id: Q9UKA1 gene_symbol: FBXL5 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL5 (F-box/LRR-repeat protein 5) is the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase that is the master sensor coupling cellular iron and oxygen status to the stability of the iron regulatory proteins IRP2/IREB2 and IRP1/ACO1. Within the SCF complex, FBXL5 binds SKP1 through its F-box domain and uses its leucine-rich repeats to recruit substrate, thereby directing CUL1-RBX1-mediated polyubiquitination and proteasomal degradation of IRP2. FBXL5 carries two metal-sensing modules: an N-terminal hemerythrin-like (Hr) domain with a diiron center that binds iron and oxygen, and a C-terminal redox-sensitive [2Fe-2S] cluster. In iron- and oxygen-replete cells the Hr domain is loaded and stable and the oxidized [2Fe-2S] cluster enables substrate (IRP2) recruitment, so the SCF(FBXL5) ligase degrades IRP2 and shuts down the iron-starvation response. Under iron deficiency or hypoxia the Hr domain cannot bind iron, FBXL5 undergoes conformational destabilization and is itself ubiquitinated and degraded, allowing IRP2 to accumulate, bind iron-responsive elements, and upregulate iron uptake. FBXL5 thus sits at the center of mammalian iron homeostasis. Additional reported substrates include the dynactin subunit DCTN1/p150-glued, the EMT transcription factor SNAI1/Snail1 (ubiquitinated in the nucleus), and the single-stranded DNA-binding protein NABP2/hSSB1, linking FBXL5 to cytoskeletal regulation, EMT, and the DNA-damage response. The oxidized [2Fe-2S] cluster only forms when both iron and oxygen are sufficient, so its redox state gates IRP2 recruitment, making FBXL5 a combined iron-and-oxygen sensor; at steady state FBXL5 also undergoes constitutive HERC2-mediated ubiquitin-dependent turnover. Loss of FBXL5 derepresses the IRP2-driven iron-acquisition program, causing intracellular iron overload; consistent with this, liver-specific Fbxl5 knockout sensitizes hepatocytes to iron-dependent ferroptosis, framing FBXL5 as a physiological brake on iron accumulation and ferroptotic injury. alternative_products: - name: '1' id: Q9UKA1-1 - name: '2' id: Q9UKA1-2 sequence_note: VSP_008417 existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of nuclear localization from the UniProt subcellular location. A real but secondary localization where FBXL5 ubiquitinates SNAI1; the dominant functional pool is cytoplasmic/perinuclear. action: KEEP_AS_NON_CORE reason: Nuclear localization is experimentally supported (PMID:24157836) but reflects the secondary SNAI1-degradation role, not the core cytoplasmic iron-sensing function. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Nucleus {ECO:0000269|PubMed:24157836} - term: id: GO:0006879 label: intracellular iron ion homeostasis evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based electronic assignment of intracellular iron ion homeostasis, the core biological process of FBXL5. action: ACCEPT reason: Correct core biological process; redundant with the experimental IMP/IEP evidence. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of perinuclear cytoplasmic localization from the UniProt subcellular location, consistent with the IDA evidence from the DCTN1 study. action: KEEP_AS_NON_CORE reason: Correct cytoplasmic localization but a specific subcellular sub-compartment; redundant with the IDA annotation. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Cytoplasm, perinuclear region {ECO:0000269|PubMed:17532294} - term: id: GO:0055080 label: monoatomic cation homeostasis evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning assignment of monoatomic cation homeostasis, a generic parent of the specific intracellular iron ion homeostasis role. action: KEEP_AS_NON_CORE reason: Correct but overly generic; the specific GO:0006879 (intracellular iron ion homeostasis) captures the actual role. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 - term: id: GO:0098771 label: inorganic ion homeostasis evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning assignment of inorganic ion homeostasis, a generic parent of intracellular iron ion homeostasis. action: KEEP_AS_NON_CORE reason: Correct but overly generic; subsumed by the specific iron ion homeostasis annotation. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19762597 qualifier: enables review: summary: IntAct interactions (e.g. SKP1, IREB2) from the foundational FBXL5/iron study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real, functionally important interactions (SKP1, IREB2) but bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; P48200: IREB2; NbExp=2; IntAct=EBI-2692340, EBI-2805796' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21516116 qualifier: enables review: summary: High-throughput interactome interaction (SKP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real SKP1 interaction but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25416956 qualifier: enables review: summary: Proteome-scale interactome interaction (SKP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: Interactome-community study interactions (HERC2, SKP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real interactions (HERC2 is the ligase that degrades FBXL5) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; O95714: HERC2; NbExp=4; IntAct=EBI-2692340, EBI-1058922' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome reference map interaction (SKP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Neurodegeneration interactome interaction (TARDBP). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real interaction (TARDBP) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; Q13148: TARDBP; NbExp=3; IntAct=EBI-2692340, EBI-372899' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Cell-specific interactome interactions (HERC2, SKP1). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Q9UKA1; O95714: HERC2; NbExp=4; IntAct=EBI-2692340, EBI-1058922' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination FBXL5 mediates. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent catabolic process annotation better captures the role. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0005634 label: nucleus evidence_type: EXP original_reference_id: PMID:24157836 qualifier: located_in review: summary: Experimental evidence that FBXL5 localizes to the nucleus, where it ubiquitinates SNAI1/Snail1. A real but secondary localization. action: KEEP_AS_NON_CORE reason: Experimentally supported nuclear pool tied to the SNAI1-degradation role, distinct from the core cytoplasmic iron-sensing function. supported_by: - reference_id: PMID:24157836 supporting_text: FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination - term: id: GO:0006879 label: intracellular iron ion homeostasis evidence_type: NAS original_reference_id: PMID:19762597 qualifier: involved_in review: summary: ComplexPortal author-statement assignment of the core iron homeostasis process for the SCF(FBXL5) complex. action: ACCEPT reason: Core biological process; consistent with IMP/IEP experimental evidence. supported_by: - reference_id: PMID:19762597 supporting_text: an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IPI original_reference_id: PMID:19762597 qualifier: part_of review: summary: ComplexPortal evidence that FBXL5 is part of the SCF (SKP1-CUL1-F-box) E3 ligase complex; the core assembly context for its function. action: ACCEPT reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF(FBXL5) complex. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:19762597 qualifier: involved_in review: summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of IRP2. Core biological process. action: ACCEPT reason: Core biological process directly demonstrated; FBXL5 targets IRP2 for SCF-dependent proteasomal degradation. supported_by: - reference_id: PMID:19762597 supporting_text: an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation - term: id: GO:0006879 label: intracellular iron ion homeostasis evidence_type: IMP original_reference_id: PMID:19762596 qualifier: involved_in review: summary: Mutant-phenotype evidence (FBXL5 depletion/overexpression, Hr-domain mutants) that FBXL5 controls cellular iron homeostasis via IRP2. Core biological process. action: ACCEPT reason: Core biological process with direct IMP support; FBXL5 depletion increases IRP2 and decreases ferritin independently of iron. FBXL5 acts as a brake on iron accumulation - its loss derepresses the IRP2-driven iron-acquisition program and (in liver-specific knockout mice) drives iron overload and ferroptosis. supported_by: - reference_id: PMID:19762596 supporting_text: FBXL5 depletion by small interfering RNA (siRNA) in HEK293 cells increased IRP2 and decreased ferritin protein levels independently of iron treatment - reference_id: file:human/FBXL5/FBXL5-deep-research-falcon.md supporting_text: a translational study used **liver-specific Fbxl5 knockout mice** to create an **iron overload–induced hepatic ferroptosis model** - term: id: GO:0006879 label: intracellular iron ion homeostasis evidence_type: IEP original_reference_id: PMID:19762597 qualifier: involved_in review: summary: Expression-pattern evidence (iron/oxygen-dependent FBXL5 abundance) linking FBXL5 to iron homeostasis. Core biological process. action: ACCEPT reason: Core biological process; FBXL5 stability is iron/oxygen-regulated, coupling sensing to IRP2 control. supported_by: - reference_id: PMID:19762597 supporting_text: a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5691108 qualifier: located_in review: summary: Reactome curation of cytosolic localization (SKP1:FBXL5:CUL1:NEDD8 ubiquitinates IREB2). Consistent with the core cytoplasmic site of action. action: ACCEPT reason: Correct cytosolic localization where the SCF(FBXL5) complex ubiquitinates IRP2. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5691167 qualifier: located_in review: summary: Reactome curation of cytosolic localization (CUL1, SKP1, FBXL5 bind). Consistent with the core cytoplasmic site of action. action: ACCEPT reason: Correct cytosolic localization for SCF(FBXL5) assembly. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-5691176 qualifier: located_in review: summary: Reactome curation of cytosolic localization (NEDD8 binds CUL1 in SKP1:CUL1:FBXL5). Consistent with the core cytoplasmic site of action. action: ACCEPT reason: Correct cytosolic localization for the SCF(FBXL5) complex. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 (neddylation of CRL1). Generic CRL-pathway localization, consistent with the cytoplasmic site of action. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but derived from generic CRL neddylation-pathway context; redundant with the substrate-specific cytosol annotations. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL neddylation-pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 binds cytosolic CRL). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 (COMMDs displace CAND1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 deneddylates CRL). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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 binds CRL1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - 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). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0005506 label: iron ion binding evidence_type: IDA original_reference_id: PMID:19762596 qualifier: enables review: summary: Direct evidence that FBXL5 binds iron through its N-terminal hemerythrin-like diiron domain, the molecular basis of its iron/oxygen-sensing function. Core molecular function. action: ACCEPT reason: Core molecular function; the hemerythrin-like domain directly coordinates iron, enabling FBXL5 to sense cellular iron status. supported_by: - reference_id: PMID:19762596 supporting_text: iron copurified with a recombinant fragment of FBXL5 (FBXL5-N199), which encompasses the hemerythrin-like domain - term: id: GO:0005506 label: iron ion binding evidence_type: IDA original_reference_id: PMID:19762597 qualifier: enables review: summary: Direct evidence that FBXL5 binds iron via its iron-responsive hemerythrin domain. Core molecular function. FBXL5 actually carries two metal-sensing modules - the N-terminal hemerythrin diiron center governing FBXL5 stability and a C-terminal redox-sensitive [2Fe-2S] cluster whose oxidation gates IRP2 recruitment - integrating both iron and oxygen status. action: ACCEPT reason: Core molecular function; iron binding by the hemerythrin domain underlies FBXL5's iron-sensing activity. The two metal centers together make FBXL5 a combined iron/oxygen sensor. supported_by: - reference_id: PMID:19762597 supporting_text: FBXL5 contains an iron- and oxygen-binding - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135;' - reference_id: file:human/FBXL5/FBXL5-deep-research-falcon.md supporting_text: FBXL5 contains an Hr-like N-terminus that binds a **diiron metal center** under high iron; loss of metal binding under low-iron conditions promotes conformational changes and FBXL5 turnover - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17532294 qualifier: enables review: summary: Interaction with DCTN1/p150-glued, a substrate of FBXL5. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real substrate interaction (DCTN1) but bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19762596 qualifier: enables review: summary: Interactions with SCF components and IRPs (e.g. CUL1, IREB2) from the foundational iron study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real, functionally central interactions (CUL1, IREB2) but bare protein binding is uninformative. supported_by: - reference_id: PMID:19762596 supporting_text: FBXL5, SKP1, and CUL1 copurify with IRP2 - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:17532294 qualifier: involved_in review: summary: Direct evidence that FBXL5 promotes ubiquitination of DCTN1/p150-glued. A real, substrate-specific ubiquitination activity (non-core substrate). action: ACCEPT reason: Directly demonstrated ubiquitination activity; consistent with FBXL5's role as an SCF substrate receptor (here for the non-core substrate DCTN1). supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 (PubMed:17532294) - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:19762596 qualifier: involved_in review: summary: Direct evidence that FBXL5 (in the SCF complex) catalyzes polyubiquitination of IRP2. Core activity. action: ACCEPT reason: Directly demonstrated ubiquitination of the core substrate IRP2. supported_by: - reference_id: PMID:19762596 supporting_text: Overexpression of Myc-FBXL5, but not Myc-FBXL5-ΔF-box, increased FLAG-IRP2 poly-ubiquitination - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:19762597 qualifier: involved_in review: summary: Direct evidence that FBXL5 mediates ubiquitination of IRP2 for proteasomal degradation. Core activity. action: ACCEPT reason: Directly demonstrated; FBXL5 targets IRP2 for ubiquitin-mediated proteasomal degradation. supported_by: - reference_id: PMID:19762597 supporting_text: an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:19762596 qualifier: part_of review: summary: Direct evidence that FBXL5 is part of the SKP1-CUL1-FBXL5 SCF complex. Core cellular component. action: ACCEPT reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF(FBXL5) complex. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:19762597 qualifier: part_of review: summary: Direct evidence that FBXL5 is part of the SCF E3 ligase complex. Core cellular component. action: ACCEPT reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF complex. supported_by: - reference_id: PMID:19762597 supporting_text: an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:17532294 qualifier: involved_in review: summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of DCTN1. A real, substrate-specific catabolic activity (non-core substrate). action: ACCEPT reason: Directly demonstrated SCF-dependent degradation; consistent with FBXL5's substrate-receptor function (here for DCTN1). supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:19762596 qualifier: involved_in review: summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of IRP2. Core biological process. action: ACCEPT reason: Core biological process directly demonstrated for the iron-regulatory substrate IRP2. supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IDA original_reference_id: PMID:17532294 qualifier: located_in review: summary: Direct localization to the perinuclear cytoplasm reported in the DCTN1 study. A real cytoplasmic sub-compartment. action: KEEP_AS_NON_CORE reason: Experimentally supported cytoplasmic sub-localization; consistent with the cytoplasmic site of action but a specific sub-compartment. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Cytoplasm, perinuclear region {ECO:0000269|PubMed:17532294} - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:10531035 qualifier: part_of review: summary: Author-statement assignment (original F-box family paper) that FBXL5 is part of a ubiquitin ligase complex. A generic parent of the specific SCF complex. action: KEEP_AS_NON_CORE reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: NAS original_reference_id: PMID:10531035 qualifier: enables review: summary: Author-statement assignment of ubiquitin-protein transferase activity from the original F-box family paper. As an F-box substrate receptor, FBXL5 does not itself catalyze ubiquitin transfer; this is a complex-level/over-generalized attribution. action: MODIFY reason: FBXL5 is the substrate-recognition (F-box) subunit, not the catalytic core; the transferase/RING activity resides in RBX1/CUL1. The informative molecular function is ubiquitin-like ligase-substrate adaptor activity (GO:1990756). proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion - term: id: GO:0016567 label: protein ubiquitination evidence_type: NAS original_reference_id: PMID:10531035 qualifier: involved_in review: summary: Author-statement assignment of involvement in protein ubiquitination from the original F-box family paper. Generic but correct. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent catabolic process annotations better capture the role. supported_by: - reference_id: file:human/FBXL5/FBXL5-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - 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:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:10531035 title: Identification of a family of human F-box proteins. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Original identification of FBXL5 as an F-box protein; source of the generic ubiquitin ligase complex / transferase / ubiquitination NAS annotations. Full text not in cache. - id: PMID:17532294 title: FBXL5 interacts with p150Glued and regulates its ubiquitination. findings: - statement: FBXL5 interacts with DCTN1/p150-glued and promotes its ubiquitination and degradation; FBXL5 localizes to the perinuclear cytoplasm. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Establishes a non-core substrate (DCTN1/dynactin) and the perinuclear cytoplasmic localization. Abstract-only in cache; supporting text drawn from UniProt summary of this paper. - id: PMID:19762596 title: Control of iron homeostasis by an iron-regulated ubiquitin ligase. findings: - statement: A SKP1-CUL1-FBXL5 SCF complex promotes iron-dependent ubiquitination and degradation of IRP2/IRP1; FBXL5 itself is degraded upon iron and oxygen depletion via its N-terminal iron-binding hemerythrin-like domain, coupling IRP2 degradation to intracellular iron levels. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; foundational study establishing FBXL5 as the iron-regulated SCF substrate receptor for IRP2 and the iron-binding hemerythrin domain. - id: PMID:19762597 title: An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. findings: - statement: An E3 ligase complex containing FBXL5 targets IRP2 for proteasomal degradation; FBXL5 stability is controlled by an iron- and oxygen-binding hemerythrin domain, linking iron sensing to IRP2 regulation and iron homeostasis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available; companion foundational study (with PMID:19762596) establishing FBXL5 iron-sensing E3 ligase function. - id: PMID:21516116 title: Next-generation sequencing to generate interactome datasets. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of a bare protein binding (SKP1) annotation. - id: PMID:24157836 title: Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability. findings: - statement: FBXL5 acts as a nuclear SCF ubiquitin ligase that binds and polyubiquitinates the EMT transcription factor SNAI1/Snail1, impairing its DNA binding and promoting its degradation; FBXL5 is downregulated by gamma-irradiation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text available; establishes the non-core nuclear SNAI1-degradation role and nuclear localization. - 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 a bare protein binding (SKP1) 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: High-throughput interactome; source of bare protein binding annotations (HERC2, SKP1). - 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 a bare protein binding (SKP1) annotation. - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Neurodegeneration interactome; source of a bare protein binding (TARDBP) annotation. Full text not in cache. - 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 bare protein binding annotations (HERC2, SKP1). - id: Reactome:R-HSA-5691108 title: SKP1:FBXL5:CUL1:NEDD8 ubiquitinylates IREB2 findings: [] - id: Reactome:R-HSA-5691167 title: CUL1, SKP1, FBXL5 bind findings: [] - id: Reactome:R-HSA-5691176 title: NEDD8 binds CUL1 (in SKP1:CUL1:FXBL5) findings: [] - 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/FBXL5/FBXL5-deep-research-falcon.md title: Falcon deep research report for human FBXL5 findings: - statement: FBXL5 is the substrate-recognition (F-box) subunit of an SCF E3 ubiquitin ligase whose three-region architecture (N-terminal hemerythrin-like domain, central F-box, C-terminal LRR) couples metal sensing to IRP2 recognition and SKP1-mediated SCF assembly. supporting_text: 'A structural/functional synthesis of FBXL5 describes three major regions: an **N-terminal hemerythrin-like (Hr) domain**, a **central F-box domain**, and a **C-terminal leucine-rich repeat (LRR) domain** (sicheri2025analysisoffbox pages 4-7). The F-box domain provides a **SKP1-binding interface**, linking FBXL5 to the SCF machinery, while the LRR region mediates key substrate-binding and cofactor-linked regulation (sicheri2025analysisoffbox pages 4-7).' - statement: FBXL5 stability is governed by both an N-terminal diiron hemerythrin-like center and an oxygen-responsive [2Fe-2S] cluster, making it a combined iron- and oxygen-sensor for IRP2 degradation. supporting_text: a review summary likewise states that FBXL5 stability depends on both a **diiron hemerythrin-like domain** and a **[2Fe–2S] cluster** (jain2026ironregulationredox pages 8-10). - statement: Under iron-replete conditions FBXL5 is stabilized and recruits IRP2 for proteasomal degradation; under iron deficiency FBXL5 is destabilized and degraded, permitting IRP2 accumulation and the iron-starvation response. supporting_text: '- **Low iron:** loss of stabilizing metal cofactor occupancy destabilizes FBXL5, leading to FBXL5 degradation and **IRP2 accumulation**, which then drives the IRP/IRE post-transcriptional iron response (chen2026regulationofmitochondrial pages 4-5, jain2026ironregulationredox pages 8-10).' - statement: FBXL5 acts as a physiological brake on iron accumulation; liver-specific Fbxl5 knockout creates an iron overload-induced hepatic ferroptosis model, demonstrating that loss of FBXL5 sensitizes tissue to ferroptotic injury. supporting_text: A translational study used **liver-specific Fbxl5 knockout mice** to create an **iron overload–induced hepatic ferroptosis model** and interrogate injury pathways in ischemia–reperfusion injury (IRI) (matsumoto2025integratedhepaticferroptosis pages 1-5, matsumoto2025integratedhepaticferroptosis pages 8-11). reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Falcon (Edison Scientific) deep-research synthesis. Treated as leads cross-checked against UniProt and the foundational IDA/IMP papers (PMID:19762596/19762597); core iron/oxygen-sensing SCF-receptor mechanism is corroborated by those experimental sources. Falcon cites author-year/DOIs (e.g. sicheri2025, jain2026, matsumoto2025) rather than PMIDs and is not independently PubMed-verified, so marked UNVERIFIED. core_functions: - description: Functions as the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-FBXL5) cullin-RING E3 ubiquitin ligase that recruits IRP2/IREB2 (and IRP1/ACO1) for polyubiquitination and proteasomal degradation, thereby acting as the master controller of intracellular iron homeostasis. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:19762596 supporting_text: a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 - reference_id: PMID:19762597 supporting_text: an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation directly_involved_in: - id: GO:0006879 label: intracellular iron ion homeostasis - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Acts as a cellular iron and oxygen sensor through its N-terminal hemerythrin-like diiron domain (and a C-terminal redox-sensitive [2Fe-2S] cluster); iron binding stabilizes FBXL5 and enables IRP2 recruitment, whereas iron/oxygen depletion destabilizes FBXL5 and leads to its own degradation, coupling SCF(FBXL5) ligase activity to iron status. molecular_function: id: GO:0005506 label: iron ion binding locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:19762596 supporting_text: iron copurified with a recombinant fragment of FBXL5 (FBXL5-N199), which encompasses the hemerythrin-like domain directly_involved_in: - id: GO:0006879 label: intracellular iron ion homeostasis proposed_new_terms: - proposed_name: iron- and oxygen-sensing ubiquitin-ligase substrate adaptor activity proposed_definition: An ubiquitin-like ligase-substrate adaptor activity in which substrate recruitment to a cullin-RING ligase is directly gated by the iron and oxygen status of the adaptor protein itself, via metal-binding cofactor modules (e.g. a hemerythrin-like diiron center and/or a redox-sensitive [2Fe-2S] cluster), such that the adaptor recruits its substrate for ubiquitination only when iron and oxygen are replete. justification: This captures the FBXL5 molecular function more precisely than the generic GO:1990756 (ubiquitin-like ligase-substrate adaptor activity), which does not convey the metal/oxygen-dependent conditional substrate recruitment that defines FBXL5 as the master iron/oxygen sensor of the IRP2 degradation axis. proposed_parent: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: PMID:19762597 supporting_text: a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation - reference_id: file:human/FBXL5/FBXL5-deep-research-falcon.md supporting_text: a review summary likewise states that FBXL5 stability depends on both a **diiron hemerythrin-like domain** and a **[2Fe–2S] cluster** (jain2026ironregulationredox pages 8-10). suggested_questions: - question: How is the choice between FBXL5's core iron-regulatory substrate (IRP2/IRP1) and its other substrates (DCTN1, SNAI1, NABP2) controlled, and are these alternative targeting events restricted to particular subcellular pools or stimuli? - question: What is the physiological relationship between the two metal-sensing modules of FBXL5 (the N-terminal hemerythrin diiron center governing FBXL5 stability and the C-terminal [2Fe-2S] cluster governing IRP2 recruitment) in integrating iron and oxygen signals? - question: Given that liver-specific Fbxl5 loss drives iron-overload-induced ferroptosis, is FBXL5's protection against ferroptosis fully explained by IRP2/IRP1-dependent iron-acquisition control, or does FBXL5 restrain ferroptosis through additional substrates or non-IRP iron-handling routes? suggested_experiments: - description: Reconstitute SCF(FBXL5)-mediated IRP2 ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2, and wild-type versus hemerythrin-domain (H15A/H57A) or [2Fe-2S]-cluster (C662S/C676S/C686S/C687S) mutant FBXL5, varying iron and oxygen to map how each metal center controls substrate recruitment and chain assembly. - description: Perform quantitative ubiquitinome/proteome profiling in FBXL5-knockout versus wild-type cells under iron-replete, iron-depleted, and hypoxic conditions to define the endogenous FBXL5 substrate repertoire and distinguish the core IRP2/IRP1 axis from secondary substrates such as DCTN1, SNAI1, and NABP2.