{"gene":"FBXO11","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2012,"finding":"FBXO11 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) ubiquitin ligase complex that directly ubiquitylates BCL6, targeting it for proteasomal degradation. Tumor-derived FBXO11 mutants displayed impaired ability to induce BCL6 degradation, and reconstitution of FBXO11 in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited proliferation, and induced cell death.","method":"Co-immunoprecipitation, ubiquitylation assays, reconstitution in FBXO11-deleted cell lines, mutagenesis of tumor-derived alleles, xenograft tumor suppression assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution in deleted cell lines, mutagenesis of disease alleles, multiple orthogonal methods, replicated in subsequent papers","pmids":["22113614"],"is_preprint":false},{"year":2014,"finding":"SCF-FBXO11 ubiquitylates SNAIL and targets it for proteasomal degradation, but only after SNAIL Ser-11 is phosphorylated by protein kinase D1 (PKD1). This PKD1-FBXO11-SNAIL axis suppresses EMT, tumor initiation, and metastasis in breast cancer models.","method":"Genome-wide E3 ligase siRNA library screen, co-immunoprecipitation, ubiquitylation assays, phospho-mutant analysis, breast cancer xenograft and metastasis models","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide screen identification followed by reconstitution, phospho-degron mutagenesis, in vivo validation, multiple orthogonal methods","pmids":["25203322"],"is_preprint":false},{"year":2006,"finding":"FBXO11 is a component of the SCF complex and acts as an adaptor protein that promotes neddylation (NEDD8 conjugation) of p53, including at Lys-320 and Lys-321, inhibiting p53 transcriptional activity. This was demonstrated both in vitro and in vivo.","method":"In vitro neddylation assay, co-immunoprecipitation, p53 transcriptional reporter assays, site-directed mutagenesis of p53 lysine residues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of neddylation, mutagenesis of target lysines, in vivo confirmation, single lab but multiple orthogonal methods","pmids":["17098746"],"is_preprint":false},{"year":2006,"finding":"FBXO11 (designated PRMT9) harbors a protein arginine methyltransferase domain and immunopurified protein exhibits methyltransferase activity, forming monomethylarginine, symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) on arginine residues.","method":"Immunopurification of recombinant protein expressed in HeLa cells and E. coli, in vitro methyltransferase activity assay, mass spectrometry identification of methylation products","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with purified protein, single lab, single study; activity not extensively validated with mutagenesis","pmids":["16487488"],"is_preprint":false},{"year":2013,"finding":"FBXO11 interacts with CDT2 (a DCAF substrate receptor of CRL4) and recruits CDT2 to the SCF-FBXO11 complex to promote its proteasomal degradation. Unlike typical SCF substrates, CDK-mediated phosphorylation of Thr464 in the CDT2 degron inhibits (rather than promotes) recognition by FBXO11. This regulation of CDT2 is evolutionarily conserved from C. elegans to humans and controls the timing of cell-cycle exit.","method":"Affinity purification and mass spectrometry, co-immunoprecipitation, ubiquitylation assays, phosphorylation mutant analysis, C. elegans genetic studies","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — AP-MS identification, reciprocal Co-IP, phospho-degron mutagenesis, cross-species conservation demonstrated, two independent labs published simultaneously","pmids":["23478441"],"is_preprint":false},{"year":2013,"finding":"CRL1-FBXO11 polyubiquitylates CDT2 and promotes its degradation, independent of CRL4A-mediated autoubiquitylation of CDT2. FBXO11-mediated CDT2 degradation stabilizes p21 and Set8/Pr-Set7, which is important for the response to TGF-β (enabling Set8-dependent shutoff of Smad2 activation) and for stimulating epithelial cell migration.","method":"Co-immunoprecipitation, ubiquitylation assays, cycloheximide chase, siRNA knockdown, TGF-β signaling assays, migration assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — replicated independently in same issue as companion paper, multiple orthogonal methods, functional pathway validation","pmids":["23478445"],"is_preprint":false},{"year":2014,"finding":"The C. elegans ortholog DRE-1/FBXO11 functions in an SCF E3 ubiquitin ligase complex to directly target the conserved transcription factor BLMP-1/BLIMP-1 for proteasomal degradation, governing developmental timing and other life history traits. Direct protein interaction and degradation function for worm and human FBXO11 with BLMP-1/BLIMP-1 was demonstrated.","method":"Genetic epistasis (suppressor analysis), co-immunoprecipitation, protein stability assays, C. elegans developmental timing assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — epistasis, direct protein interaction, degradation assay, cross-species conservation, multiple orthogonal methods","pmids":["24613396"],"is_preprint":false},{"year":2016,"finding":"FBXO11 loss in germinal center (GC)-specific knockout mice leads to increased GC B cells, altered dark zone/light zone ratio, elevated BCL6 protein, and reduced BCR-mediated BCL6 degradation, establishing that FBXO11 physiologically controls BCL6 levels during the GC reaction and that its inactivation leads to lymphoproliferative disease.","method":"GC-specific conditional FBXO11 knockout mice, flow cytometry, immunofluorescence, BCL6 protein stability assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype, multiple readouts, in vivo model","pmids":["27166359"],"is_preprint":false},{"year":2015,"finding":"FBXO11 promotes ubiquitin-mediated degradation of multiple Snail family members (SNAI1, SNAI2/Slug, Scratch), independent of SNAI1 phosphorylation in vitro. Depletion of FBXO11 in epithelial cancer cells causes Snail accumulation, EMT, and invasion. In FBXO11-knockout mice, neonatal lethality, epidermal thickening, and increased Snail protein in epidermis confirm FBXO11 as a physiological ubiquitin ligase of Snail. C. elegans fbxo11 mutant phenotype is suppressed by inactivation of Snail homologs.","method":"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockout mice, C. elegans genetic epistasis, cell invasion assays","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro ubiquitylation, KO mouse with substrate accumulation, cross-species genetic epistasis, multiple orthogonal methods","pmids":["25827072"],"is_preprint":false},{"year":2021,"finding":"FBXO11 promotes ubiquitin-mediated proteasomal degradation of BAHD1, an H3K27me3 reader that recruits transcriptional corepressors and physically interacts with PRC2. In FBXO11-deficient erythroblasts, BAHD1 accumulates at bivalent gene promoters, prevents GATA1 binding, and blocks erythroid maturation genes. Depletion of either BAHD1 or PRC2 restores gene expression in FBXO11-/- erythroblasts.","method":"FBXO11 knockout mouse erythroblasts, co-immunoprecipitation, ChIP-seq, ubiquitylation assays, rescue experiments by BAHD1/PRC2 depletion, gene expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — KO model, substrate identification with ubiquitylation assay, ChIP-seq mechanistic validation, epistasis rescue, multiple orthogonal methods","pmids":["33156908"],"is_preprint":false},{"year":2022,"finding":"FBXO11 mediates ubiquitin-dependent proteasomal degradation of CIITA (the master transcriptional regulator of MHC class II), thereby suppressing MHC class II surface expression. FBXO11 was identified as a CIITA-binding partner by unbiased proteomics, and cycloheximide chase assays showed FBXO11 mainly controls CIITA half-life. FBXO11-deficient cells show increased MHC-II and related gene expression.","method":"Unbiased proteomic screen (co-IP/MS), cycloheximide chase, ubiquitylation assays, FBXO11 knockout cells, MHC-II surface expression (flow cytometry), promoter/transcriptional reporter assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — two independent papers (PMID 36179686 and 37279268) with overlapping mechanistic conclusions, unbiased proteomics, ubiquitylation assay, KO functional validation","pmids":["36179686","37279268"],"is_preprint":false},{"year":2023,"finding":"FBXO11 directly binds hnRNPA2B1 and promotes its ubiquitylation and proteasomal degradation via the SCF-FBXO11 complex. This axis is disrupted by CAND1, which dissociates the SCF complex, leading to hnRNPA2B1 accumulation and lipid metabolic reprogramming in hepatocellular carcinoma.","method":"Mass spectrometry, co-immunoprecipitation, GST pull-down, ubiquitylation assays, AAV-shCAND1 in vivo tumor models","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification, reciprocal Co-IP, GST pull-down, in vivo validation, single lab","pmids":["37837399"],"is_preprint":false},{"year":2015,"finding":"FBXO11 represses HIF-1α expression by destabilizing HIF-1α mRNA (not by direct ubiquitylation of HIF-1α protein). A FBXO11 mutant lacking the F-box domain failed to rescue HIF-1α expression upon FBXO11 knockdown, implicating the E3 ligase activity of FBXO11 in ubiquitinating proteins that control HIF-1α mRNA stability.","method":"siRNA knockdown, HIF-1α reporter assays, mRNA stability assay, F-box deletion mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — mRNA stability assay with domain mutant, single lab, indirect mechanism, limited orthogonal validation","pmids":["26187670"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the UBR-box domain from human UBR6/FBXO11 reveals a unique zinc-mediated domain-swapped dimer (three protein chains reconstituting the monomeric UBR-box fold). Structural analysis indicates that UBR6/FBXO11 lacks an amino acid binding pocket, explaining why it does not bind N-terminal degradation signals unlike other UBR family members.","method":"X-ray crystallography","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure determined, but functional validation of substrate-binding absence is structural inference without mutagenesis confirmation; single lab","pmids":["28691247"],"is_preprint":false},{"year":2025,"finding":"A new crystal structure of the UBR-box from human UBR6/FBXO11 at 1.5 Å resolution shows a monomer with a classical UBR fold, contradicting the previously reported domain-swapped dimer. N-degron binding assays confirmed no binding of basic type-1 N-degrons by UBR6/FBXO11.","method":"X-ray crystallography (1.5 Å), N-degron binding assay","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — high-resolution structure with binding assay, single lab; contradicts prior structure, raising uncertainty about which structural model is correct","pmids":["40099808"],"is_preprint":false},{"year":2009,"finding":"In the Jeff mouse model carrying a mutation in Fbxo11, phospho-Smad2 (pSmad2) is significantly upregulated and shows increased nuclear localization in epithelia. Mice heterozygous for both Jeff and Smad2 mutations recapitulate many Jeff homozygous phenotypes. No direct physical interaction between Fbxo11 and Smad2 was detected by tissue immunoprecipitation. Fbxo11 mutation reduces p53 levels, suggesting Fbxo11 stabilizes p53 which in turn limits pSmad2 nuclear accumulation.","method":"Immunohistochemistry, tissue immunoprecipitation (negative for direct interaction), genetic epistasis (Jeff/Smad2 double heterozygotes), p53 protein level analysis","journal":"PathoGenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double mutants, negative Co-IP for direct interaction, protein level measurement; two orthogonal approaches, single lab","pmids":["19580641"],"is_preprint":false},{"year":2015,"finding":"In mouse embryonic lung, FBXO11 and p53 physically interact, and the Jeff mutation in Fbxo11 prevents this interaction. p53 homozygous mutants and Jeff/p53 double heterozygotes show similar epithelial developmental defects and raised pSMAD2 levels as Fbxo11 homozygotes, establishing genetic epistasis between FBXO11 and p53 in regulating TGF-β pathway output.","method":"Co-immunoprecipitation from embryonic lung tissue, genetic epistasis (p53 KO and Jeff/p53 double heterozygote mice), immunofluorescence for pSMAD2","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue Co-IP, genetic epistasis with double mutants, multiple phenotypic readouts, single lab","pmids":["26471094"],"is_preprint":false},{"year":2021,"finding":"FBXO11 mutations are found in 23% of Burkitt lymphoma patients and impair BCL6 degradation. Conditional deletion of one or two FBXO11 copies in mice cooperated with oncogenic MYC to accelerate B-cell lymphoma onset, establishing FBXO11 as a haploinsufficient tumor suppressor in B-cell lymphoma.","method":"Sequencing of patient samples, BCL6 degradation assays in human BL cell lines, conditional FBXO11 knockout mouse B-cell lymphoma model","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional BCL6 degradation assay, in vivo mouse lymphoma model with haploinsufficiency, patient mutation validation, multiple orthogonal methods","pmids":["34625792"],"is_preprint":false},{"year":2023,"finding":"FBXO11 facilitates the assembly of the TRAF3-TBK1-IRF3 complex by mediating K63-linked ubiquitination of TRAF3 in a NEDD8-dependent manner, thereby promoting TBK1 and IRF3 phosphorylation and amplifying type I interferon signaling. The NEDD8-activating enzyme inhibitor MLN4921 blocked this FBXO11-TRAF3-IFN-I axis.","method":"Co-immunoprecipitation, K63 ubiquitination assay, phosphorylation assays (TBK1, IRF3), MLN4921 pharmacological inhibition, FBXO11 overexpression/knockdown with IFN reporter assays","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP complex assembly, ubiquitination assay with linkage specificity, pharmacological inhibition, single lab","pmids":["36977592"],"is_preprint":false},{"year":2024,"finding":"NDR1 phosphorylates β-catenin at Ser33/Ser37, facilitating its interaction with FBXO11. FBXO11 then mediates ubiquitylation and cytoplasmic degradation of β-catenin. Additionally, the NDR1-FBXO11 complex induces JNK2 ubiquitination, impeding β-catenin nuclear translocation. This dual mechanism suppresses EMT and prostate cancer metastasis.","method":"Immunoprecipitation, Western blotting, immunofluorescence, ubiquitylation assays, protein stability assays, nude mouse lung metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, in vivo metastasis model, multiple substrates identified, single lab","pmids":["39309441"],"is_preprint":false},{"year":2023,"finding":"FBXO11 mediates ubiquitin-dependent proteasomal degradation of BAHD1 and also promotes BCL6 ubiquitylation and degradation in macrophages. FBXO11 regulates C5aR1 expression at the mRNA level and dampens IL-1β secretion after NLRP3 activation through BCL6-dependent and BCL6-independent mechanisms in response to bacterial PVL toxin.","method":"Genome-wide CRISPR/Cas9 screen, FBXO11 genetic deletion, C5aR1 expression assays, IL-1β ELISA, ectopic C5aR1 rescue experiments","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO screen, genetic rescue experiments, cytokine assays; mechanism of C5aR1 mRNA regulation not fully resolved, single lab","pmids":["36977592"],"is_preprint":false},{"year":2023,"finding":"FBXO11 governs macrophage cell death and inflammation in response to Panton-Valentine leukocidin (PVL). Genetic deletion of FBXO11 reduced C5aR1 expression at the mRNA level, and ectopic C5aR1 expression or LPS priming in FBXO11-/- macrophages restored PVL toxicity. FBXO11 also dampens IL-1β secretion after NLRP3 activation via BCL6-dependent and BCL6-independent mechanisms.","method":"Genome-wide CRISPR/Cas9 screen, FBXO11 genetic deletion, C5aR1 rescue experiments, NLRP3 activation assays, IL-1β measurement","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus genetic KO with functional rescue, multiple mechanistic readouts, single lab","pmids":["36977592"],"is_preprint":false},{"year":2023,"finding":"FBXO11 deficiency in osteoblasts leads to Snail1 protein accumulation (reduced Snail1 ubiquitylation), suppression of osteogenic activity, and inhibition of bone matrix mineralization. Osteoblast-specific conditional FBXO11 knockout mice showed reduced bone growth and osteogenic activity without changes in osteoclast activity.","method":"Lentiviral FBXO11 knockdown and overexpression in MC3T3-E1 cells, osteoblast-specific conditional KO mouse models (Col1a1-ERT2 and Bglap2 promoters), ubiquitylation assay, osteogenic differentiation assays","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse model with defined substrate accumulation and cellular phenotype, ubiquitylation assay, two cKO lines, single lab","pmids":["36863499"],"is_preprint":false},{"year":2024,"finding":"ERK3 interacts with Snail and enhances Snail protein stability by inhibiting the binding of FBXO11 to Snail, thereby preventing FBXO11-mediated Snail ubiquitylation and degradation. ERK3 could not directly phosphorylate Snail but acted by blocking FBXO11-Snail interaction.","method":"Co-immunoprecipitation, ubiquitylation assays, protein stability assays, competitive binding assays, pancreatic cancer clinical sample analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP showing competitive displacement of FBXO11 from Snail, ubiquitylation assay, stability assay, single lab","pmids":["38201533"],"is_preprint":false},{"year":2024,"finding":"FBXO11 recognizes and promotes ubiquitin-mediated proteasomal degradation of ZEB1, a core inducer of EMT. Depletion of FBXO11 in lung cancer cells causes ZEB1 accumulation and increased invasion, while FBXO11 overexpression reduces ZEB1 and invasiveness. ZEB1 depletion suppresses the increased migration/invasion caused by FBXO11 knockdown.","method":"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockdown/overexpression, rescue by ZEB1 depletion, xenograft tumor assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, epistasis rescue, in vivo xenograft, single lab","pmids":["39409891"],"is_preprint":false},{"year":2024,"finding":"FBXO11 directly interacts with EBNA3C (an EBV latent antigen) through EBNA3C residues 50-100, and the presence of both EBNA3C and FBXO11 significantly enhances BCL6 ubiquitylation and degradation via the SCF-FBXO11 complex. FBXO11 knockdown suppresses EBV-driven lymphoblastoid cell line transformation.","method":"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockdown, LCL transformation assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, functional transformation assay, single lab","pmids":["38864622"],"is_preprint":false},{"year":2025,"finding":"FBXO11 interacts with and catalyzes K63-linked ubiquitylation of LONP1 in the cytosol, promoting LONP1 entry into mitochondria. FBXO11 or LONP1 depletion reduces mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV, imparting myeloid-biased stem cell properties in HSPCs. In a xenograft model, FBXO11 depletion cooperated with AML1-ETO and KRAS-G12D to generate transplantable AML.","method":"Co-immunoprecipitation, K63 ubiquitination assay, mitochondrial fractionation, electron transport chain complex IV assembly assay, CD34+ HSPC culture, xenograft transplantation model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP, K63 ubiquitination assay, mitochondrial import validation, functional in vivo xenograft, multiple orthogonal methods, single lab","pmids":["41289019"],"is_preprint":false},{"year":2026,"finding":"SCF-FBXO11 facilitates ubiquitylation of NPM1, and FBXO11 deletion results in reorganization of NPM1 and de-repression of alternative splicing. FBXO11 and NPM1 form a network regulating spliceosome and ribosome components. Rare FBXO11 mutations map to an intrinsically disordered N-terminal region responsible for NPM1 binding. MYC was found to occupy the FBXO11 promoter and its eviction by TLR2 activation explains reduced FBXO11 expression in MDS.","method":"Multi-omics (proteomics, transcriptomics), label-free quantitative proteomics, co-immunoprecipitation, ubiquitylation assays, Fbxo11 knockout mouse MDS models, ChIP assay for MYC at FBXO11 promoter","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus Co-IP plus ubiquitylation assay and mouse KO model, multiple orthogonal methods, single lab, preprint not yet replicated","pmids":["41542766"],"is_preprint":false},{"year":2024,"finding":"FBXO11 promotes K48-linked ubiquitylation and proteasomal degradation of KIF2C. Conditional FBXO11 expression suppresses ovarian cancer cell proliferation, migration, invasion, and xenograft tumor growth; KIF2C knockdown reverses tumor-promoting effects of FBXO11 downregulation. ZNF217 transcriptionally represses FBXO11 expression.","method":"Tet-on inducible FBXO11 expression, ubiquitylation assay (K48-linkage specific), KIF2C knockdown rescue, xenograft and peritoneal metastasis models, ChIP for ZNF217 at FBXO11 promoter","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — K48 ubiquitylation assay, epistasis rescue, in vivo models, transcriptional regulation validation, single lab","pmids":["40447129"],"is_preprint":false},{"year":2024,"finding":"FBXO11 mediates ubiquitin-dependent proteasomal degradation of Fosl2. FBXO11 overexpression in podocytes reduced Fosl2 protein via ubiquitin-dependent degradation, maintained mitochondrial function, and prevented podocyte apoptosis in adriamycin-induced nephropathy. Fosl2 overexpression abolished protective effects of FBXO11, and the mitochondrial fission inhibitor mdivi-1 reversed effects of the FBXO11/Fosl2 axis.","method":"Lentiviral FBXO11 overexpression, ubiquitylation assays, Fosl2 rescue experiments, mitochondrial function assays, mdivi-1 pharmacological inhibition, in vivo mouse ADR nephropathy model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ubiquitylation assay, epistasis rescue, in vivo model, single lab","pmids":["39581215"],"is_preprint":false},{"year":2006,"finding":"A mutation in Fbxo11 underlies the Jeff mouse mutant that develops chronic suppurative otitis media. Fbxo11 is expressed in epithelial cells of the middle ear from late embryonic stages through postnatal day 13. Homozygous Jeff mutants and a hypomorphic Mutt allele show cleft palate and facial clefting, establishing FBXO11 as important in epithelial development of the middle ear and palate.","method":"Positional cloning, mutant mouse characterization, immunohistochemistry/in situ hybridization for tissue expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning with allelic series, tissue expression localization with functional phenotype, but mechanism not biochemically defined beyond F-box membership","pmids":["17035249"],"is_preprint":false},{"year":2010,"finding":"In melanocytes, FBXO11 knockdown causes ER swelling and retention of tyrosinase co-localized with calreticulin in the ER, preventing its export. Tyrosinase protein levels were markedly elevated following FBXO11 siRNA, suggesting FBXO11 is required for proper ER function and tyrosinase export from the ER in melanocytes.","method":"siRNA knockdown, electron microscopy (ER morphology), confocal co-localization of tyrosinase and calreticulin, Western blot","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, morphological and co-localization data without direct biochemical mechanism linking FBXO11 to tyrosinase export","pmids":["20514423"],"is_preprint":false},{"year":2025,"finding":"Loss of FBXO11 in human iPSC-derived neurons causes disrupted transcriptional networks related to neuronal differentiation, migration, and cell signaling, impaired neuronal migration, and abnormal proliferation/differentiation balance. In Drosophila, fbxo11 knockdown impairs dendritic development and behavior. Proteasome-activating substances (including verapamil) alleviated these FBXO11-deficiency phenotypes in both human neurons and flies.","method":"CRISPR-Cas9 FBXO11-deficient human iPSC-derived neurons, Drosophila tissue-specific knockdown, RNA sequencing, neuronal migration assay, pharmacological proteasome activation","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — iPSC neuronal model plus Drosophila model, transcriptomics plus functional phenotypes, pharmacological rescue, two species convergence, single lab","pmids":["40114442"],"is_preprint":false}],"current_model":"FBXO11 is the substrate-recognition subunit of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex that targets multiple substrates — including BCL6, SNAIL family members, CDT2, CIITA, BAHD1, p53 (via neddylation), BLMP-1/BLIMP-1, NPM1, LONP1, ZEB1, KIF2C, hnRNPA2B1, Fosl2, and β-catenin — for ubiquitylation and proteasomal degradation, thereby regulating germinal center reactions, epithelial-mesenchymal transition, erythropoiesis, immune antigen presentation, type I interferon signaling, cell-cycle exit, TGF-β pathway output, and mitochondrial function; additionally, through its arginine methyltransferase (PRMT9) domain it can catalyze symmetric dimethylarginine formation, and it promotes p53 neddylation to suppress p53 transcriptional activity."},"narrative":{"mechanistic_narrative":"FBXO11 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that selects diverse regulatory proteins for ubiquitylation and proteasomal degradation, thereby controlling germinal-center B-cell biology, epithelial-mesenchymal transition (EMT), cell-cycle exit, hematopoietic differentiation, and immune output [PMID:22113614, PMID:23478441, PMID:33156908]. Its best-established target is the transcriptional repressor BCL6: SCF-FBXO11 directly ubiquitylates BCL6 for degradation, tumor-derived mutants fail to do so, and germinal-center-specific knockout elevates BCL6 and expands GC B cells, defining FBXO11 as a haploinsufficient tumor suppressor in B-cell lymphoma that cooperates with MYC [PMID:22113614, PMID:27166359, PMID:34625792]. FBXO11 enforces an anti-EMT program by degrading SNAIL family members (SNAI1, SNAI2/Slug, Scratch) and ZEB1, with SNAIL recognition gated by PKD1 phosphorylation; loss causes SNAIL/ZEB1 accumulation, invasion, and metastasis [PMID:25203322, PMID:25827072, PMID:39409891]. The ligase also degrades the CRL4 receptor CDT2 to time cell-cycle exit and stabilize p21/Set8 for TGF-β control [PMID:23478441, PMID:23478445], the H3K27me3 reader BAHD1 to permit GATA1-dependent erythroid maturation [PMID:33156908], the MHC-II master regulator CIITA to dampen antigen presentation [PMID:36179686, PMID:37279268], and additional substrates including hnRNPA2B1, NPM1, KIF2C, Fosl2, and β-catenin [PMID:37837399, PMID:41542766, PMID:40447129, PMID:39581215, PMID:39309441]. Beyond canonical K48-linked degradation, FBXO11 acts as an adaptor promoting NEDD8 conjugation of p53 to repress its transcriptional activity [PMID:17098746] and catalyzes K63-linked ubiquitylation of TRAF3 and of cytosolic LONP1, the latter promoting LONP1 mitochondrial import and electron-transport-chain Complex IV assembly [PMID:36977592, PMID:41289019]. Mutation of Fbxo11 in mice (the Jeff allele) causes epithelial defects of the middle ear and palate linked to elevated phospho-Smad2 and reduced p53 [PMID:17035249, PMID:19580641, PMID:26471094], and FBXO11 loss disrupts neuronal differentiation and migration in iPSC and Drosophila models [PMID:40114442].","teleology":[{"year":2006,"claim":"Established the first biochemical activities of FBXO11: that beyond SCF membership it acts as an adaptor promoting p53 neddylation to repress p53, and that it carries an arginine methyltransferase domain (PRMT9) with in vitro activity.","evidence":"In vitro neddylation and methyltransferase assays, p53 reporter assays, mutagenesis of p53 lysines, mass spectrometry of methylation products","pmids":["17098746","16487488"],"confidence":"Medium","gaps":["Methyltransferase activity not validated by domain mutagenesis or in cells","Physiological relevance of p53 neddylation versus FBXO11's ligase function unclear"]},{"year":2006,"claim":"Linked FBXO11 to mammalian development via the Jeff mouse, showing it is required for epithelial development of the middle ear and palate.","evidence":"Positional cloning, mutant mouse characterization, tissue expression by IHC/in situ hybridization","pmids":["17035249"],"confidence":"Medium","gaps":["Molecular substrate underlying the epithelial phenotype not defined","Mechanism beyond F-box membership not biochemically established"]},{"year":2009,"claim":"Connected the Jeff epithelial phenotype to dysregulated TGF-β signaling, showing Fbxo11 limits phospho-Smad2 nuclear accumulation indirectly through p53 stabilization rather than direct Smad2 binding.","evidence":"Immunohistochemistry, negative tissue Co-IP, Jeff/Smad2 double-heterozygote genetic epistasis, p53 protein measurement","pmids":["19580641"],"confidence":"Medium","gaps":["No direct FBXO11-Smad2 interaction","Mechanism by which p53 limits pSmad2 unresolved"]},{"year":2012,"claim":"Defined FBXO11's flagship function: SCF-FBXO11 directly ubiquitylates BCL6 for degradation, and tumor mutations abolish this, establishing FBXO11 as a tumor suppressor in DLBCL.","evidence":"Co-IP, ubiquitylation assays, reconstitution in FBXO11-deleted DLBCL lines, mutagenesis of disease alleles, xenograft suppression","pmids":["22113614"],"confidence":"High","gaps":["Degron/recognition motif on BCL6 not mapped","Upstream signals controlling BCL6 recognition not defined here"]},{"year":2013,"claim":"Revealed that FBXO11 degrades the CRL4 receptor CDT2 through an atypical phospho-inhibited degron, coupling FBXO11 to cell-cycle exit timing and TGF-β output via p21/Set8 stabilization.","evidence":"AP-MS, reciprocal Co-IP, ubiquitylation assays, phospho-mutant analysis, cycloheximide chase, C. elegans genetics, TGF-β and migration assays","pmids":["23478441","23478445"],"confidence":"High","gaps":["Kinase responsible for the inhibitory CDT2 phosphorylation only partially defined","Quantitative contribution of CDT2 versus other substrates to TGF-β output unclear"]},{"year":2014,"claim":"Showed FBXO11 enforces an anti-EMT program by degrading phospho-SNAIL downstream of PKD1, and confirmed conserved DRE-1/FBXO11 degradation of the BLIMP-1 transcription factor controlling developmental timing.","evidence":"Genome-wide siRNA screen, Co-IP, ubiquitylation assays, phospho-degron mutagenesis, breast cancer metastasis models; C. elegans epistasis and protein stability assays","pmids":["25203322","24613396"],"confidence":"High","gaps":["Whether all SNAIL family recognition requires phosphorylation unresolved at this stage","Tissue specificity of SNAIL versus BLIMP-1 targeting not addressed"]},{"year":2015,"claim":"Generalized SNAIL-family control by FBXO11, showing phosphorylation-independent degradation of SNAI1/SNAI2/Scratch in vivo, and added an indirect role in destabilizing HIF-1α mRNA.","evidence":"Co-IP, ubiquitylation assays, FBXO11 knockout mice with epidermal Snail accumulation, C. elegans epistasis; siRNA, mRNA stability assay and F-box deletion mutant for HIF-1α","pmids":["25827072","26187670"],"confidence":"High","gaps":["Reconciliation of phosphorylation-dependent versus -independent SNAIL recognition","Identity of the FBXO11 substrate controlling HIF-1α mRNA stability unknown"]},{"year":2015,"claim":"Strengthened the FBXO11-p53 axis by demonstrating direct physical interaction in vivo abolished by the Jeff mutation, placing p53 epistatically upstream of TGF-β pathway control in epithelial development.","evidence":"Tissue Co-IP from embryonic lung, p53 KO and Jeff/p53 double-heterozygote genetic epistasis, pSMAD2 immunofluorescence","pmids":["26471094"],"confidence":"Medium","gaps":["Whether FBXO11 stabilizes or modifies p53 in this context not biochemically resolved","Single lab"]},{"year":2016,"claim":"Provided physiological proof that FBXO11 controls BCL6 in vivo during the germinal-center reaction, with loss driving lymphoproliferation.","evidence":"GC-specific conditional FBXO11 knockout mice, flow cytometry, immunofluorescence, BCL6 stability assays","pmids":["27166359"],"confidence":"High","gaps":["Whether BCL6 is the sole relevant substrate in GC B cells not excluded"]},{"year":2017,"claim":"Attempted a structural explanation for substrate selection, showing the UBR-box of FBXO11 lacks an amino-acid binding pocket and so does not read N-terminal degrons.","evidence":"X-ray crystallography of the UBR-box (domain-swapped dimer)","pmids":["28691247"],"confidence":"Medium","gaps":["Functional consequence inferred without mutagenesis","Dimer assignment later contradicted"]},{"year":2021,"claim":"Expanded FBXO11 substrate biology to chromatin and hematopoiesis, identifying BAHD1 as a target whose degradation permits erythroid maturation, and quantifying FBXO11 mutation/haploinsufficiency in Burkitt lymphoma cooperating with MYC.","evidence":"Knockout erythroblasts, ChIP-seq, ubiquitylation assays, BAHD1/PRC2 depletion rescue; patient sequencing, BCL6 degradation assays, conditional KO/MYC lymphoma model","pmids":["33156908","34625792"],"confidence":"High","gaps":["Recognition determinants on BAHD1 not mapped","How a single ligase coordinates lineage-specific substrate choice unclear"]},{"year":2022,"claim":"Linked FBXO11 to adaptive immunity by establishing CIITA as a degradation substrate, so FBXO11 loss elevates MHC class II expression.","evidence":"Unbiased Co-IP/MS, cycloheximide chase, ubiquitylation assays, FBXO11 KO cells, MHC-II flow cytometry (two independent papers)","pmids":["36179686","37279268"],"confidence":"High","gaps":["CIITA degron not defined","Interplay with FBXO11's tumor-suppressor and antigen-presentation roles not integrated"]},{"year":2023,"claim":"Extended FBXO11 into innate immunity, metabolism, and inflammation, showing K63-ubiquitylation of TRAF3 to amplify type I IFN, degradation of hnRNPA2B1 (antagonized by CAND1), and BCL6/BAHD1-dependent control of macrophage responses to bacterial toxins.","evidence":"Co-IP, K63-ubiquitination assays, IFN reporters, MLN4921 inhibition; MS, GST pull-down, in vivo tumor models; genome-wide CRISPR screen, genetic KO, C5aR1 and IL-1β assays","pmids":["36977592","37837399"],"confidence":"Medium","gaps":["NEDD8-dependence of TRAF3 K63 ubiquitylation mechanistically thin","Mechanism of C5aR1 mRNA regulation unresolved","Single labs for each axis"]},{"year":2024,"claim":"Broadened the EMT/migration program and tissue contexts, adding ZEB1, β-catenin (via NDR1 phosphorylation), KIF2C, Fosl2, and Snail1 in bone as degradation substrates, and showing regulatory inputs from ERK3, ZNF217, and EBNA3C.","evidence":"Co-IP, K48-linked ubiquitylation assays, epistasis rescue, xenograft/metastasis and conditional KO mouse models, competitive binding assays, ChIP for transcriptional repressors","pmids":["39409891","39309441","40447129","39581215","36863499","38201533","38864622"],"confidence":"Medium","gaps":["Most axes from single labs","Substrate-recognition motifs largely unmapped","Relative physiological hierarchy of the many substrates unknown"]},{"year":2025,"claim":"Revealed a non-degradative mitochondrial role: FBXO11 K63-ubiquitylates cytosolic LONP1 to promote its mitochondrial import and Complex IV assembly, with loss imparting myeloid-biased stem cell properties and cooperating in AML; a re-determined UBR-box structure corrected the prior dimer to a monomer.","evidence":"Co-IP, K63-ubiquitination assays, mitochondrial fractionation, Complex IV assembly assays, HSPC culture and xenograft; 1.5 Å crystallography and N-degron binding assay; iPSC-neuron and Drosophila models with proteasome-activator rescue","pmids":["41289019","40099808","40114442"],"confidence":"Medium","gaps":["How K63 ubiquitylation drives LONP1 import mechanistically unclear","Conflicting UBR-box structural models","Neuronal substrate(s) not identified"]},{"year":2026,"claim":"Connected FBXO11 to RNA processing and myeloid malignancy, showing SCF-FBXO11 ubiquitylates NPM1 to restrain alternative splicing, with disease mutations clustering in a disordered NPM1-binding N-terminus and MYC/TLR2 controlling FBXO11 expression in MDS.","evidence":"Multi-omics proteomics/transcriptomics, Co-IP, ubiquitylation assays, Fbxo11 KO mouse MDS models, ChIP for MYC at the FBXO11 promoter","pmids":["41542766"],"confidence":"Medium","gaps":["Whether NPM1 ubiquitylation is degradative or regulatory not fully resolved","Single lab, not independently replicated"]},{"year":null,"claim":"How a single F-box protein achieves selective recognition of such a broad substrate set, and how its degradative versus non-degradative (neddylation, K63-ubiquitylation, methyltransferase) activities are partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying degron/recognition code mapped across substrates","Physiological relevance of the PRMT9 methyltransferase activity unestablished","Structural model of the substrate-binding region disputed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,8,9,10,24,28]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,5,18,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19,26]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,27]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,8,9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,10,18,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,30,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,17,24,26]}],"complexes":["SCF (SKP1-CUL1-FBXO11) E3 ubiquitin ligase"],"partners":["BCL6","SNAI1","CDT2","CIITA","BAHD1","ZEB1","LONP1","NPM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86XK2","full_name":"F-box only protein 11","aliases":["Protein arginine N-methyltransferase 9","Vitiligo-associated protein 1","VIT-1"],"length_aa":927,"mass_kda":103.6,"function":"Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as DTL/CDT2, BCL6, SNAI1 and PRDM1/BLIMP1 (PubMed:17098746, PubMed:22113614, PubMed:23478441, PubMed:23478445, PubMed:23892434, PubMed:24613396, PubMed:24968003, PubMed:25827072, PubMed:29059170). The SCF(FBXO11) complex mediates ubiquitination and degradation of BCL6, thereby playing a role in the germinal center B-cells terminal differentiation toward memory B-cells and plasma cells (PubMed:22113614). The SCF(FBXO11) complex also mediates ubiquitination and degradation of DTL, an important step for the regulation of TGF-beta signaling, cell migration and the timing of the cell-cycle progression and exit (PubMed:23478441, PubMed:23478445). The SCF(FBXO11) complex also catalyzes ubiquitination and degradation of GSK3B-phosphorylated SNAI1 (PubMed:25827072, PubMed:29059170). Binds to and neddylates phosphorylated p53/TP53, inhibiting its transcriptional activity (PubMed:17098746). Plays a role in the regulatiom of erythropoiesis but not myelopoiesis or megakaryopoiesis (PubMed:33156908). Mechanistically, activates erythroid genes by mediating the degradation of BAHD1, a heterochromatin-associated protein that recruits corepressors to H3K27me3 marks (PubMed:33156908). Participates in macrophage cell death and inflammation in response to bacterial toxins by regulating the expression of complement 5a receptor 1/C5AR1 and IL-1beta (PubMed:33156908). Acts as a critical regulator to determine the level of MHC-II by mediating the recognition of degron at the P/S/T domain of CIITA leading to its ubiquitination and subsequent degradation via the proteasome (PubMed:37279268). Participates in the antiviral repsonse by initiating the activation of TBK1-IRF3-IFN-I axis (PubMed:36897010). Mediates the 'Lys-63'-linked ubiquitination of TRAF3 to strengthen the interaction between TRAF3 and TBK1 (PubMed:36897010)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q86XK2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO11","classification":"Not Classified","n_dependent_lines":226,"n_total_lines":1208,"dependency_fraction":0.1870860927152318},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO11","total_profiled":1310},"omim":[{"mim_id":"618089","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND BEHAVIORAL ABNORMALITIES; IDDFBA","url":"https://www.omim.org/entry/618089"},{"mim_id":"607871","title":"F-BOX ONLY PROTEIN 11; FBXO11","url":"https://www.omim.org/entry/607871"},{"mim_id":"191170","title":"TUMOR PROTEIN p53; TP53","url":"https://www.omim.org/entry/191170"},{"mim_id":"109565","title":"BCL6 TRANSCRIPTION REPRESSOR; BCL6","url":"https://www.omim.org/entry/109565"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXO11"},"hgnc":{"alias_symbol":["FBX11","UBR6"],"prev_symbol":[]},"alphafold":{"accession":"Q86XK2","domains":[{"cath_id":"1.20.1280.50","chopping":"158-240","consensus_level":"medium","plddt":92.9288,"start":158,"end":240},{"cath_id":"-","chopping":"243-291","consensus_level":"medium","plddt":88.1624,"start":243,"end":291},{"cath_id":"-","chopping":"292-433","consensus_level":"medium","plddt":93.7349,"start":292,"end":433},{"cath_id":"-","chopping":"846-891","consensus_level":"high","plddt":88.1524,"start":846,"end":891}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XK2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XK2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86XK2-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO11","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO11"},"sequence":{"accession":"Q86XK2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86XK2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86XK2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86XK2"}},"corpus_meta":[{"pmid":"22113614","id":"PMC_22113614","title":"FBXO11 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regulating FBXO11 expression.","date":"2024","source":"Clinics (Sao Paulo, Brazil)","url":"https://pubmed.ncbi.nlm.nih.gov/38677194","citation_count":7,"is_preprint":false},{"pmid":"32117459","id":"PMC_32117459","title":"Mutation in Fbxo11 Leads to Altered Immune Cell Content in Jeff Mouse Model of Otitis Media.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32117459","citation_count":7,"is_preprint":false},{"pmid":"33811277","id":"PMC_33811277","title":"Constitutional 2p16.3 deletion including MSH6 and FBXO11 in a boy with developmental delay and diffuse large B-cell lymphoma.","date":"2021","source":"Familial cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33811277","citation_count":6,"is_preprint":false},{"pmid":"39409891","id":"PMC_39409891","title":"FBXO11 Mediates Ubiquitination of ZEB1 and Modulates Epithelial-to-Mesenchymal Transition in Lung Cancer 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40889797","citation_count":2,"is_preprint":false},{"pmid":"36897010","id":"PMC_36897010","title":"FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.","date":"2023","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/36897010","citation_count":2,"is_preprint":false},{"pmid":"40045615","id":"PMC_40045615","title":"MiR-21-5p enhances differentiation and mitigates oleic acid-induced lipid droplet accumulation in C2C12 myoblasts by targeting FBXO11.","date":"2025","source":"Animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/40045615","citation_count":2,"is_preprint":false},{"pmid":"39581215","id":"PMC_39581215","title":"Fbxo11 maintains mitochondrial function and prevents podocyte injury in adriamycin-induced nephropathy by mediating the ubiquitin degradation of Fosl2.","date":"2024","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39581215","citation_count":1,"is_preprint":false},{"pmid":"40104748","id":"PMC_40104748","title":"The miR-155-5p/FBXO11 axis inhibits the progression of gastric cancer via the mTOR pathway.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40104748","citation_count":1,"is_preprint":false},{"pmid":"20646433","id":"PMC_20646433","title":"[Expression of InnVit/FBXO11 in vitiligo and its role in tyrosinase export from endoplasmic reticulum].","date":"2010","source":"Zhonghua yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/20646433","citation_count":1,"is_preprint":false},{"pmid":"34878147","id":"PMC_34878147","title":"[Corrigendum] The role of VIT1/FBXO11 in the regulation of apoptosis and tyrosinase export from endoplasmic reticulum in cultured melanocytes.","date":"2021","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34878147","citation_count":1,"is_preprint":false},{"pmid":"38679370","id":"PMC_38679370","title":"How many phenotypes for the FBXO11 related disease? Report on a new patient with a tricho-rhino-phalangeal like phenotype.","date":"2024","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38679370","citation_count":0,"is_preprint":false},{"pmid":"41289019","id":"PMC_41289019","title":"Loss of FBXO11 establishes a stem cell program in acute myeloid leukemia by dysregulating LONP1.","date":"2025","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41289019","citation_count":0,"is_preprint":false},{"pmid":"40447129","id":"PMC_40447129","title":"Tumor suppressor FBXO11 drives ubiquitin proteasomal degradation of KIF2C to limit ovarian cancer progression and is transcriptionally repressed by ZNF217.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40447129","citation_count":0,"is_preprint":false},{"pmid":"40114442","id":"PMC_40114442","title":"Proteasomal activation ameliorates neuronal phenotypes linked to FBXO11-deficiency.","date":"2025","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/40114442","citation_count":0,"is_preprint":false},{"pmid":"40099808","id":"PMC_40099808","title":"Revisiting the structure of UBR box from human UBR6.","date":"2025","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/40099808","citation_count":0,"is_preprint":false},{"pmid":"37219054","id":"PMC_37219054","title":"Retraction statement: Shao, L., Zhang, X. and Yao, Q. (2020), The F-box protein FBXO11 restrains hepatocellular carcinoma stemness via promotion of ubiquitin-mediated degradation of Snail. FEBS Open Bio, 10: 1810-1820.","date":"2023","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/37219054","citation_count":0,"is_preprint":false},{"pmid":"42059032","id":"PMC_42059032","title":"RBM15-Mediated m6A Modification Regulates Proliferation and Migration of Pancreatic Cancer Cells via the lncRNA LINC01320/miR-1287-5p/FBXO11 Axis.","date":"2026","source":"Biomolecules & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/42059032","citation_count":0,"is_preprint":false},{"pmid":"37441362","id":"PMC_37441362","title":"Partial Response to Crizotinib in a Lung Adenocarcinoma Patient with a Novel FBXO11 (Intergenic)-ALK (Exon 20-29) Fusion.","date":"2023","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37441362","citation_count":0,"is_preprint":false},{"pmid":"41230589","id":"PMC_41230589","title":"[Clinical and genetic analysis of a child with Intellectual developmental disorder with dysmorphic features and behavioral abnormalities due to a de novo variant of FBXO11 gene].","date":"2025","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41230589","citation_count":0,"is_preprint":false},{"pmid":"41542766","id":"PMC_41542766","title":"FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome.","date":"2026","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/41542766","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.03.24318397","title":"Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.03.24318397","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37536,"output_tokens":9143,"usd":0.124877,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19019,"output_tokens":6054,"usd":0.123222,"stage2_stop_reason":"end_turn"},"total_usd":0.248099,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"FBXO11 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) ubiquitin ligase complex that directly ubiquitylates BCL6, targeting it for proteasomal degradation. Tumor-derived FBXO11 mutants displayed impaired ability to induce BCL6 degradation, and reconstitution of FBXO11 in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited proliferation, and induced cell death.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, reconstitution in FBXO11-deleted cell lines, mutagenesis of tumor-derived alleles, xenograft tumor suppression assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution in deleted cell lines, mutagenesis of disease alleles, multiple orthogonal methods, replicated in subsequent papers\",\n      \"pmids\": [\"22113614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SCF-FBXO11 ubiquitylates SNAIL and targets it for proteasomal degradation, but only after SNAIL Ser-11 is phosphorylated by protein kinase D1 (PKD1). This PKD1-FBXO11-SNAIL axis suppresses EMT, tumor initiation, and metastasis in breast cancer models.\",\n      \"method\": \"Genome-wide E3 ligase siRNA library screen, co-immunoprecipitation, ubiquitylation assays, phospho-mutant analysis, breast cancer xenograft and metastasis models\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide screen identification followed by reconstitution, phospho-degron mutagenesis, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"25203322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FBXO11 is a component of the SCF complex and acts as an adaptor protein that promotes neddylation (NEDD8 conjugation) of p53, including at Lys-320 and Lys-321, inhibiting p53 transcriptional activity. This was demonstrated both in vitro and in vivo.\",\n      \"method\": \"In vitro neddylation assay, co-immunoprecipitation, p53 transcriptional reporter assays, site-directed mutagenesis of p53 lysine residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of neddylation, mutagenesis of target lysines, in vivo confirmation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17098746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FBXO11 (designated PRMT9) harbors a protein arginine methyltransferase domain and immunopurified protein exhibits methyltransferase activity, forming monomethylarginine, symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) on arginine residues.\",\n      \"method\": \"Immunopurification of recombinant protein expressed in HeLa cells and E. coli, in vitro methyltransferase activity assay, mass spectrometry identification of methylation products\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with purified protein, single lab, single study; activity not extensively validated with mutagenesis\",\n      \"pmids\": [\"16487488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FBXO11 interacts with CDT2 (a DCAF substrate receptor of CRL4) and recruits CDT2 to the SCF-FBXO11 complex to promote its proteasomal degradation. Unlike typical SCF substrates, CDK-mediated phosphorylation of Thr464 in the CDT2 degron inhibits (rather than promotes) recognition by FBXO11. This regulation of CDT2 is evolutionarily conserved from C. elegans to humans and controls the timing of cell-cycle exit.\",\n      \"method\": \"Affinity purification and mass spectrometry, co-immunoprecipitation, ubiquitylation assays, phosphorylation mutant analysis, C. elegans genetic studies\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — AP-MS identification, reciprocal Co-IP, phospho-degron mutagenesis, cross-species conservation demonstrated, two independent labs published simultaneously\",\n      \"pmids\": [\"23478441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRL1-FBXO11 polyubiquitylates CDT2 and promotes its degradation, independent of CRL4A-mediated autoubiquitylation of CDT2. FBXO11-mediated CDT2 degradation stabilizes p21 and Set8/Pr-Set7, which is important for the response to TGF-β (enabling Set8-dependent shutoff of Smad2 activation) and for stimulating epithelial cell migration.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, cycloheximide chase, siRNA knockdown, TGF-β signaling assays, migration assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — replicated independently in same issue as companion paper, multiple orthogonal methods, functional pathway validation\",\n      \"pmids\": [\"23478445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C. elegans ortholog DRE-1/FBXO11 functions in an SCF E3 ubiquitin ligase complex to directly target the conserved transcription factor BLMP-1/BLIMP-1 for proteasomal degradation, governing developmental timing and other life history traits. Direct protein interaction and degradation function for worm and human FBXO11 with BLMP-1/BLIMP-1 was demonstrated.\",\n      \"method\": \"Genetic epistasis (suppressor analysis), co-immunoprecipitation, protein stability assays, C. elegans developmental timing assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — epistasis, direct protein interaction, degradation assay, cross-species conservation, multiple orthogonal methods\",\n      \"pmids\": [\"24613396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXO11 loss in germinal center (GC)-specific knockout mice leads to increased GC B cells, altered dark zone/light zone ratio, elevated BCL6 protein, and reduced BCR-mediated BCL6 degradation, establishing that FBXO11 physiologically controls BCL6 levels during the GC reaction and that its inactivation leads to lymphoproliferative disease.\",\n      \"method\": \"GC-specific conditional FBXO11 knockout mice, flow cytometry, immunofluorescence, BCL6 protein stability assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined cellular phenotype, multiple readouts, in vivo model\",\n      \"pmids\": [\"27166359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO11 promotes ubiquitin-mediated degradation of multiple Snail family members (SNAI1, SNAI2/Slug, Scratch), independent of SNAI1 phosphorylation in vitro. Depletion of FBXO11 in epithelial cancer cells causes Snail accumulation, EMT, and invasion. In FBXO11-knockout mice, neonatal lethality, epidermal thickening, and increased Snail protein in epidermis confirm FBXO11 as a physiological ubiquitin ligase of Snail. C. elegans fbxo11 mutant phenotype is suppressed by inactivation of Snail homologs.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockout mice, C. elegans genetic epistasis, cell invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro ubiquitylation, KO mouse with substrate accumulation, cross-species genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"25827072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO11 promotes ubiquitin-mediated proteasomal degradation of BAHD1, an H3K27me3 reader that recruits transcriptional corepressors and physically interacts with PRC2. In FBXO11-deficient erythroblasts, BAHD1 accumulates at bivalent gene promoters, prevents GATA1 binding, and blocks erythroid maturation genes. Depletion of either BAHD1 or PRC2 restores gene expression in FBXO11-/- erythroblasts.\",\n      \"method\": \"FBXO11 knockout mouse erythroblasts, co-immunoprecipitation, ChIP-seq, ubiquitylation assays, rescue experiments by BAHD1/PRC2 depletion, gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — KO model, substrate identification with ubiquitylation assay, ChIP-seq mechanistic validation, epistasis rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33156908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXO11 mediates ubiquitin-dependent proteasomal degradation of CIITA (the master transcriptional regulator of MHC class II), thereby suppressing MHC class II surface expression. FBXO11 was identified as a CIITA-binding partner by unbiased proteomics, and cycloheximide chase assays showed FBXO11 mainly controls CIITA half-life. FBXO11-deficient cells show increased MHC-II and related gene expression.\",\n      \"method\": \"Unbiased proteomic screen (co-IP/MS), cycloheximide chase, ubiquitylation assays, FBXO11 knockout cells, MHC-II surface expression (flow cytometry), promoter/transcriptional reporter assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — two independent papers (PMID 36179686 and 37279268) with overlapping mechanistic conclusions, unbiased proteomics, ubiquitylation assay, KO functional validation\",\n      \"pmids\": [\"36179686\", \"37279268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO11 directly binds hnRNPA2B1 and promotes its ubiquitylation and proteasomal degradation via the SCF-FBXO11 complex. This axis is disrupted by CAND1, which dissociates the SCF complex, leading to hnRNPA2B1 accumulation and lipid metabolic reprogramming in hepatocellular carcinoma.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, GST pull-down, ubiquitylation assays, AAV-shCAND1 in vivo tumor models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification, reciprocal Co-IP, GST pull-down, in vivo validation, single lab\",\n      \"pmids\": [\"37837399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FBXO11 represses HIF-1α expression by destabilizing HIF-1α mRNA (not by direct ubiquitylation of HIF-1α protein). A FBXO11 mutant lacking the F-box domain failed to rescue HIF-1α expression upon FBXO11 knockdown, implicating the E3 ligase activity of FBXO11 in ubiquitinating proteins that control HIF-1α mRNA stability.\",\n      \"method\": \"siRNA knockdown, HIF-1α reporter assays, mRNA stability assay, F-box deletion mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — mRNA stability assay with domain mutant, single lab, indirect mechanism, limited orthogonal validation\",\n      \"pmids\": [\"26187670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the UBR-box domain from human UBR6/FBXO11 reveals a unique zinc-mediated domain-swapped dimer (three protein chains reconstituting the monomeric UBR-box fold). Structural analysis indicates that UBR6/FBXO11 lacks an amino acid binding pocket, explaining why it does not bind N-terminal degradation signals unlike other UBR family members.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure determined, but functional validation of substrate-binding absence is structural inference without mutagenesis confirmation; single lab\",\n      \"pmids\": [\"28691247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A new crystal structure of the UBR-box from human UBR6/FBXO11 at 1.5 Å resolution shows a monomer with a classical UBR fold, contradicting the previously reported domain-swapped dimer. N-degron binding assays confirmed no binding of basic type-1 N-degrons by UBR6/FBXO11.\",\n      \"method\": \"X-ray crystallography (1.5 Å), N-degron binding assay\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — high-resolution structure with binding assay, single lab; contradicts prior structure, raising uncertainty about which structural model is correct\",\n      \"pmids\": [\"40099808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In the Jeff mouse model carrying a mutation in Fbxo11, phospho-Smad2 (pSmad2) is significantly upregulated and shows increased nuclear localization in epithelia. Mice heterozygous for both Jeff and Smad2 mutations recapitulate many Jeff homozygous phenotypes. No direct physical interaction between Fbxo11 and Smad2 was detected by tissue immunoprecipitation. Fbxo11 mutation reduces p53 levels, suggesting Fbxo11 stabilizes p53 which in turn limits pSmad2 nuclear accumulation.\",\n      \"method\": \"Immunohistochemistry, tissue immunoprecipitation (negative for direct interaction), genetic epistasis (Jeff/Smad2 double heterozygotes), p53 protein level analysis\",\n      \"journal\": \"PathoGenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double mutants, negative Co-IP for direct interaction, protein level measurement; two orthogonal approaches, single lab\",\n      \"pmids\": [\"19580641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In mouse embryonic lung, FBXO11 and p53 physically interact, and the Jeff mutation in Fbxo11 prevents this interaction. p53 homozygous mutants and Jeff/p53 double heterozygotes show similar epithelial developmental defects and raised pSMAD2 levels as Fbxo11 homozygotes, establishing genetic epistasis between FBXO11 and p53 in regulating TGF-β pathway output.\",\n      \"method\": \"Co-immunoprecipitation from embryonic lung tissue, genetic epistasis (p53 KO and Jeff/p53 double heterozygote mice), immunofluorescence for pSMAD2\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue Co-IP, genetic epistasis with double mutants, multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"26471094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FBXO11 mutations are found in 23% of Burkitt lymphoma patients and impair BCL6 degradation. Conditional deletion of one or two FBXO11 copies in mice cooperated with oncogenic MYC to accelerate B-cell lymphoma onset, establishing FBXO11 as a haploinsufficient tumor suppressor in B-cell lymphoma.\",\n      \"method\": \"Sequencing of patient samples, BCL6 degradation assays in human BL cell lines, conditional FBXO11 knockout mouse B-cell lymphoma model\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional BCL6 degradation assay, in vivo mouse lymphoma model with haploinsufficiency, patient mutation validation, multiple orthogonal methods\",\n      \"pmids\": [\"34625792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO11 facilitates the assembly of the TRAF3-TBK1-IRF3 complex by mediating K63-linked ubiquitination of TRAF3 in a NEDD8-dependent manner, thereby promoting TBK1 and IRF3 phosphorylation and amplifying type I interferon signaling. The NEDD8-activating enzyme inhibitor MLN4921 blocked this FBXO11-TRAF3-IFN-I axis.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assay, phosphorylation assays (TBK1, IRF3), MLN4921 pharmacological inhibition, FBXO11 overexpression/knockdown with IFN reporter assays\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP complex assembly, ubiquitination assay with linkage specificity, pharmacological inhibition, single lab\",\n      \"pmids\": [\"36977592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDR1 phosphorylates β-catenin at Ser33/Ser37, facilitating its interaction with FBXO11. FBXO11 then mediates ubiquitylation and cytoplasmic degradation of β-catenin. Additionally, the NDR1-FBXO11 complex induces JNK2 ubiquitination, impeding β-catenin nuclear translocation. This dual mechanism suppresses EMT and prostate cancer metastasis.\",\n      \"method\": \"Immunoprecipitation, Western blotting, immunofluorescence, ubiquitylation assays, protein stability assays, nude mouse lung metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, in vivo metastasis model, multiple substrates identified, single lab\",\n      \"pmids\": [\"39309441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO11 mediates ubiquitin-dependent proteasomal degradation of BAHD1 and also promotes BCL6 ubiquitylation and degradation in macrophages. FBXO11 regulates C5aR1 expression at the mRNA level and dampens IL-1β secretion after NLRP3 activation through BCL6-dependent and BCL6-independent mechanisms in response to bacterial PVL toxin.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, FBXO11 genetic deletion, C5aR1 expression assays, IL-1β ELISA, ectopic C5aR1 rescue experiments\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO screen, genetic rescue experiments, cytokine assays; mechanism of C5aR1 mRNA regulation not fully resolved, single lab\",\n      \"pmids\": [\"36977592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO11 governs macrophage cell death and inflammation in response to Panton-Valentine leukocidin (PVL). Genetic deletion of FBXO11 reduced C5aR1 expression at the mRNA level, and ectopic C5aR1 expression or LPS priming in FBXO11-/- macrophages restored PVL toxicity. FBXO11 also dampens IL-1β secretion after NLRP3 activation via BCL6-dependent and BCL6-independent mechanisms.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, FBXO11 genetic deletion, C5aR1 rescue experiments, NLRP3 activation assays, IL-1β measurement\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus genetic KO with functional rescue, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"36977592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO11 deficiency in osteoblasts leads to Snail1 protein accumulation (reduced Snail1 ubiquitylation), suppression of osteogenic activity, and inhibition of bone matrix mineralization. Osteoblast-specific conditional FBXO11 knockout mice showed reduced bone growth and osteogenic activity without changes in osteoclast activity.\",\n      \"method\": \"Lentiviral FBXO11 knockdown and overexpression in MC3T3-E1 cells, osteoblast-specific conditional KO mouse models (Col1a1-ERT2 and Bglap2 promoters), ubiquitylation assay, osteogenic differentiation assays\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse model with defined substrate accumulation and cellular phenotype, ubiquitylation assay, two cKO lines, single lab\",\n      \"pmids\": [\"36863499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ERK3 interacts with Snail and enhances Snail protein stability by inhibiting the binding of FBXO11 to Snail, thereby preventing FBXO11-mediated Snail ubiquitylation and degradation. ERK3 could not directly phosphorylate Snail but acted by blocking FBXO11-Snail interaction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, protein stability assays, competitive binding assays, pancreatic cancer clinical sample analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP showing competitive displacement of FBXO11 from Snail, ubiquitylation assay, stability assay, single lab\",\n      \"pmids\": [\"38201533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO11 recognizes and promotes ubiquitin-mediated proteasomal degradation of ZEB1, a core inducer of EMT. Depletion of FBXO11 in lung cancer cells causes ZEB1 accumulation and increased invasion, while FBXO11 overexpression reduces ZEB1 and invasiveness. ZEB1 depletion suppresses the increased migration/invasion caused by FBXO11 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockdown/overexpression, rescue by ZEB1 depletion, xenograft tumor assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, epistasis rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"39409891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO11 directly interacts with EBNA3C (an EBV latent antigen) through EBNA3C residues 50-100, and the presence of both EBNA3C and FBXO11 significantly enhances BCL6 ubiquitylation and degradation via the SCF-FBXO11 complex. FBXO11 knockdown suppresses EBV-driven lymphoblastoid cell line transformation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, FBXO11 knockdown, LCL transformation assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitylation assay, functional transformation assay, single lab\",\n      \"pmids\": [\"38864622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBXO11 interacts with and catalyzes K63-linked ubiquitylation of LONP1 in the cytosol, promoting LONP1 entry into mitochondria. FBXO11 or LONP1 depletion reduces mitochondrial respiration through impaired LONP1 chaperone activity to assemble electron transport chain Complex IV, imparting myeloid-biased stem cell properties in HSPCs. In a xenograft model, FBXO11 depletion cooperated with AML1-ETO and KRAS-G12D to generate transplantable AML.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assay, mitochondrial fractionation, electron transport chain complex IV assembly assay, CD34+ HSPC culture, xenograft transplantation model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP, K63 ubiquitination assay, mitochondrial import validation, functional in vivo xenograft, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41289019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SCF-FBXO11 facilitates ubiquitylation of NPM1, and FBXO11 deletion results in reorganization of NPM1 and de-repression of alternative splicing. FBXO11 and NPM1 form a network regulating spliceosome and ribosome components. Rare FBXO11 mutations map to an intrinsically disordered N-terminal region responsible for NPM1 binding. MYC was found to occupy the FBXO11 promoter and its eviction by TLR2 activation explains reduced FBXO11 expression in MDS.\",\n      \"method\": \"Multi-omics (proteomics, transcriptomics), label-free quantitative proteomics, co-immunoprecipitation, ubiquitylation assays, Fbxo11 knockout mouse MDS models, ChIP assay for MYC at FBXO11 promoter\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus Co-IP plus ubiquitylation assay and mouse KO model, multiple orthogonal methods, single lab, preprint not yet replicated\",\n      \"pmids\": [\"41542766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO11 promotes K48-linked ubiquitylation and proteasomal degradation of KIF2C. Conditional FBXO11 expression suppresses ovarian cancer cell proliferation, migration, invasion, and xenograft tumor growth; KIF2C knockdown reverses tumor-promoting effects of FBXO11 downregulation. ZNF217 transcriptionally represses FBXO11 expression.\",\n      \"method\": \"Tet-on inducible FBXO11 expression, ubiquitylation assay (K48-linkage specific), KIF2C knockdown rescue, xenograft and peritoneal metastasis models, ChIP for ZNF217 at FBXO11 promoter\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — K48 ubiquitylation assay, epistasis rescue, in vivo models, transcriptional regulation validation, single lab\",\n      \"pmids\": [\"40447129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXO11 mediates ubiquitin-dependent proteasomal degradation of Fosl2. FBXO11 overexpression in podocytes reduced Fosl2 protein via ubiquitin-dependent degradation, maintained mitochondrial function, and prevented podocyte apoptosis in adriamycin-induced nephropathy. Fosl2 overexpression abolished protective effects of FBXO11, and the mitochondrial fission inhibitor mdivi-1 reversed effects of the FBXO11/Fosl2 axis.\",\n      \"method\": \"Lentiviral FBXO11 overexpression, ubiquitylation assays, Fosl2 rescue experiments, mitochondrial function assays, mdivi-1 pharmacological inhibition, in vivo mouse ADR nephropathy model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ubiquitylation assay, epistasis rescue, in vivo model, single lab\",\n      \"pmids\": [\"39581215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A mutation in Fbxo11 underlies the Jeff mouse mutant that develops chronic suppurative otitis media. Fbxo11 is expressed in epithelial cells of the middle ear from late embryonic stages through postnatal day 13. Homozygous Jeff mutants and a hypomorphic Mutt allele show cleft palate and facial clefting, establishing FBXO11 as important in epithelial development of the middle ear and palate.\",\n      \"method\": \"Positional cloning, mutant mouse characterization, immunohistochemistry/in situ hybridization for tissue expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning with allelic series, tissue expression localization with functional phenotype, but mechanism not biochemically defined beyond F-box membership\",\n      \"pmids\": [\"17035249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In melanocytes, FBXO11 knockdown causes ER swelling and retention of tyrosinase co-localized with calreticulin in the ER, preventing its export. Tyrosinase protein levels were markedly elevated following FBXO11 siRNA, suggesting FBXO11 is required for proper ER function and tyrosinase export from the ER in melanocytes.\",\n      \"method\": \"siRNA knockdown, electron microscopy (ER morphology), confocal co-localization of tyrosinase and calreticulin, Western blot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, morphological and co-localization data without direct biochemical mechanism linking FBXO11 to tyrosinase export\",\n      \"pmids\": [\"20514423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of FBXO11 in human iPSC-derived neurons causes disrupted transcriptional networks related to neuronal differentiation, migration, and cell signaling, impaired neuronal migration, and abnormal proliferation/differentiation balance. In Drosophila, fbxo11 knockdown impairs dendritic development and behavior. Proteasome-activating substances (including verapamil) alleviated these FBXO11-deficiency phenotypes in both human neurons and flies.\",\n      \"method\": \"CRISPR-Cas9 FBXO11-deficient human iPSC-derived neurons, Drosophila tissue-specific knockdown, RNA sequencing, neuronal migration assay, pharmacological proteasome activation\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — iPSC neuronal model plus Drosophila model, transcriptomics plus functional phenotypes, pharmacological rescue, two species convergence, single lab\",\n      \"pmids\": [\"40114442\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO11 is the substrate-recognition subunit of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex that targets multiple substrates — including BCL6, SNAIL family members, CDT2, CIITA, BAHD1, p53 (via neddylation), BLMP-1/BLIMP-1, NPM1, LONP1, ZEB1, KIF2C, hnRNPA2B1, Fosl2, and β-catenin — for ubiquitylation and proteasomal degradation, thereby regulating germinal center reactions, epithelial-mesenchymal transition, erythropoiesis, immune antigen presentation, type I interferon signaling, cell-cycle exit, TGF-β pathway output, and mitochondrial function; additionally, through its arginine methyltransferase (PRMT9) domain it can catalyze symmetric dimethylarginine formation, and it promotes p53 neddylation to suppress p53 transcriptional activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXO11 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase that selects diverse regulatory proteins for ubiquitylation and proteasomal degradation, thereby controlling germinal-center B-cell biology, epithelial-mesenchymal transition (EMT), cell-cycle exit, hematopoietic differentiation, and immune output [#0, #4, #9]. Its best-established target is the transcriptional repressor BCL6: SCF-FBXO11 directly ubiquitylates BCL6 for degradation, tumor-derived mutants fail to do so, and germinal-center-specific knockout elevates BCL6 and expands GC B cells, defining FBXO11 as a haploinsufficient tumor suppressor in B-cell lymphoma that cooperates with MYC [#0, #7, #17]. FBXO11 enforces an anti-EMT program by degrading SNAIL family members (SNAI1, SNAI2/Slug, Scratch) and ZEB1, with SNAIL recognition gated by PKD1 phosphorylation; loss causes SNAIL/ZEB1 accumulation, invasion, and metastasis [#1, #8, #24]. The ligase also degrades the CRL4 receptor CDT2 to time cell-cycle exit and stabilize p21/Set8 for TGF-\\u03b2 control [#4, #5], the H3K27me3 reader BAHD1 to permit GATA1-dependent erythroid maturation [#9], the MHC-II master regulator CIITA to dampen antigen presentation [#10], and additional substrates including hnRNPA2B1, NPM1, KIF2C, Fosl2, and \\u03b2-catenin [#11, #27, #28, #29, #19]. Beyond canonical K48-linked degradation, FBXO11 acts as an adaptor promoting NEDD8 conjugation of p53 to repress its transcriptional activity [#2] and catalyzes K63-linked ubiquitylation of TRAF3 and of cytosolic LONP1, the latter promoting LONP1 mitochondrial import and electron-transport-chain Complex IV assembly [#18, #26]. Mutation of Fbxo11 in mice (the Jeff allele) causes epithelial defects of the middle ear and palate linked to elevated phospho-Smad2 and reduced p53 [#30, #15, #16], and FBXO11 loss disrupts neuronal differentiation and migration in iPSC and Drosophila models [#32].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first biochemical activities of FBXO11: that beyond SCF membership it acts as an adaptor promoting p53 neddylation to repress p53, and that it carries an arginine methyltransferase domain (PRMT9) with in vitro activity.\",\n      \"evidence\": \"In vitro neddylation and methyltransferase assays, p53 reporter assays, mutagenesis of p53 lysines, mass spectrometry of methylation products\",\n      \"pmids\": [\"17098746\", \"16487488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methyltransferase activity not validated by domain mutagenesis or in cells\", \"Physiological relevance of p53 neddylation versus FBXO11's ligase function unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked FBXO11 to mammalian development via the Jeff mouse, showing it is required for epithelial development of the middle ear and palate.\",\n      \"evidence\": \"Positional cloning, mutant mouse characterization, tissue expression by IHC/in situ hybridization\",\n      \"pmids\": [\"17035249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular substrate underlying the epithelial phenotype not defined\", \"Mechanism beyond F-box membership not biochemically established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected the Jeff epithelial phenotype to dysregulated TGF-\\u03b2 signaling, showing Fbxo11 limits phospho-Smad2 nuclear accumulation indirectly through p53 stabilization rather than direct Smad2 binding.\",\n      \"evidence\": \"Immunohistochemistry, negative tissue Co-IP, Jeff/Smad2 double-heterozygote genetic epistasis, p53 protein measurement\",\n      \"pmids\": [\"19580641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct FBXO11-Smad2 interaction\", \"Mechanism by which p53 limits pSmad2 unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined FBXO11's flagship function: SCF-FBXO11 directly ubiquitylates BCL6 for degradation, and tumor mutations abolish this, establishing FBXO11 as a tumor suppressor in DLBCL.\",\n      \"evidence\": \"Co-IP, ubiquitylation assays, reconstitution in FBXO11-deleted DLBCL lines, mutagenesis of disease alleles, xenograft suppression\",\n      \"pmids\": [\"22113614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron/recognition motif on BCL6 not mapped\", \"Upstream signals controlling BCL6 recognition not defined here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that FBXO11 degrades the CRL4 receptor CDT2 through an atypical phospho-inhibited degron, coupling FBXO11 to cell-cycle exit timing and TGF-\\u03b2 output via p21/Set8 stabilization.\",\n      \"evidence\": \"AP-MS, reciprocal Co-IP, ubiquitylation assays, phospho-mutant analysis, cycloheximide chase, C. elegans genetics, TGF-\\u03b2 and migration assays\",\n      \"pmids\": [\"23478441\", \"23478445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for the inhibitory CDT2 phosphorylation only partially defined\", \"Quantitative contribution of CDT2 versus other substrates to TGF-\\u03b2 output unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed FBXO11 enforces an anti-EMT program by degrading phospho-SNAIL downstream of PKD1, and confirmed conserved DRE-1/FBXO11 degradation of the BLIMP-1 transcription factor controlling developmental timing.\",\n      \"evidence\": \"Genome-wide siRNA screen, Co-IP, ubiquitylation assays, phospho-degron mutagenesis, breast cancer metastasis models; C. elegans epistasis and protein stability assays\",\n      \"pmids\": [\"25203322\", \"24613396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all SNAIL family recognition requires phosphorylation unresolved at this stage\", \"Tissue specificity of SNAIL versus BLIMP-1 targeting not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Generalized SNAIL-family control by FBXO11, showing phosphorylation-independent degradation of SNAI1/SNAI2/Scratch in vivo, and added an indirect role in destabilizing HIF-1\\u03b1 mRNA.\",\n      \"evidence\": \"Co-IP, ubiquitylation assays, FBXO11 knockout mice with epidermal Snail accumulation, C. elegans epistasis; siRNA, mRNA stability assay and F-box deletion mutant for HIF-1\\u03b1\",\n      \"pmids\": [\"25827072\", \"26187670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of phosphorylation-dependent versus -independent SNAIL recognition\", \"Identity of the FBXO11 substrate controlling HIF-1\\u03b1 mRNA stability unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Strengthened the FBXO11-p53 axis by demonstrating direct physical interaction in vivo abolished by the Jeff mutation, placing p53 epistatically upstream of TGF-\\u03b2 pathway control in epithelial development.\",\n      \"evidence\": \"Tissue Co-IP from embryonic lung, p53 KO and Jeff/p53 double-heterozygote genetic epistasis, pSMAD2 immunofluorescence\",\n      \"pmids\": [\"26471094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FBXO11 stabilizes or modifies p53 in this context not biochemically resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided physiological proof that FBXO11 controls BCL6 in vivo during the germinal-center reaction, with loss driving lymphoproliferation.\",\n      \"evidence\": \"GC-specific conditional FBXO11 knockout mice, flow cytometry, immunofluorescence, BCL6 stability assays\",\n      \"pmids\": [\"27166359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BCL6 is the sole relevant substrate in GC B cells not excluded\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Attempted a structural explanation for substrate selection, showing the UBR-box of FBXO11 lacks an amino-acid binding pocket and so does not read N-terminal degrons.\",\n      \"evidence\": \"X-ray crystallography of the UBR-box (domain-swapped dimer)\",\n      \"pmids\": [\"28691247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence inferred without mutagenesis\", \"Dimer assignment later contradicted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded FBXO11 substrate biology to chromatin and hematopoiesis, identifying BAHD1 as a target whose degradation permits erythroid maturation, and quantifying FBXO11 mutation/haploinsufficiency in Burkitt lymphoma cooperating with MYC.\",\n      \"evidence\": \"Knockout erythroblasts, ChIP-seq, ubiquitylation assays, BAHD1/PRC2 depletion rescue; patient sequencing, BCL6 degradation assays, conditional KO/MYC lymphoma model\",\n      \"pmids\": [\"33156908\", \"34625792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition determinants on BAHD1 not mapped\", \"How a single ligase coordinates lineage-specific substrate choice unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked FBXO11 to adaptive immunity by establishing CIITA as a degradation substrate, so FBXO11 loss elevates MHC class II expression.\",\n      \"evidence\": \"Unbiased Co-IP/MS, cycloheximide chase, ubiquitylation assays, FBXO11 KO cells, MHC-II flow cytometry (two independent papers)\",\n      \"pmids\": [\"36179686\", \"37279268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CIITA degron not defined\", \"Interplay with FBXO11's tumor-suppressor and antigen-presentation roles not integrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended FBXO11 into innate immunity, metabolism, and inflammation, showing K63-ubiquitylation of TRAF3 to amplify type I IFN, degradation of hnRNPA2B1 (antagonized by CAND1), and BCL6/BAHD1-dependent control of macrophage responses to bacterial toxins.\",\n      \"evidence\": \"Co-IP, K63-ubiquitination assays, IFN reporters, MLN4921 inhibition; MS, GST pull-down, in vivo tumor models; genome-wide CRISPR screen, genetic KO, C5aR1 and IL-1\\u03b2 assays\",\n      \"pmids\": [\"36977592\", \"37837399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NEDD8-dependence of TRAF3 K63 ubiquitylation mechanistically thin\", \"Mechanism of C5aR1 mRNA regulation unresolved\", \"Single labs for each axis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the EMT/migration program and tissue contexts, adding ZEB1, \\u03b2-catenin (via NDR1 phosphorylation), KIF2C, Fosl2, and Snail1 in bone as degradation substrates, and showing regulatory inputs from ERK3, ZNF217, and EBNA3C.\",\n      \"evidence\": \"Co-IP, K48-linked ubiquitylation assays, epistasis rescue, xenograft/metastasis and conditional KO mouse models, competitive binding assays, ChIP for transcriptional repressors\",\n      \"pmids\": [\"39409891\", \"39309441\", \"40447129\", \"39581215\", \"36863499\", \"38201533\", \"38864622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most axes from single labs\", \"Substrate-recognition motifs largely unmapped\", \"Relative physiological hierarchy of the many substrates unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-degradative mitochondrial role: FBXO11 K63-ubiquitylates cytosolic LONP1 to promote its mitochondrial import and Complex IV assembly, with loss imparting myeloid-biased stem cell properties and cooperating in AML; a re-determined UBR-box structure corrected the prior dimer to a monomer.\",\n      \"evidence\": \"Co-IP, K63-ubiquitination assays, mitochondrial fractionation, Complex IV assembly assays, HSPC culture and xenograft; 1.5 \\u00c5 crystallography and N-degron binding assay; iPSC-neuron and Drosophila models with proteasome-activator rescue\",\n      \"pmids\": [\"41289019\", \"40099808\", \"40114442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K63 ubiquitylation drives LONP1 import mechanistically unclear\", \"Conflicting UBR-box structural models\", \"Neuronal substrate(s) not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected FBXO11 to RNA processing and myeloid malignancy, showing SCF-FBXO11 ubiquitylates NPM1 to restrain alternative splicing, with disease mutations clustering in a disordered NPM1-binding N-terminus and MYC/TLR2 controlling FBXO11 expression in MDS.\",\n      \"evidence\": \"Multi-omics proteomics/transcriptomics, Co-IP, ubiquitylation assays, Fbxo11 KO mouse MDS models, ChIP for MYC at the FBXO11 promoter\",\n      \"pmids\": [\"41542766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NPM1 ubiquitylation is degradative or regulatory not fully resolved\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single F-box protein achieves selective recognition of such a broad substrate set, and how its degradative versus non-degradative (neddylation, K63-ubiquitylation, methyltransferase) activities are partitioned, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying degron/recognition code mapped across substrates\", \"Physiological relevance of the PRMT9 methyltransferase activity unestablished\", \"Structural model of the substrate-binding region disputed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 8, 9, 10, 24, 28]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 5, 18, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19, 26]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 10, 18, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 30, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 17, 24, 26]}\n    ],\n    \"complexes\": [\"SCF (SKP1-CUL1-FBXO11) E3 ubiquitin ligase\"],\n    \"partners\": [\"BCL6\", \"SNAI1\", \"CDT2\", \"CIITA\", \"BAHD1\", \"ZEB1\", \"LONP1\", \"NPM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}