id: Q8NCQ5 gene_symbol: FBXO15 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO15 (F-box only protein 15, FBX15) is a 510-amino-acid F-box protein of the "FBXO/other" class that serves as the substrate-recognition component of an SCF (SKP1-CUL1-F-box protein, also called CRL1) cullin-RING E3 ubiquitin ligase complex. Like other F-box proteins, it docks onto the SCF core through its F-box domain (residues 77-117), which binds the adaptor SKP1; SKP1 in turn bridges to the scaffold CUL1 and the catalytic RING subunit RBX1 that recruits the ubiquitin-charged E2 enzyme. FBXO15 therefore does not itself possess catalytic ubiquitin-transfer activity; it confers substrate specificity on the ligase, positioning a bound target protein for poly-ubiquitination and subsequent proteasomal degradation. Several substrates have been experimentally reported, often recruited through modification-dependent degrons: FBXO15 uniquely associates with and degrades cardiolipin synthase 1 (CLS1) in a PINK1-linked module (phospho-Thr219-dependent recognition; CLS1 Lys174 ubiquitination), an ER/cytosol-associated activity that limits mitochondrial cardiolipin and has been implicated in pneumonia/lung-injury models; it cooperates with the E2 CDC34/UBE2R1 to ubiquitinate the drug-efflux transporter P-glycoprotein (ABCB1/MDR1), so that FBXO15 loss raises P-gp levels and multidrug resistance; and in breast cancer it promotes ubiquitin-dependent degradation of the stemness/signaling factors SOX2 and STAT3, dampening EGFR/ERK/STAT3 signaling and acting as a tumor suppressor (higher FBXO15 expression correlating with better survival). In mouse embryonic stem cells the ortholog recognizes an acetyldegron on KBP (acetyl-Lys501) and is preferentially expressed in undifferentiated cells, linking it to pluripotency biology. FBXO15 is expressed broadly with enhancement in testis and fallopian tube. Two splice isoforms are produced, the shorter of which lacks the N-terminal region preceding the F-box domain. Despite these reports, most substrate-pathway links rest on individual studies and the integrated physiological role of human FBXO15 remains only partly defined. alternative_products: - name: '1' id: Q8NCQ5-1 - name: '2' id: Q8NCQ5-2 sequence_note: VSP_043033 existing_annotations: - 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 that FBXO15 is part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the core localization/assembly for an F-box substrate receptor. action: ACCEPT reason: Core localization; FBXO15 is an F-box protein that, per UniProt, directly interacts with SKP1 and CUL1 and is the substrate-recognition component of the SCF complex. This is the central, family-conserved assignment. supported_by: - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: NAS original_reference_id: PMID:34445249 qualifier: enables review: summary: Proposed NEW molecular-function annotation. As an F-box protein, FBXO15 is the substrate-recognition (substrate-adaptor) subunit of an SCF/CRL1 E3 ligase; it does not itself catalyze ubiquitin transfer (the RING subunit RBX1 is catalytic). The appropriate informative MF for an F-box substrate receptor is ubiquitin-like ligase-substrate adaptor activity (GO:1990756) rather than ubiquitin protein ligase activity. GOA currently carries no MF annotation for FBXO15, so this is added as NEW. action: NEW reason: Captures the core substrate-adaptor molecular function of FBXO15 as an F-box protein; consistent with UniProt (substrate-recognition component directly interacting with SKP1 and CUL1) and the ComplexPortal FBXO15-variant SCF complex. supported_by: - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: 'Directly interacts with SKP1 and CUL1.' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: IntAct interaction with junctophilin-3 (JPH3, Q8WXH2) captured in a neurodegenerative-disease yeast two-hybrid interactome. Records a real binary interaction, but bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Documents a real interaction (FBXO15-JPH3) but the bare protein binding term carries no functional information per curation guidelines; not a core function. supported_by: - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: 'Q8NCQ5; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-6660598, EBI-1055254;' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal author-statement assignment (CPX-7925, "SCF E3 ubiquitin ligase complex, FBXO15 variant") that FBXO15 is part of the SCF complex. Redundant with the IBA assignment and consistent with the UniProt SUBUNIT data. action: ACCEPT reason: Core localization; consistent with UniProt (direct SKP1/CUL1 interaction) and with the ComplexPortal FBXO15-variant SCF complex. Redundant with the IBA SCF annotation. supported_by: - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: 'Directly interacts with SKP1 and CUL1.' - 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 author-statement assignment that FBXO15, as an SCF substrate receptor, participates in SCF-dependent proteasomal ubiquitin-dependent protein catabolism. This is the core biological process inferred for an F-box protein. action: ACCEPT reason: Core biological process for an SCF substrate-recognition subunit; consistent with the reviewed SCF complexes targeting substrates for proteasomal degradation and with the UniProt FUNCTION/keyword (Ubl conjugation pathway). Falcon-sourced primary literature grounds this with specific reported substrates (CLS1, ABCB1/P-gp, SOX2, STAT3), confirming FBXO15 directs targets into SCF-dependent proteasomal degradation and matching the functional placement of FBXO15 as an F-box/SCF (CRL1) substrate-recognition receptor. 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. - reference_id: file:human/FBXO15/FBXO15-deep-research-falcon.md supporting_text: its primary biochemical role is **protein–protein interaction–mediated substrate recruitment** to an SCF-type E3 ligase, enabling **target protein polyubiquitination** and **proteasomal degradation**. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome generic cytosol localization within the neddylation/CRL pathway reactions. A plausible but generic localization not tied to a specific demonstrated FBXO15 function. action: KEEP_AS_NON_CORE reason: Generic compartment from pathway-level Reactome curation (CRL neddylation); plausible for a cytosolic SCF subunit but not specific to FBXO15 and subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome generic cytosol localization (NEDD8:UBE2M binds CRL1) propagated to all CRL1 F-box subunits. Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization and not a specific demonstrated FBXO15 site. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome generic cytosol localization (CAND1 binds cytosolic CRL E3 ligases) propagated to CRL components. Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome generic cytosol localization (COMMDs displace CAND1 from cytosolic CRLs). Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome generic cytosol localization (COP9 signalosome deneddylates cytosolic CRLs). Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome generic cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to CRL1 subunits. Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome generic cytosol localization (transfer of Ub from E2 to substrate) within the general ubiquitination machinery. Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome generic cytosol localization (release of E3 from polyubiquitinated substrate). Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome generic cytosol localization (polyubiquitination of substrate). Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome generic cytosol localization (interaction of E3 with substrate and E2-Ub complex). Generic, non-specific. action: KEEP_AS_NON_CORE reason: Generic pathway-level Reactome compartment; subsidiary to the SCF complex localization. references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: - statement: Large-scale yeast two-hybrid interactome of neurodegenerative-disease-related proteins; source of the FBXO15-JPH3 (junctophilin-3) binary interaction recorded in IntAct. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: Abstract-only in cache (full_text_available false); high-throughput Y2H interactome. Source of the single bare protein binding annotation (interactor JPH3/Q8WXH2 per UniProt INTERACTION line and GOA WITH/FROM). No direct functional claim about FBXO15. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: Review of the 69 human SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes, in which variable F-box proteins determine substrate specificity and direct substrates to proteasomal degradation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Int J Mol Sci 2021, DOI 10.3390/ijms22168544); abstract-only in cache. Review used by ComplexPortal as the NAS source for the SCF-complex and SCF-dependent proteasomal catabolism annotations. Supports the general SCF framework, not a FBXO15-specific substrate. - 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/FBXO15/FBXO15-deep-research-falcon.md title: Falcon deep research report for human FBXO15 findings: - statement: FBXO15 is the substrate-recruiting F-box subunit of an SCF (SKP1-CUL1-FBXO15) E3 ligase whose primary biochemical role is protein-protein-interaction-mediated substrate recruitment for polyubiquitination and proteasomal degradation, not small-molecule catalysis. supporting_text: its primary biochemical role is **protein–protein interaction–mediated substrate recruitment** to an SCF-type E3 ligase, enabling **target protein polyubiquitination** and **proteasomal degradation**. - statement: FBXO15 uniquely associates with and degrades cardiolipin synthase 1 (CLS1) in a PINK1-linked pathway, recognizing CLS1 via Thr219 and directing ubiquitination at Lys174, an ER/cytosol-associated activity affecting mitochondrial cardiolipin. supporting_text: In an unbiased screen of >27 F-box proteins, **FBXO15 uniquely associated with endogenous CLS1**, and **only FBXO15 expression decreased CLS1 levels** - statement: FBXO15 physically associates with and promotes ubiquitination of P-glycoprotein (ABCB1/MDR1) with the E2 CDC34/UBE2R1, so that FBXO15 knockdown increases P-gp and multidrug resistance. supporting_text: FBXO15 is described as part of a **Skp1–Cullin1–FBXO15** E3 complex and physically associates with **P-gp** by co-immunoprecipitation - statement: In breast cancer FBXO15 promotes ubiquitin-dependent degradation of SOX2 and STAT3, dampening EGFR/ERK/STAT3 signaling and behaving as a tumor suppressor. supporting_text: FBXO15 overexpression decreases **SOX2 protein stability** (CHX chase) and increases **SOX2 ubiquitination** reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: >- Falcon synthesis anchored on real primary studies: Chen et al. 2014 (E3 ligase subunit FBXO15; CLS1/PINK1, lung injury), Katayama et al. 2013 (FBXO15 regulates P-glycoprotein/ABCB1), Zhao et al. 2021 (FBXO15 degrades SOX2/STAT3 in breast cancer), and Werner et al. 2017 (mouse ESC KBP acetyldegron). These substantially upgrade the prior "poorly characterized" framing by providing several modification-dependent-degron substrates. Falcon cites author-year/DOIs not PMIDs and the papers are not in the local cache, so the substrates are treated as strong leads (UNVERIFIED) pending curator confirmation; no substrate-specific GO terms are added on this basis alone. core_functions: - description: Substrate-recognition (substrate-adaptor) subunit of an SCF/CRL1 (SKP1-CUL1-F-box) E3 ubiquitin ligase complex; FBXO15 binds SKP1 and CUL1 through its F-box domain and recruits target proteins to the ligase core, directing their SCF-dependent poly-ubiquitination and proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity in_complex: id: GO:0019005 label: SCF ubiquitin ligase complex supported_by: - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO15/FBXO15-uniprot.txt supporting_text: 'Directly interacts with SKP1 and CUL1.' directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: Of the reported FBXO15 substrates (CLS1, ABCB1/P-gp, SOX2, STAT3 in human; KBP in mouse), which are bona fide direct, F-box/SKP1-dependent SCF(FBXO15) substrates, and do they reflect a common modification-dependent degron logic (phospho-degron for CLS1, acetyl-degron for KBP)? - question: Does the FBXO15-PINK1-CLS1 axis represent a genuine physiological pathway for mitochondrial cardiolipin/lipid homeostasis, and is FBXO15 itself ER/cytosol-restricted (excluded from mitochondria) as reported? - question: Is the testis/fallopian-tube-enhanced expression of FBXO15 reflective of a tissue-specific substrate or process, and does the pluripotency-associated expression seen for the mouse ortholog translate to a human stem-cell role? suggested_experiments: - description: Affinity-purification mass spectrometry of tagged FBXO15 (full-length and the isoform-2 form lacking residues 1-76) from cells, validating SKP1/CUL1/RBX1 association and identifying candidate substrates enriched upon proteasome inhibition or by neddylation/CRL trapping; directly test CLS1, ABCB1, SOX2 and STAT3 for F-box-dependent ubiquitination. - description: Reconstitute SCF(FBXO15) (SKP1-CUL1-RBX1-FBXO15) with CDC34/UBE2R1 and assay ubiquitination of CLS1 (and Thr219/Lys174 variants) and ABCB1 in vitro to confirm direct substrate-adaptor activity and the proposed degron/ubiquitination sites. - description: Define the FBXO15 substrate repertoire by quantitative ubiquitinome/proteome profiling comparing FBXO15-knockout versus wild-type cells (and rescue), to detect proteins stabilized in the absence of FBXO15 as candidate SCF-FBXO15 targets across tissue contexts.