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.
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.
Parent term: ubiquitin-like ligase-substrate adaptor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Nuclear localization is experimentally supported (PMID:24157836) but reflects the secondary SNAI1-degradation role, not the core cytoplasmic iron-sensing function. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Nucleus {ECO:0000269|PubMed:24157836} |
| GO:0006879 intracellular iron ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic assignment of intracellular iron ion homeostasis, the core biological process of FBXL5. Reason: Correct core biological process; redundant with the experimental IMP/IEP evidence. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt 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 |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of perinuclear cytoplasmic localization from the UniProt subcellular location, consistent with the IDA evidence from the DCTN1 study. Reason: Correct cytoplasmic localization but a specific subcellular sub-compartment; redundant with the IDA annotation. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Cytoplasm, perinuclear region {ECO:0000269|PubMed:17532294} |
| GO:0055080 monoatomic cation homeostasis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of monoatomic cation homeostasis, a generic parent of the specific intracellular iron ion homeostasis role. Reason: Correct but overly generic; the specific GO:0006879 (intracellular iron ion homeostasis) captures the actual role. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 |
| GO:0098771 inorganic ion homeostasis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of inorganic ion homeostasis, a generic parent of intracellular iron ion homeostasis. Reason: Correct but overly generic; subsumed by the specific iron ion homeostasis annotation. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 |
| GO:0005515 protein binding | IPI PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | KEEP AS NON CORE | Summary: IntAct interactions (e.g. SKP1, IREB2) from the foundational FBXL5/iron study. Bare protein binding is uninformative. Reason: Records real, functionally important interactions (SKP1, IREB2) but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; P48200: IREB2; NbExp=2; IntAct=EBI-2692340, EBI-2805796 |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | KEEP AS NON CORE | Summary: High-throughput interactome interaction (SKP1). Bare protein binding is uninformative. Reason: Records a real SKP1 interaction but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Proteome-scale interactome interaction (SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: Interactome-community study interactions (HERC2, SKP1). Bare protein binding is uninformative. Reason: Records real interactions (HERC2 is the ligase that degrades FBXL5) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; O95714: HERC2; NbExp=4; IntAct=EBI-2692340, EBI-1058922 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map interaction (SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; P63208: SKP1; NbExp=15; IntAct=EBI-2692340, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome interaction (TARDBP). Bare protein binding is uninformative. Reason: Records a real interaction (TARDBP) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; Q13148: TARDBP; NbExp=3; IntAct=EBI-2692340, EBI-372899 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome interactions (HERC2, SKP1). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Q9UKA1; O95714: HERC2; NbExp=4; IntAct=EBI-2692340, EBI-1058922 |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination FBXL5 mediates. Reason: Correct but generic; the specific SCF-dependent catabolic process annotation better captures the role. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0005634 nucleus | EXP PMID:24157836 Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding... | KEEP AS NON CORE | Summary: Experimental evidence that FBXL5 localizes to the nucleus, where it ubiquitinates SNAI1/Snail1. A real but secondary localization. Reason: Experimentally supported nuclear pool tied to the SNAI1-degradation role, distinct from the core cytoplasmic iron-sensing function. Supporting Evidence: PMID:24157836 FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination |
| GO:0006879 intracellular iron ion homeostasis | NAS PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: ComplexPortal author-statement assignment of the core iron homeostasis process for the SCF(FBXL5) complex. Reason: Core biological process; consistent with IMP/IEP experimental evidence. Supporting Evidence: PMID:19762597 an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation |
| GO:0019005 SCF ubiquitin ligase complex | IPI PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: ComplexPortal evidence that FBXL5 is part of the SCF (SKP1-CUL1-F-box) E3 ligase complex; the core assembly context for its function. Reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF(FBXL5) complex. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of IRP2. Core biological process. Reason: Core biological process directly demonstrated; FBXL5 targets IRP2 for SCF-dependent proteasomal degradation. Supporting Evidence: PMID:19762597 an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation |
| GO:0006879 intracellular iron ion homeostasis | IMP PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | ACCEPT | Summary: Mutant-phenotype evidence (FBXL5 depletion/overexpression, Hr-domain mutants) that FBXL5 controls cellular iron homeostasis via IRP2. Core biological process. 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. Supporting Evidence: PMID:19762596 FBXL5 depletion by small interfering RNA (siRNA) in HEK293 cells increased IRP2 and decreased ferritin protein levels independently of iron treatment file:human/FBXL5/FBXL5-deep-research-falcon.md a translational study used **liver-specific Fbxl5 knockout mice** to create an **iron overloadβinduced hepatic ferroptosis model** |
| GO:0006879 intracellular iron ion homeostasis | IEP PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: Expression-pattern evidence (iron/oxygen-dependent FBXL5 abundance) linking FBXL5 to iron homeostasis. Core biological process. Reason: Core biological process; FBXL5 stability is iron/oxygen-regulated, coupling sensing to IRP2 control. Supporting Evidence: PMID:19762597 a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5691108 | ACCEPT | Summary: Reactome curation of cytosolic localization (SKP1:FBXL5:CUL1:NEDD8 ubiquitinates IREB2). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic localization where the SCF(FBXL5) complex ubiquitinates IRP2. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5691167 | ACCEPT | Summary: Reactome curation of cytosolic localization (CUL1, SKP1, FBXL5 bind). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic localization for SCF(FBXL5) assembly. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5691176 | ACCEPT | Summary: Reactome curation of cytosolic localization (NEDD8 binds CUL1 in SKP1:CUL1:FBXL5). Consistent with the core cytoplasmic site of action. Reason: Correct cytosolic localization for the SCF(FBXL5) complex. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (neddylation of CRL1). Generic CRL-pathway localization, consistent with the cytoplasmic site of action. Reason: Correct cytosolic compartment but derived from generic CRL neddylation-pathway context; redundant with the substrate-specific cytosol annotations. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL neddylation-pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRL). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; redundant. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0005506 iron ion binding | IDA PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | ACCEPT | 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. Reason: Core molecular function; the hemerythrin-like domain directly coordinates iron, enabling FBXL5 to sense cellular iron status. Supporting Evidence: PMID:19762596 iron copurified with a recombinant fragment of FBXL5 (FBXL5-N199), which encompasses the hemerythrin-like domain |
| GO:0005506 iron ion binding | IDA PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | 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. 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. Supporting Evidence: PMID:19762597 FBXL5 contains an iron- and oxygen-binding file:human/FBXL5/FBXL5-uniprot.txt Name=[2Fe-2S] cluster; Xref=ChEBI:CHEBI:190135; file:human/FBXL5/FBXL5-deep-research-falcon.md 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 |
| GO:0005515 protein binding | IPI PMID:17532294 FBXL5 interacts with p150Glued and regulates its ubiquitinat... | KEEP AS NON CORE | Summary: Interaction with DCTN1/p150-glued, a substrate of FBXL5. Bare protein binding is uninformative. Reason: Records a real substrate interaction (DCTN1) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 |
| GO:0005515 protein binding | IPI PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | KEEP AS NON CORE | Summary: Interactions with SCF components and IRPs (e.g. CUL1, IREB2) from the foundational iron study. Bare protein binding is uninformative. Reason: Records real, functionally central interactions (CUL1, IREB2) but bare protein binding is uninformative. Supporting Evidence: PMID:19762596 FBXL5, SKP1, and CUL1 copurify with IRP2 |
| GO:0016567 protein ubiquitination | IDA PMID:17532294 FBXL5 interacts with p150Glued and regulates its ubiquitinat... | ACCEPT | Summary: Direct evidence that FBXL5 promotes ubiquitination of DCTN1/p150-glued. A real, substrate-specific ubiquitination activity (non-core substrate). Reason: Directly demonstrated ubiquitination activity; consistent with FBXL5's role as an SCF substrate receptor (here for the non-core substrate DCTN1). Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 (PubMed:17532294) |
| GO:0016567 protein ubiquitination | IDA PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | ACCEPT | Summary: Direct evidence that FBXL5 (in the SCF complex) catalyzes polyubiquitination of IRP2. Core activity. Reason: Directly demonstrated ubiquitination of the core substrate IRP2. Supporting Evidence: PMID:19762596 Overexpression of Myc-FBXL5, but not Myc-FBXL5-ΞF-box, increased FLAG-IRP2 poly-ubiquitination |
| GO:0016567 protein ubiquitination | IDA PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: Direct evidence that FBXL5 mediates ubiquitination of IRP2 for proteasomal degradation. Core activity. Reason: Directly demonstrated; FBXL5 targets IRP2 for ubiquitin-mediated proteasomal degradation. Supporting Evidence: PMID:19762597 an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | ACCEPT | Summary: Direct evidence that FBXL5 is part of the SKP1-CUL1-FBXL5 SCF complex. Core cellular component. Reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF(FBXL5) complex. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:19762597 An E3 ligase possessing an iron-responsive hemerythrin domai... | ACCEPT | Summary: Direct evidence that FBXL5 is part of the SCF E3 ligase complex. Core cellular component. Reason: Core cellular component; FBXL5 is the F-box substrate receptor of the SCF complex. Supporting Evidence: PMID:19762597 an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:17532294 FBXL5 interacts with p150Glued and regulates its ubiquitinat... | ACCEPT | Summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of DCTN1. A real, substrate-specific catabolic activity (non-core substrate). Reason: Directly demonstrated SCF-dependent degradation; consistent with FBXL5's substrate-receptor function (here for DCTN1). Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:19762596 Control of iron homeostasis by an iron-regulated ubiquitin l... | ACCEPT | Summary: Direct evidence that FBXL5 drives SCF-dependent proteasomal degradation of IRP2. Core biological process. Reason: Core biological process directly demonstrated for the iron-regulatory substrate IRP2. Supporting Evidence: PMID:19762596 a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:17532294 FBXL5 interacts with p150Glued and regulates its ubiquitinat... | KEEP AS NON CORE | Summary: Direct localization to the perinuclear cytoplasm reported in the DCTN1 study. A real cytoplasmic sub-compartment. Reason: Experimentally supported cytoplasmic sub-localization; consistent with the cytoplasmic site of action but a specific sub-compartment. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Cytoplasm, perinuclear region {ECO:0000269|PubMed:17532294} |
| GO:0000151 ubiquitin ligase complex | NAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | 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. Reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex |
| GO:0004842 ubiquitin-protein transferase activity | NAS PMID:10531035 Identification of a family of human F-box proteins. | MODIFY | 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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion |
| GO:0016567 protein ubiquitination | NAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author-statement assignment of involvement in protein ubiquitination from the original F-box family paper. Generic but correct. Reason: Correct but generic; the specific SCF-dependent catabolic process annotations better capture the role. Supporting Evidence: file:human/FBXL5/FBXL5-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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