id: Q96EF6 gene_symbol: FBXO17 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO17 (also FBG4, FBXO26) is a cytoplasmic F-box protein of the FBA/FBG (F-box-associated, "sugar-recognizing") lectin subfamily that also includes FBXO2, FBXO6, FBXO27 and FBXO44. It is built from an N-terminal F-box domain, which binds the adaptor SKP1 and thereby docks the protein into a canonical SCF (SKP1-CUL1-F-box, with RBX1) E3 ubiquitin-protein ligase complex, and a C-terminal FBA/G domain that functions as a carbohydrate-binding (lectin) module. Within the SCF complex FBXO17 acts as the interchangeable substrate-recognition subunit: it has no intrinsic catalytic activity, and ubiquitin transfer is carried out by an E2 enzyme recruited through the RBX1 RING subunit. The FBA/G domain uses a conserved hydrophobic pocket (the Ser-Trp pair around residues 257-258) to recognize glycans on target glycoproteins. Unlike the high-mannose-binding members FBXO2 and FBXO6, FBXO17 does not bind high-mannose glycans; instead it binds complex-type N-glycans on glycoproteins and sulfated glycans (e.g. heparin), placing it in the glycoprotein quality-control / glycoprotein catabolism arm of the ubiquitin-proteasome system. FBXO17 is expressed across several tissues with notable expression in liver, kidney, heart, skeletal muscle and brain. By selecting substrates and delivering them to the SCF machinery it contributes to SCF-dependent, proteasome-mediated protein turnover. Beyond a family-level lectin role, the best-validated FBXO17 substrate is a protein rather than a glycan: in lung epithelium SCF(FBXO17) binds and polyubiquitinates the kinase GSK3-beta (GSK3B), driving its proteasomal degradation and thereby dampening GSK3-beta-dependent pro-inflammatory cytokine production (IL-6, CXCL1). FBXO17 also has a documented non-canonical, SCF-independent mode in antiviral innate immunity: through its F-box-associated region (not its F-box) it binds the transcription factor IRF3 and recruits protein phosphatase 2A (PP2A) to promote IRF3 dephosphorylation, negatively regulating type I interferon signaling. existing_annotations: - term: id: GO:0036503 label: ERAD pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic (PAN-GO/PANTHER) transfer of an ERAD role from the FBA lectin-ligase family. action: MARK_AS_OVER_ANNOTATED reason: >- ERAD/GERAD is the role of the high-mannose-binding members of this family (FBXO2, FBXO6), which recognize the high-mannose signal on retrotranslocated misfolded ER glycoproteins. The experimental characterization of FBXO17 shows it does NOT bind high-mannose glycans and instead binds complex-type and sulfated glycans, so the authors explicitly conclude only FBXO2 and FBXO6 are likely to function in GERAD. The more general glycoprotein catabolic process / SCF-dependent catabolism terms better capture FBXO17's role; the specific ERAD assignment is a family-level over-propagation. supported_by: - reference_id: PMID:18203720 supporting_text: Our results lead us to conclude that only some members of the FBA family (FBXO2 and FBXO6) could function in GERAD by recognizing the signature high mannose glycan moiety present on retrotranslocated ER proteins. - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: Does not bind high-mannose glycoproteins. - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of cytoplasmic localization, consistent with FBXO17 being a cytoplasmic SCF substrate-recognition subunit. action: ACCEPT reason: >- FBA proteins are described as cytoplasmic F-box proteins; the localization is consistent with cytosolic SCF assembly. Correct but generic relative to the SCF complex annotation. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0006516 label: glycoprotein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic transfer of a glycoprotein-catabolism role; FBXO17 recognizes glycans on glycoprotein substrates and feeds them to the SCF/proteasome system. action: ACCEPT reason: >- Captures the core biological role of the FBA family in glycoprotein quality control. FBXO17 binds complex and sulfated glycoproteins via its FBA/G domain and is a substrate receptor that targets glycoproteins for degradation, consistent with this term. supported_by: - reference_id: PMID:18203720 supporting_text: These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control. - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: Phylogenetic assignment of SCF complex membership, the defining cellular context for FBXO17 as an F-box protein. action: ACCEPT reason: >- Core localization/context. Directly demonstrated experimentally for FBXO17 (co-precipitates SKP1, CUL1 and RBX1) and supported by ComplexPortal (CPX-7927, SCF E3 ubiquitin ligase complex, FBXO17 variant). supported_by: - reference_id: PMID:18203720 supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF complexes containing FBXO17. action: ACCEPT reason: >- Core biological process. As an F-box substrate receptor, FBXO17 directs target glycoproteins into SCF-dependent, proteasome-mediated degradation. supported_by: - reference_id: PMID:18203720 supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein. - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: contributes_to review: summary: Phylogenetic assignment of ubiquitin ligase activity with the contributes_to qualifier, reflecting that the F-box subunit contributes substrate specificity to the catalytically active SCF complex. action: KEEP_AS_NON_CORE reason: >- F-box proteins have no intrinsic catalytic activity; ubiquitin transfer is performed by the E2 enzyme recruited through the RBX1 RING subunit. The contributes_to qualifier correctly attributes the holo-complex activity to FBXO17 as a substrate receptor, but FBXO17 itself is not the catalytic entity, so this is retained as non-core rather than as a core molecular function (the lectin/carbohydrate-binding activity is the core MF). supported_by: - reference_id: PMID:18203720 supporting_text: As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: ARBA machine-learning electronic assignment of cytoplasmic localization, redundant with the IBA cytoplasm annotation. action: ACCEPT reason: Consistent with FBXO17 being a cytoplasmic F-box/SCF substrate receptor; redundant with the IBA cytoplasm annotation. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21145461 qualifier: enables review: summary: IntAct interaction with CUL1 (Q13616) from a quantitative proteomics survey of cullin-RING ligase networks; CUL1 is the scaffold of the SCF complex. action: KEEP_AS_NON_CORE reason: >- Records the functionally meaningful FBXO17-CUL1 interaction (SCF scaffold), but bare protein binding is uninformative per curation guidelines; the SCF membership is captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: IntAct interaction with SKP1 (P63208) from a proteome-scale interactome map; SKP1 is the F-box adaptor that links FBXO17 into the SCF complex. action: KEEP_AS_NON_CORE reason: >- Records the core SKP1 interaction, but bare protein binding is uninformative; the SCF membership is captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: IntAct interaction with SKP1 (P63208) captured in a Polycomb complexome AP-MS map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from a large-scale interactome (BioPlex). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the SKP1/CUL1 SCF interactions but bare protein binding is uninformative; captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome reference map capturing numerous FBXO17 partners (SKP1 plus many candidate substrates/Y2H hits such as ADAMTSL4, KRT75, RUNX1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: >- High-throughput binary interactome; many partners may be candidate glycoprotein substrates but bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Cell-specific interactome capturing FBXO17 partners SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-map study capturing FBXO17 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal (NAS) assignment of SCF complex membership, consistent with the FBXO17-variant SCF complex (CPX-7927). action: ACCEPT reason: >- Core context; FBXO17 is the F-box substrate-recognition subunit of an SCF complex, supported experimentally and by ComplexPortal CPX-7927. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'ComplexPortal; CPX-7927; SCF E3 ubiquitin ligase complex, FBXO17 variant.' - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal (NAS) assignment of SCF-dependent proteasomal degradation, the generic process executed by SCF complexes. action: ACCEPT reason: >- Core biological process for an F-box substrate receptor; SCF complexes poly-ubiquitinate substrates to target them for proteasomal degradation. supported_by: - reference_id: PMID:34445249 supporting_text: The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome curation of cytosolic localization within the CRL1/SCF neddylation pathway. Consistent with cytoplasmic SCF assembly. action: ACCEPT reason: Correct localization; cytosol is the compartment of SCF assembly/neddylation. Redundant with the cytoplasm annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome curation of cytosolic localization (CRL1 neddylation reaction). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome curation of cytosolic localization (CAND1 binding to cytosolic CRL ligases). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome curation of cytosolic localization (COMMD displacement of CAND1 from cytosolic CRL ligases). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation of cytosolic CRL ligases). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate, antigen processing/proteasome pathway). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub complex). Redundant cytosol annotation. action: ACCEPT reason: Correct localization; redundant with other cytoplasm/cytosol annotations. supported_by: - reference_id: PMID:18203720 supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins - term: id: GO:0005515 label: protein binding evidence_type: IDA original_reference_id: PMID:18203720 qualifier: enables review: summary: Direct experimental demonstration that FBXO17 binds SCF components (SKP1, CUL1) by co-immunoprecipitation. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: >- Records the experimentally demonstrated FBXO17-SCF interaction, but bare protein binding is uninformative; SCF membership is captured by GO:0019005. supported_by: - reference_id: PMID:18203720 supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18203720 qualifier: enables review: summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from the FBXO17 characterization study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the core SKP1/CUL1 SCF interactions, but bare protein binding is uninformative; captured by GO:0019005. supported_by: - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:18203720 qualifier: part_of review: summary: Direct experimental evidence that FBXO17 assembles into an SCF complex (co-precipitation of SKP1, CUL1 and RBX1; mutagenesis of the glycan-binding pocket). Core cellular context. action: ACCEPT reason: >- Core, experimentally demonstrated localization/context. FBXO17 binds SKP1 directly via its F-box domain and incorporates into a full SCF complex. supported_by: - reference_id: PMID:18203720 supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: Interacts with SKP1 and CUL1. {ECO:0000269|PubMed:18203720}. - term: id: GO:0030246 label: carbohydrate binding evidence_type: IDA original_reference_id: PMID:18203720 qualifier: enables review: summary: >- Proposed annotation for FBXO17's core lectin molecular function, which is not currently in GOA. The FBA/G domain directly binds glycans (complex-type glycoproteins and sulfated glycans such as heparin) via a conserved hydrophobic pocket; FBXO17 does not bind high-mannose glycans. action: NEW reason: >- The defining molecular function of FBXO17 as a sugar-recognizing F-box protein is carbohydrate binding, demonstrated experimentally by glycan arrays and glycoprotein pulldowns (heparin, chondroitin sulfate, lactoferrin), yet there is no corresponding molecular-function annotation in the existing GOA set. Adding GO:0030246 captures this lectin activity. supported_by: - reference_id: PMID:18203720 supporting_text: FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans. - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:18203720 title: Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. findings: - statement: >- FBXO17 is a member of the FBA lectin family of F-box proteins; it does NOT bind high-mannose glycans but binds complex-type glycoproteins (e.g. lactoferrin) and sulfated glycans (heparin strongly, chondroitin sulfate weakly) via a conserved hydrophobic pocket in the FBA/G domain, and it assembles into a canonical SCF complex with SKP1, CUL1 and RBX1. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Full text available (PMC2442310). Definitive experimental characterization of human FBXO17 substrate binding and SCF complex formation; establishes that FBXO17 binds complex and sulfated glycans, NOT high-mannose glycans, and that FBA F-box proteins have no intrinsic catalytic activity. Source of the SCF complex (IDA) and substrate-binding annotations. - id: PMID:21145461 title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Quantitative CRL-network proteomics; source of the FBXO17-CUL1 (Q13616) interaction. Abstract-only in cache. - id: PMID:25416956 title: A proteome-scale map of the human interactome network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of the FBXO17-SKP1 (P63208) bare protein binding annotation. - id: PMID:27705803 title: A High-Density Map for Navigating the Human Polycomb Complexome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: AP-MS complexome map; source of an FBXO17-SKP1 (P63208) bare protein binding annotation. - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: BioPlex-type interactome; source of FBXO17-SKP1/CUL1 bare protein binding annotations. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of many FBXO17 bare protein binding annotations (SKP1 plus diverse Y2H hits). - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Cell-specific interactome; source of FBXO17-SKP1/CUL1 bare protein binding annotations. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: SCF (SKP1-CUL1-F-box) complexes are E3 ubiquitin ligases that modify substrates with poly-ubiquitin chains for proteasomal degradation, with the variable F-box protein conferring substrate specificity. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review of SCF biology; basis for the ComplexPortal NAS SCF complex and SCF-dependent catabolism annotations. Abstract-only in cache. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Multimodal cell-map study; source of FBXO17-SKP1/CUL1 bare protein binding annotations. - id: Reactome:R-HSA-8952618 title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952620 title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956040 title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956200 title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-983140 title: Transfer of Ub from E2 to substrate and release of E2 findings: [] - id: Reactome:R-HSA-983147 title: Release of E3 from polyubiquitinated substrate findings: [] - id: Reactome:R-HSA-983156 title: Polyubiquitination of substrate findings: [] - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] - id: file:human/FBXO17/FBXO17-deep-research-falcon.md title: Falcon deep research report for human FBXO17 findings: - statement: FBXO17 (also known as FBG4) is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase (SCF^FBXO17), with the ~40-aa F-box domain binding SKP1 to link the substrate-recognition module to the CUL1-RBX1 catalytic core. supporting_text: SCF E3 ubiquitin ligases use F-box proteins as substrate adaptors**; the ~40-aa **F-box domain** binds **SKP1**, linking the variable substrate-recognition module to the CUL1-RBX1 catalytic core. - statement: The best-validated FBXO17 substrate is the protein kinase GSK3-beta; SCF^FBXO17 associates with GSK3-beta, promotes its polyubiquitination, and drives proteasome-dependent turnover in lung epithelial cells. supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β. - statement: By degrading GSK3-beta, FBXO17 dampens GSK3-beta-dependent pro-inflammatory cytokine production; FBXO17 overexpression reduces TNF-alpha/LPS-induced IL-6 and KC/CXCL1, partially rescued by GSK3-beta re-expression. supporting_text: FBXO17 overexpression reduces **TNFα- and LPS-induced IL-6 and KC/CXCL1**. - statement: FBXO17 has a non-canonical, SCF-independent mode that does not require the F-box domain - it binds IRF3 and recruits PP2A to promote IRF3 dephosphorylation, negatively regulating type I interferon signaling. supporting_text: FBXO17 can regulate signaling **independently of its canonical SCF function** by recruiting **PP2A** to the transcription factor **IRF3** to promote IRF3 dephosphorylation and suppress type I interferon signaling. This is explicitly described as not requiring the F-box domain and using the "F-box associated region." - statement: FBXO17 and its demonstrated substrate GSK3-beta colocalize in the cytoplasm, consistent with a cytoplasmic site of action. supporting_text: Direct experimental localization in the mechanistic SCF substrate study indicates **cytoplasmic colocalization** of FBXO17 with its demonstrated substrate GSK3β. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis anchored on primary mechanistic papers (Suber et al. J Biol Chem 2017 for SCF^FBXO17-GSK3beta degradation/inflammation; Peng et al. J Immunol 2017 for the non-canonical IRF3/PP2A scaffold) and the Skaar 2013 SCF review. These establish a validated PROTEIN substrate (GSK3beta) and a non-canonical signaling-scaffold role, both absent from current GOA; cross-checked against UniProt (which records the complex/sulfated-glycan lectin activity). Cancer association studies are model-dependent and treated as leads only. core_functions: - description: >- Carbohydrate-binding (lectin) substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex. The C-terminal FBA/G domain binds glycans on glycoprotein substrates (complex-type N-glycans and sulfated glycans such as heparin, but not high-mannose glycans) via a conserved hydrophobic pocket, selecting glycosylated targets for the SCF machinery. molecular_function: id: GO:0030246 label: carbohydrate binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:18203720 supporting_text: FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans. - reference_id: file:human/FBXO17/FBXO17-uniprot.txt supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans. directly_involved_in: - id: GO:0006516 label: glycoprotein catabolic process - description: >- F-box substrate receptor that links selected glycoprotein substrates into a SKP1-CUL1-RBX1 SCF complex (binding SKP1 via its F-box domain), contributing substrate specificity to SCF-dependent, proteasome-mediated protein degradation. FBXO17 has no intrinsic catalytic activity; ubiquitin transfer is performed by the SCF-associated E2/RBX1 module. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:18203720 supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) - reference_id: file:human/FBXO17/FBXO17-deep-research-falcon.md supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: >- Beyond glycoprotein recognition, SCF(FBXO17) targets at least one validated protein substrate, the kinase GSK3-beta (GSK3B): FBXO17 binds GSK3-beta and promotes its polyubiquitination and proteasomal degradation in lung epithelium, thereby restraining GSK3-beta-dependent pro-inflammatory cytokine production (IL-6, CXCL1). This indicates FBXO17's substrate scope is not limited to its lectin/glycan-recognition activity. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO17/FBXO17-deep-research-falcon.md supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: What are the physiological glycoprotein substrates that FBXO17 selects for SCF-dependent ubiquitination, and through which complex-type or sulfated glycan determinants are they recognized? - question: In which subcellular/secretory context do cytoplasmic FBXO17 and its Golgi-processed (sulfated/complex) glycoprotein substrates meet, given that sulfation and complex-glycan maturation occur in the Golgi? - question: Is recognition of the validated protein substrate GSK3-beta glycan-dependent (requiring the FBA/G-domain pocket and the 151-200 region) or glycan-independent, and how broad is FBXO17's protein-substrate repertoire relative to its glycoprotein substrates? - question: How is FBXO17's non-canonical, F-box-independent IRF3/PP2A scaffolding function partitioned from its canonical SCF substrate-receptor activity, and which domains/post-translational signals switch FBXO17 between these modes? suggested_experiments: - description: Identify endogenous FBXO17 substrates by comparing the ubiquitinome/proteome of FBXO17-knockout versus wild-type cells, with parallel glycoproteomics to test enrichment for complex-type and sulfated glycoproteins, and to confirm GSK3-beta as an endogenous substrate. - description: Reconstitute SCF(FBXO17) in vitro with SKP1, CUL1, RBX1 and an E2 to test ubiquitination of candidate complex/sulfated glycoproteins and of GSK3-beta, using the FBA/G-domain pocket mutant (S257A/W258A) and the 151-200 deletion as substrate-recognition-deficient controls to dissect glycan-dependent versus protein-dependent recognition. - description: Dissect the non-canonical IRF3/PP2A scaffold mode by testing whether F-box-deletion and FBA-region mutants of FBXO17 still recruit PP2A to IRF3 and suppress type I interferon reporter activity, separating it from SCF-dependent ubiquitination.