id: Q96IG2 gene_symbol: FBXL20 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL20 (F-box/LRR-repeat protein 20; FBL2; the mouse ortholog is named SCRAPPER) is a substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex. Its F-box motif binds SKP1, linking it to the CUL1-RBX1 catalytic core, while its leucine-rich repeat domain provides substrate selectivity, directing substrate-specific polyubiquitination and proteasomal degradation. FBXL20 carries a C-terminal CAAX motif that is isoprenylated, targeting it to membranes, and its localization governs which substrates it engages. A well-characterized human substrate is VPS34/PIK3C3, the catalytic subunit of class III PI3K: FBXL20 binds VPS34 through its C-terminal LRR region (engaging the VPS34 C2 domain) and, downstream of DNA damage, promotes CDK-dependent (VPS34 Thr159) phosphodegron-gated ubiquitination and proteasomal degradation of VPS34. FBXL20 is itself a p53-inducible gene (and a miR-3151 target), so the p53 to FBXL20 to VPS34 axis lowers PtdIns3P output, dampening autophagy and slowing endosomal receptor (e.g. EGFR) degradation under genotoxic stress. FBXL20 also promotes ubiquitination and degradation of PR55alpha/PPP2R2A, a regulatory B subunit of the PP2A serine/threonine phosphatase. In the nervous system the SCRAPPER/FBXL20 ortholog is a membrane-associated presynaptic regulator that ubiquitinates the active-zone protein RIM1/RIMS1, controlling synaptic vesicle release and neurotransmission; accordingly the protein has documented roles at the presynapse and at glutamatergic synapses (largely inferred from the mouse ortholog). FBXL20 acts in the cytoplasm/cytosol and at membranes. alternative_products: - name: '1' id: Q96IG2-1 - name: '2' id: Q96IG2-2 sequence_note: VSP_030769 existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location, consistent with a cytosolic SCF substrate receptor. action: ACCEPT reason: Correct localization for a cytosolic SCF F-box protein; consistent with the cytosolic Reactome annotations. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0098793 label: presynapse evidence_type: IEA original_reference_id: GO_REF:0000108 qualifier: located_in review: summary: Inter-ontology logical inference placing FBXL20 at the presynapse, consistent with the SCRAPPER ortholog's presynaptic role in regulating RIM1 and synaptic vesicle release. action: KEEP_AS_NON_CORE reason: Plausible localization inferred from the mouse SCRAPPER ortholog's presynaptic function; not directly demonstrated for the human protein, and secondary to the core SCF substrate-receptor activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the FBXL20-SKP1 association required for SCF assembly, but bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a binary interactome reference map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a cell-specific proteome-scale interactome. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:34731788 qualifier: enables review: summary: Interaction with PPP2R2A/PR55alpha (P63151), the FBXL20 substrate identified in the p53/FBXL20/PR55alpha study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL20-PR55alpha substrate interaction, but bare protein binding is uninformative; the relationship is captured by the catabolic-process context. supported_by: - reference_id: PMID:34731788 supporting_text: the protein-stability of PR55α via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a multimodal cell-map genomics study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486;' - term: id: GO:0045202 label: synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Ortholog-based electronic assignment of synaptic activity, reflecting the mouse SCRAPPER ortholog's synaptic function. action: KEEP_AS_NON_CORE reason: Plausible from the mouse ortholog (SCRAPPER), but not directly demonstrated for the human protein; secondary to the core SCF substrate-receptor activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:0098685 label: Schaffer collateral - CA1 synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Ortholog-based electronic assignment of activity at the Schaffer collateral-CA1 synapse, from the mouse SCRAPPER ortholog. action: KEEP_AS_NON_CORE reason: Highly specific synaptic localization inferred from the mouse ortholog; not demonstrated for the human protein and secondary to the core activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:0098978 label: glutamatergic synapse evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: is_active_in review: summary: Ortholog-based electronic assignment of activity at glutamatergic synapses, from the mouse SCRAPPER ortholog. action: KEEP_AS_NON_CORE reason: Plausible from the mouse ortholog; not directly demonstrated for the human protein and secondary to the core activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:0099575 label: regulation of protein catabolic process at presynapse, modulating synaptic transmission evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of presynaptic protein-catabolism regulation, reflecting the SCRAPPER ortholog's ubiquitination of the active-zone protein RIM1 to control synaptic vesicle release. action: KEEP_AS_NON_CORE reason: Plausible role inferred from the mouse SCRAPPER ortholog (RIM1 ubiquitination at the presynapse); not directly demonstrated for the human protein and a context-specific process distinct from the generic core activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:2000300 label: regulation of synaptic vesicle exocytosis evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of synaptic-vesicle-exocytosis regulation, reflecting the SCRAPPER ortholog's control of presynaptic release. action: KEEP_AS_NON_CORE reason: Plausible role inferred from the mouse ortholog; not directly demonstrated for the human protein and downstream of the core SCF substrate-receptor activity. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:33234069 qualifier: involved_in review: summary: ComplexPortal author statement that FBXL20 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. action: ACCEPT reason: Core biological process for an SCF F-box substrate receptor; supported by PR55alpha degradation (PMID:34731788) and the SCRAPPER ortholog's RIM1 turnover. supported_by: - reference_id: PMID:34731788 supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL20-specific function. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome cytosolic localization within a generic CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction. action: KEEP_AS_NON_CORE reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-release reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction. action: KEEP_AS_NON_CORE reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000250}.' - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:34731788 qualifier: enables review: summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL20), FBXL20 selects substrates (PR55alpha/PPP2R2A in human cells; RIM1 for the SCRAPPER ortholog) for SCF-dependent ubiquitination. This more informative MF term is not in the GOA. action: NEW reason: Captures the precise molecular function of FBXL20 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations. supported_by: - reference_id: PMID:34731788 supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins references: - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: PMID:27705803 title: A High-Density Map for Navigating the Human Polycomb Complexome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput complexome map; source of an SKP1 interaction (bare protein binding). - 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 an SKP1 interaction (bare protein binding). - id: PMID:33234069 title: 'The FBXL family of F-box proteins: variations on a theme.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review of the FBXL family; basis for the ComplexPortal NAS SCF-catabolic-process annotation. - 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: High-throughput interactome; source of an SKP1 interaction (bare protein binding). - id: PMID:34731788 title: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase. findings: - statement: FBXL20 is a p53-target gene whose product is the substrate-recognition component of an SCF E3 ligase that promotes ubiquitination and proteasomal degradation of PR55alpha/PPP2R2A; FBXL20 knockdown reduces PR55alpha ubiquitination and increases its stability. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Neoplasia 2021), full text available; establishes PR55alpha/PPP2R2A as a human SCF(FBXL20) substrate and the p53 regulatory axis. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput cell-map genomics; source of an SKP1 interaction (bare protein binding). - 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: file:human/FBXL20/FBXL20-deep-research-falcon.md title: Falcon deep research report for human FBXL20 findings: - statement: FBXL20 is the substrate-recognition subunit of an SCF (CUL1-SKP1-FBXL20) E3 ligase that promotes ubiquitination and proteasomal degradation of VPS34/PIK3C3, binding VPS34 through its C-terminal LRR region (VPS34 C2 domain). supporting_text: >- FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)** E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation** of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes. - statement: DNA damage drives a p53 to FBXL20 to VPS34 checkpoint in which CDK-dependent VPS34 Thr159 phosphorylation creates a phosphodegron required for FBXL20-mediated ubiquitination. supporting_text: >- phosphorylation at **T159** is required for efficient FBXL20-mediated ubiquitination and degradation. Specifically, VPS34 **T159A** (nonphosphorylatable) is largely resistant, whereas **T159E** (phosphomimetic) remains sensitive - statement: By lowering VPS34 and PtdIns3P output, FBXL20 acts as a negative regulator of autophagy under genotoxic stress and slows endosomal degradation of receptors such as EGFR. supporting_text: >- FBXL20 knockdown increases VPS34 and increases an autophagy marker readout (LC3-II ratio), whereas FBXL20 overexpression lowers VPS34; collectively this supports FBXL20 as a **negative regulator of autophagy** under genotoxic stress - statement: FBXL20 contains a CAAX motif that is isoprenylated, directing it to membranes, and this localization is required for ubiquitylation-dependent degradation of RIM1. supporting_text: >- FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to **membranes**; this localization is required for ubiquitylation-dependent degradation of **RIM1** (RAB3-interacting molecule 1) reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Falcon adds the human VPS34/PIK3C3 substrate axis (Xiao et al. 2015 Genes & Dev, DOI 10.1101/gad.252528.114) and the CAAX-isoprenylation/membrane-localization requirement for RIM1 degradation (Skaar et al. 2013 Nat Rev Mol Cell Biol review). These are reported via author-year DOIs not in the PMID cache; cross-checked against UniProt and the existing PR55alpha study (PMID:34731788), and treated as well-supported leads rather than added as new GOA terms. - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] core_functions: - description: Substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex that selects substrates for SCF-dependent polyubiquitination and proteasomal degradation; in human cells it targets PR55alpha/PPP2R2A (a PP2A regulatory subunit) downstream of p53. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:34731788 supporting_text: substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: As the SCF(FBXL20) substrate receptor, targets VPS34/PIK3C3 for phosphodegron-gated (VPS34 Thr159) ubiquitination and proteasomal degradation downstream of p53/DNA-damage signaling, lowering PtdIns3P output to negatively regulate autophagy and endosomal receptor (e.g. EGFR) trafficking. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/FBXL20/FBXL20-deep-research-falcon.md supporting_text: >- FBXL20 acts as the substrate-recognition component of an **SCF (SKP1-CUL1-FBXL20)** E3 ubiquitin ligase that promotes **ubiquitination and proteasomal degradation** of **VPS34 (PIK3C3)**, the catalytic subunit of class III PI3K complexes. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Membrane-associated presynaptic SCF substrate receptor (SCRAPPER ortholog), targeted to membranes via CAAX-motif isoprenylation, that regulates protein catabolism at the presynapse to modulate synaptic vesicle release and neurotransmission, via ubiquitination of active-zone substrates such as RIM1/RIMS1. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0098793 label: presynapse supported_by: - reference_id: file:human/FBXL20/FBXL20-uniprot.txt supporting_text: Role in neural transmission (By similarity). - reference_id: file:human/FBXL20/FBXL20-deep-research-falcon.md supporting_text: >- FBXL20 contains a **CAAX motif** that is **isoprenylated**, directing FBXL20 to **membranes**; this localization is required for ubiquitylation-dependent degradation of **RIM1** (RAB3-interacting molecule 1) directly_involved_in: - id: GO:0099575 label: regulation of protein catabolic process at presynapse, modulating synaptic transmission proposed_new_terms: [] suggested_questions: - question: Which of the FBXL20 functions established for the mouse SCRAPPER ortholog (RIM1 ubiquitination, regulation of synaptic vesicle release) are conserved and directly demonstrable for the human protein, and is CAAX isoprenylation required? - question: How do the membrane/autophagy (VPS34/PIK3C3, p53-DNA-damage axis), synaptic (RIM1), and PP2A (PR55alpha) substrate-targeting activities of FBXL20 relate, and are they coordinated by CAAX-dependent localization or by distinct phosphodegrons? suggested_experiments: - description: Reconstitute SCF(FBXL20)-mediated ubiquitination in vitro with purified SKP1-CUL1-RBX1-FBXL20, an E2, and candidate substrates (VPS34/PIK3C3 phosphorylated at Thr159, PR55alpha/PPP2R2A, RIM1) to confirm direct ubiquitination, test phosphodegron dependence, and map sites. - description: Use FBXL20 knockout/knockdown (and CAAX-motif mutants) in human neurons and epithelial cells with quantitative ubiquitinome/proteome profiling and autophagy/PtdIns3P readouts to define the endogenous substrate repertoire, test the p53-FBXL20-VPS34 autophagy checkpoint, and assess conservation of the presynaptic role.