogB blocks endogenous FBXO22 substrate turnover not shown\", \"No structural definition of the GogB F-box mimic interface\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination and half-life assays, subcellular fractionation, D-serine measurement\",\n      \"pmids\": [\"25336657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of localization control unresolved\", \"Physiological relevance in neurons not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected FBXO22 to senescence and tumor suppression by showing it degrades KDM4A-bound methylated p53, with an in vivo growth phenotype in knockout mice.\",\n      \"evidence\": \"Co-IP, catalytic KDM4A mutant, ubiquitination assays, Fbxo22-knockout mouse model and senescence readouts\",\n      \"pmids\": [\"26868148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How methylation status of p53 is read by the complex not fully defined\", \"Tissue-specific consequences of p53 accumulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, patient-derived W52R mutant, ChIP, live-cell imaging, in vitro/in vivo metastasis and xenograft models\",\n      \"pmids\": [\"29945959\", \"30418174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling tumor-suppressive versus tumor-promoting roles across tissues\", \"Determinants of substrate switching not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, CHX chase, linkage-specific ubiquitination, kinase assays, proteome screen, xenograft and 4T1 metastasis models\",\n      \"pmids\": [\"30808376\", \"31138683\", \"31217475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What dictates K48 versus K63 chain output is unknown\", \"Apparently opposing effects on p21 versus HDM2 not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated compartment- and site-specific substrate targeting by showing FBXO22 ubiquitinates only nuclear PTEN at K221.\",\n      \"evidence\": \"Co-IP, lysine-mutant ubiquitination assays, nuclear/cytoplasmic fractionation, functional assays\",\n      \"pmids\": [\"32249768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear restriction of activity is achieved unclear\", \"Upstream signals controlling nuclear PTEN turnover unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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).\",\n      \"evidence\": \"Phosphoproteomics, co-IP, ubiquitination assays, phosphomutants, ChIP-seq, knockout/overexpressing mice, drug-sensitization assays\",\n      \"pmids\": [\"34795058\", \"33706682\", \"34215846\", \"34182063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all substrates share the XXPpSPXPXX degron unresolved\", \"Kinases that license each substrate not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Broadened the cell-cycle and tumor-pathway substrate set (p57Kip2, KDM5A-p16 axis, LATS2/Hippo), reinforcing roles in proliferation and metastasis.\",\n      \"evidence\": \"Co-IP, ubiquitination/half-life assays, flow cytometry, RNA-seq, xenograft and rescue experiments\",\n      \"pmids\": [\"36127346\", \"36112263\", \"36515852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without reciprocal validation for some substrates\", \"Tissue selectivity of substrate choice unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established in vivo genetic substrate dependency in leukemia (BACH1) and added GAK as a substrate, linking FBXO22 to LSC self-renewal.\",\n      \"evidence\": \"Conditional/global Fbxo22 knockout mice, AP-MS, BACH1 heterozygous rescue, serial transplantation, proteomics\",\n      \"pmids\": [\"36774506\", \"37442264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why BACH1 degradation is pro-leukemogenic versus tumor-suppressive elsewhere unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Linkage- and site-specific ubiquitination, GCN2 phosphorylation cascade, tissue-specific knockout mice, AOM/DSS and viral models, reconstituted heme-dependent BACH1 assay\",\n      \"pmids\": [\"37979583\", \"39485803\", \"39223933\", \"39809956\", \"38673728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FBXO22 distinguishes mTOR modification states to choose degradative versus inhibitory ubiquitination unclear\", \"Heme cofactor requirement generalizability beyond BACH1 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified FBXO22 as a recruitable E3 for targeted protein degradation through covalent engagement of reactive cysteines by aldehyde- and electrophile-bearing degraders.\",\n      \"evidence\": \"Intact-protein MS, CRISPR activation screen, cysteine mutagenesis (Cys326, Cys227/228), degradation assays across FKBP12/NSD2/XIAP/BRD4\",\n      \"pmids\": [\"38926334\", \"38965383\", \"38965384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous role of these cysteines unknown\", \"Determinants of neo-substrate selectivity incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided a structural mechanism for covalent degrader engagement and human disease validation, and identified regulators that disassemble the SCF(FBXO22)-BACH1 complex.\",\n      \"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\",\n      \"pmids\": [\"42026065\", \"40215970\", \"40263598\", \"41096745\", \"42240618\", \"41314902\", \"41292500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full endogenous substrate degron map still incomplete\", \"How accessory proteins gate substrate access across tissues unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 7, 8, 11, 18, 30]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 3, 7, 17, 24]},\n      {\"term_id\": \"GO:0031386\", \"supporting_discovery_ids\": [0, 6, 18, 24, 30]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 16, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 7, 8, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 5, 15, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 16, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 18, 19, 28]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7, 17, 32]}\n    ],\n    \"complexes\": [\"SCF(FBXO22) (SKP1-CUL1-FBXO22) E3 ubiquitin ligase\"],\n    \"partners\": [\"SKP1\", \"CUL1\", \"KDM4A\", \"KDM4B\", \"SNAIL\", \"BACH1\", \"mTOR\", \"SDCBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}