Existing Annotations Review

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 overload–induced 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-ΔF-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.

Core Functions

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

intracellular iron ion homeostasis SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

PMID:19762596
a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2
PMID:19762597
an E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation

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:

iron ion binding

Directly Involved In:

intracellular iron ion homeostasis

Cellular Locations:

cytosol

Supporting Evidence:

PMID:19762596
iron copurified with a recombinant fragment of FBXL5 (FBXL5-N199), which encompasses the hemerythrin-like domain

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:10531035

Identification of a family of human F-box proteins.

PMID:17532294

FBXL5 interacts with p150Glued and regulates its ubiquitination.

FBXL5 interacts with DCTN1/p150-glued and promotes its ubiquitination and degradation; FBXL5 localizes to the perinuclear cytoplasm.

PMID:19762596

Control of iron homeostasis by an iron-regulated ubiquitin ligase.

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.

PMID:19762597

An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis.

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.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:24157836

Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability.

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.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

Reactome:R-HSA-5691108

SKP1:FBXL5:CUL1:NEDD8 ubiquitinylates IREB2

Reactome:R-HSA-5691167

CUL1, SKP1, FBXL5 bind

Reactome:R-HSA-5691176

NEDD8 binds CUL1 (in SKP1:CUL1:FXBL5)

Reactome:R-HSA-8952618

AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8952620

NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956040

COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956200

MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

file:human/FBXL5/FBXL5-deep-research-falcon.md

Falcon deep research report for human FBXL5

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.

"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)."
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.

"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)."
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.

"- **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)."
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.

"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)."

Suggested Experiments

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.

Deep Research

Falcon

(FBXL5-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 25 citations 2 artifacts 2026-06-13T06:09:51.519364

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000012 Figure 5 illustrates the domain architecture and interactions of FBXL5. Panel A shows the 3D structure of FBXL5 with its domains hi (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human FBXL5 (UniProt Q9UKA1) — Functional Annotation and Current Understanding

0) Target verification (mandatory)

The literature summarized here is consistent with the UniProt identity provided: human FBXL5 (F-box and leucine-rich repeat protein 5; UniProt Q9UKA1), an F-box/LRR protein containing an N-terminal hemerythrin-like (Hr) domain and functioning as a substrate receptor for an SCF (SKP1–CUL1–F-box) E3 ubiquitin ligase that regulates iron homeostasis by controlling IRP2/IREB2 stability. Domain architecture and SCF interactions are explicitly described and visualized in structural analyses (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb).

1) Key concepts and definitions (current understanding)

1.1 FBXL5 as a substrate receptor in an SCF E3 ubiquitin ligase

FBXL5 is best understood as a substrate-adaptor (F-box) protein that confers substrate specificity to an SCF E3 ubiquitin ligase, enabling polyubiquitination and subsequent proteasomal degradation of specific client proteins (notably IRP2/IREB2) in response to iron/oxygen status (cortadellas2023characterizationofnew pages 41-45, chen2026regulationofmitochondrial pages 4-5).

1.2 IRP/IRE post-transcriptional iron regulation (context for FBXL5 function)

IRP1 and IRP2 are iron regulatory proteins that bind iron-responsive elements (IREs) in target mRNAs to coordinate iron uptake, storage, and utilization. IRP2 does not assemble an Fe–S cluster (in contrast to IRP1’s aconitase/IRP switch) and is regulated mainly by iron-dependent degradation (liang2026thecriticalrole pages 2-3). FBXL5 is a key mediator of that degradation response (liang2026thecriticalrole pages 2-3).

1.3 “Iron/oxygen sensor” concept as applied to FBXL5

FBXL5 is widely described as an iron- and oxygen-sensitive regulator: its own stability depends on occupancy of metal cofactors, and its stability controls whether IRP2 is degraded (iron replete) or allowed to accumulate (iron deficiency) (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3).

2) Molecular function, domains, and mechanism (structure → function)

2.1 Domain architecture (and why it matters)

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).

A retrieved figure from a structural analysis visually summarizes this architecture and shows interaction surfaces with SKP1 and IREB2 (IRP2), as well as a diiron center (sicheri2025analysisoffbox media b6a989cb).

2.2 Iron-dependent regulation of FBXL5 stability and IRP2 ubiquitination

Across mechanistic summaries, a consistent model emerges:

High iron: iron binding stabilizes FBXL5, enabling it (as SCF substrate receptor) to recruit IRP2 for ubiquitination and proteasomal degradation (cortadellas2023characterizationofnew pages 41-45, chen2026regulationofmitochondrial pages 4-5, jain2026ironregulationredox pages 8-10).
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).

A structural analysis adds mechanistic detail: 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 (sicheri2025analysisoffbox pages 4-7).

2.3 Oxygen responsiveness and Fe–S cluster-linked sensing

Recent literature continues to emphasize oxygen sensitivity in the FBXL5–IRP2 axis. Review-level evidence states that “iron- and oxygen-dependent degradation of IRP2 is mediated by FBXL5 E3 ligase,” and that FBXL5 structural stability is disrupted under iron deficiency, preventing IRP2 degradation (liang2026thecriticalrole pages 2-3).

Mechanistic work cited in 2024 (and discussed in a Molecular Cell 2024 paper’s contextual citations) points to an oxygen-responsive [2Fe–2S] cluster as part of FBXL5-linked sensing (ast2024mettl17isan pages 24-26). A structural/functional synthesis further describes a [2Fe–2S] cluster association tied to the LRR region and IRP2 recruitment (sicheri2025analysisoffbox pages 4-7), and 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).

2.4 Substrates and interaction partners

The dominant, repeatedly supported substrate is IRP2 (IREB2) (chen2026regulationofmitochondrial pages 4-5, cortadellas2023characterizationofnew pages 41-45, jain2026ironregulationredox pages 8-10). Interaction with SKP1 as part of SCF complex assembly is supported by structural/interaction summaries (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb).

2.5 Subcellular localization

Evidence retrieved here is limited and partly inconsistent across summaries. One review places FBXL5 activity “in the nucleus” while also noting IRP2/IRP1 function in the cytosol as RNA-binding proteins (chen2026regulationofmitochondrial pages 4-5). Other sources discuss the pathway without strong compartment specificity (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3). Thus, based strictly on retrieved evidence, FBXL5 can operate in nuclear-associated contexts, but the full compartment distribution cannot be conclusively resolved from the current evidence set.

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2023 JBC perspective on oxygen modulation of iron homeostasis

A 2023 Journal of Biological Chemistry article on oxygen modulation of iron homeostasis discusses regulation of the IRP system and references FBXL5 in SCF^FBXL5-mediated control of IRP2, including Fe–S/iron-linked sensing concepts (publication date: May 2023; URL: https://doi.org/10.1016/j.jbc.2023.104701) (guo2024novelbiallelicvariants pages 9-9).

3.2 2024 PNAS work highlighting FBXL5 as an “iron-sensing” [2Fe–2S] case

A 2024 PNAS paper on cytosolic [2Fe–2S] protein biogenesis explicitly frames FBXL5 as an “iron-sensing protein” with a hemerythrin domain and discusses oxygen-dependent binding behavior in the context of Fe–S biology (publication date: May 2024; URL: https://doi.org/10.1073/pnas.2400740121) (guo2024novelbiallelicvariants pages 9-9).

3.3 2024 Inorganics review on regulatory/sensing Fe–S clusters

A 2024 review focuses on Fe–S clusters as regulatory sensors and includes FBXL5 among mammalian proteins whose stability/function is tied to Fe–S chemistry and oxygen sensitivity (publication date: March 2024; URL: https://doi.org/10.3390/inorganics12040101) (guo2024novelbiallelicvariants pages 9-9).

3.4 2024 Molecular Cell context for oxygen-responsive [2Fe–2S] cluster regulation

A 2024 Molecular Cell study (focused on METTL17) cites mechanistic work describing FBXL5 regulation via an oxygen-responsive [2Fe–2S] cluster in iron homeostasis (publication date: January 2024; URL: https://doi.org/10.1016/j.molcel.2023.12.016) (ast2024mettl17isan pages 24-26).

4) Current applications and real-world implementations

4.1 FBXL5 perturbation as a preclinical model of iron overload–driven ferroptosis and liver injury

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). This represents a concrete “implementation” in experimental medicine: FBXL5 loss serves as a lever to elevate intracellular iron and sensitize tissue to ferroptotic injury.

4.2 Therapeutic modulation: ferroptosis inhibition (ferrostatin-1)

In the same study, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was administered (1 h prior to IRI) and was used to suppress injury readouts in FBXL5 liver-KO mice (matsumoto2025integratedhepaticferroptosis pages 20-23, matsumoto2025integratedhepaticferroptosis pages 11-13). This is an explicit example of pathway-targeted intervention built around iron/ferroptosis mechanisms that are unmasked or exacerbated by altered FBXL5 function.

4.3 Biomarker development: “iFerroptosis” hepatic gene signature and iron/lipid-peroxidation markers

The study created an integrated hepatic ferroptosis gene signature (iFerroptosis) and applied it to mouse injury models and human liver samples, alongside histochemical iron staining (Perls) and lipid peroxidation markers (e.g., 4-HNE) (matsumoto2025integratedhepaticferroptosis pages 20-23). This constitutes a practical framework for stratifying ferroptosis-associated pathology in liver injury settings.

5) Disease relevance, expert analysis, and authoritative perspectives

5.1 Pathophysiological framing: FBXL5 as a “brake” on iron accumulation

Review-level sources emphasize that the FBXL5–IRP2 axis constrains excessive intracellular iron and that disruption of this axis can contribute to oxidative stress and ferroptosis-linked pathology (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3). This aligns with mechanistic disease models where IRP2-dependent iron acquisition programs remain inappropriately active when FBXL5 is destabilized.

5.2 Evidence of clinical or phenotypic association from Open Targets

Open Targets lists FBXL5 disease/trait associations (e.g., neurodegenerative disease and certain syndromic phenotypes) based on linked evidence sets (publication database record; URL not provided in the tool output) (OpenTargets Search: -FBXL5). These associations should be treated as hypothesis-generating and interpreted alongside mechanistic evidence.

6) Relevant statistics and quantitative data from recent studies

6.1 Mouse IRI/ferroptosis intervention study: group sizes and significance thresholds

In the hepatic ischemia–reperfusion model using liver-specific Fbxl5 knockout mice, reported group sizes include: control sham n=16, control IRI n=15; FBXL5 liver-KO sham n=10, FBXL5 liver-KO IRI n=13, FBXL5 liver-KO IRI + Fer-1 n=6 (matsumoto2025integratedhepaticferroptosis pages 20-23). Outcomes included serum enzymes (AST/ALT/LDH), histology, and lipid peroxidation staining, with reported very strong statistical significance in some comparisons (e.g., ****p < 0.0001 in presented analyses) (matsumoto2025integratedhepaticferroptosis pages 20-23).

6.2 Human cohort: iron stratification and clinical correlation

The same work analyzed a human liver resection cohort (n=174) and stratified subsets by iron status (n=143 low-iron vs n=31 high-iron) for certain analyses, reporting that elevated serum iron correlated with sustained/delayed post-operative liver damage recovery (matsumoto2025integratedhepaticferroptosis pages 1-5, matsumoto2025integratedhepaticferroptosis pages 20-23).

7) Summary table (evidence-grounded functional annotation)

Functional role	Molecular mechanism	Key domains/cofactors	Key substrates/interactions	Localization/compartment (if evidenced)	Evidence notes with citations placeholders
Iron-responsive substrate receptor in SCF E3 ubiquitin ligase	Under iron-replete conditions, FBXL5 is stabilized and recruits IRP2/IREB2 for ubiquitination and proteasomal degradation, thereby suppressing IRP2-dependent iron-starvation responses	F-box domain; leucine-rich repeat (LRR) region; N-terminal hemerythrin-like domain; diiron center; [2Fe-2S] cluster reported in LRR-associated sensing model	IRP2/IREB2 substrate; SKP1 interaction as SCF component	Nucleus explicitly mentioned in one review; broader IRP pathway acts in cytoplasmic iron-response circuitry	Human FBXL5 is described as hemerythrin-like/F-box/LRR and as the substrate-recognition component of SCF targeting IRP2 (sicheri2025analysisoffbox pages 4-7, chen2026regulationofmitochondrial pages 4-5, cortadellas2023characterizationofnew pages 41-45)
Iron/oxygen sensor controlling its own stability	Iron binding stabilizes FBXL5; low iron destabilizes FBXL5 and permits IRP2 accumulation; oxygen sensitivity has been linked to an oxygen-responsive Fe-S-based mechanism	Hemerythrin-like diiron-binding module; oxygen-responsive [2Fe-2S] cluster mechanism	Functional coupling to IRP2 turnover	Nuclear mention reported; no stronger consensus localization extracted here	Reviews and cited mechanistic work describe FBXL5 as iron- and oxygen-sensitive, with stability governed by metal cofactor occupancy (ast2024mettl17isan pages 24-26, jain2026ironregulationredox pages 8-10, chen2026regulationofmitochondrial pages 4-5)
Structural adapter linking metal sensing to ubiquitin machinery	F-box mediates SCF assembly through SKP1, while substrate-binding surfaces in the LRR/other conserved regions support IREB2 recognition	Central F-box (SKP1-binding hotspot); C-terminal LRR substrate-binding region; hemerythrin-like metal-sensing domain	SKP1; IREB2; diiron center visualized in structural summary	Not specifically assigned by structural summary	Structural analysis and retrieved figure summarize domain architecture and interactions with SKP1 and IREB2 (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb)

Table: This table summarizes the core functional annotation of human FBXL5 (UniProt Q9UKA1) using only evidence established in the conversation. It highlights FBXL5’s role as an iron/oxygen-sensitive SCF substrate receptor for IRP2, the domains/cofactors supporting that function, and the limited localization evidence retrieved.

8) Key figure (domain architecture and interactions)

A figure from a structural analysis illustrates FBXL5’s Hr/F-box/LRR architecture and interaction with SCF component SKP1 and substrate IREB2/IRP2 (sicheri2025analysisoffbox media b6a989cb).

9) Limitations of the current evidence set

The retrieved evidence strongly supports FBXL5’s core role in the SCF^FBXL5 → IRP2 degradation pathway and its metal/oxygen-linked sensing features, but provides limited direct experimental localization detail (nuclear vs cytosolic distribution) beyond a single review statement (chen2026regulationofmitochondrial pages 4-5).
While the user requested heavy emphasis on 2023–2024, many mechanistic details in this evidence set appear in later reviews/analyses or as cited prior work; where possible, 2023–2024 sources are highlighted for the iron/oxygen/Fe–S framing (ast2024mettl17isan pages 24-26, guo2024novelbiallelicvariants pages 9-9).

10) Source URLs and publication dates (from retrieved context)

Kuno & Iwai, J Biol Chem (May 2023): https://doi.org/10.1016/j.jbc.2023.104701 (guo2024novelbiallelicvariants pages 9-9)
Braymer et al., PNAS (May 2024): https://doi.org/10.1073/pnas.2400740121 (guo2024novelbiallelicvariants pages 9-9)
SantaMaria & Rouault, Inorganics (Mar 2024): https://doi.org/10.3390/inorganics12040101 (guo2024novelbiallelicvariants pages 9-9)
Ast et al., Molecular Cell (Jan 2024): https://doi.org/10.1016/j.molcel.2023.12.016 (ast2024mettl17isan pages 24-26)
Matsumoto et al., Hepatology Communications / preprint DOI (Oct 2025, preprint DOI indicates 2024-10-27 submission): https://doi.org/10.1101/2024.10.27.620461 (matsumoto2025integratedhepaticferroptosis pages 1-5, matsumoto2025integratedhepaticferroptosis pages 20-23)
Guo et al., Orphanet J Rare Dis (Nov 2024): https://doi.org/10.1186/s13023-024-03465-7 (guo2024novelbiallelicvariants pages 9-9)

References

(sicheri2025analysisoffbox pages 4-7): Elliot Sicheri, Daniel Mao, Michael Tyers, and Frank Sicheri. Analysis of fbox substrate adapter proteins using proteosync, a program for projection of evolutionary conservation onto protein atomic coordinates. Computational and Structural Biotechnology Journal, 27:4026-4039, Sep 2025. URL: https://doi.org/10.1016/j.csbj.2025.09.012, doi:10.1016/j.csbj.2025.09.012. This article has 0 citations and is from a peer-reviewed journal.
(sicheri2025analysisoffbox media b6a989cb): Elliot Sicheri, Daniel Mao, Michael Tyers, and Frank Sicheri. Analysis of fbox substrate adapter proteins using proteosync, a program for projection of evolutionary conservation onto protein atomic coordinates. Computational and Structural Biotechnology Journal, 27:4026-4039, Sep 2025. URL: https://doi.org/10.1016/j.csbj.2025.09.012, doi:10.1016/j.csbj.2025.09.012. This article has 0 citations and is from a peer-reviewed journal.
(cortadellas2023characterizationofnew pages 41-45): L Romero Cortadellas. Characterization of new mutations in transferrin, dmt1 and sec23b causing rare iron metabolism-related diseases; and the discovery of racgap1 as the gene …. Unknown journal, 2023.
(chen2026regulationofmitochondrial pages 4-5): Xuyang Chen, Saijun Xiao, Ziwei Zhang, Jiapeng Gong, Jiaqi Wu, Jiayi Wu, Liqin Jin, Jianxin Lyu, and Xiaojun Ren. Regulation of mitochondrial iron homeostasis in tumor cells. Molecular Medicine, Feb 2026. URL: https://doi.org/10.1186/s10020-026-01436-1, doi:10.1186/s10020-026-01436-1. This article has 1 citations and is from a peer-reviewed journal.
(liang2026thecriticalrole pages 2-3): Tiantian Liang, Jiasen Xu, Yan Zhu, He Zhao, Xiaoyu Zhai, Qi Wang, Xiaohui Ma, Limei Cui, and Yan Sun. The critical role of iron homeostasis in neurodegenerative diseases. Neural regeneration research, Apr 2026. URL: https://doi.org/10.4103/nrr.nrr-d-24-01382, doi:10.4103/nrr.nrr-d-24-01382. This article has 1 citations and is from a peer-reviewed journal.
(jain2026ironregulationredox pages 8-10): Chesta Jain and Yatrik M. Shah. Iron: regulation, redox homeostasis, and ferroptosis in cancer. Ferroptosis and oxidative stress, Mar 2026. URL: https://doi.org/10.70401/fos.2026.0022, doi:10.70401/fos.2026.0022. This article has 0 citations.
(ast2024mettl17isan pages 24-26): Tslil Ast, Yuzuru Itoh, Shayan Sadre, Jason G. McCoy, Gil Namkoong, Jordan C. Wengrod, Ivan Chicherin, Pallavi R. Joshi, Piotr Kamenski, Daniel L.M. Suess, Alexey Amunts, and Vamsi K. Mootha. Mettl17 is an fe-s cluster checkpoint for mitochondrial translation. Molecular Cell, 84:359-374.e8, Jan 2024. URL: https://doi.org/10.1016/j.molcel.2023.12.016, doi:10.1016/j.molcel.2023.12.016. This article has 54 citations and is from a highest quality peer-reviewed journal.
(guo2024novelbiallelicvariants pages 9-9): Zhenglong Guo, Dawei Huo, Yingying Shao, Wenke Yang, Jinming Wang, Yuwei Zhang, Hai Xiao, Bingtao Hao, and Shixiu Liao. Novel biallelic variants in ireb2 cause an early-onset neurodegenerative disorder in a chinese pedigree. Orphanet Journal of Rare Diseases, Nov 2024. URL: https://doi.org/10.1186/s13023-024-03465-7, doi:10.1186/s13023-024-03465-7. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 1-5): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 8-11): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 20-23): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 11-13): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXL5): Open Targets Query (-FBXL5, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Edison artifact artifact-00

Citations

liang2026thecriticalrole pages 2-3
sicheri2025analysisoffbox pages 4-7
jain2026ironregulationredox pages 8-10
chen2026regulationofmitochondrial pages 4-5
guo2024novelbiallelicvariants pages 9-9
matsumoto2025integratedhepaticferroptosis pages 20-23
cortadellas2023characterizationofnew pages 41-45
matsumoto2025integratedhepaticferroptosis pages 1-5
matsumoto2025integratedhepaticferroptosis pages 8-11
matsumoto2025integratedhepaticferroptosis pages 11-13
2Fe–2S
2Fe-2S
https://doi.org/10.1016/j.jbc.2023.104701
https://doi.org/10.1073/pnas.2400740121
https://doi.org/10.3390/inorganics12040101
https://doi.org/10.1016/j.molcel.2023.12.016
https://doi.org/10.1101/2024.10.27.620461
https://doi.org/10.1186/s13023-024-03465-7
https://doi.org/10.1016/j.csbj.2025.09.012,
https://doi.org/10.1186/s10020-026-01436-1,
https://doi.org/10.4103/nrr.nrr-d-24-01382,
https://doi.org/10.70401/fos.2026.0022,
https://doi.org/10.1016/j.molcel.2023.12.016,
https://doi.org/10.1186/s13023-024-03465-7,
https://doi.org/10.1101/2024.10.27.620461,

📚 Additional Documentation

Pn Notes

(FBXL5-pn-notes.md)

FBXL5 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UKA1
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXL5/FBXL5-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXL5/FBXL5-ai-review.html
Gene notes: missing - genes/human/FBXL5/FBXL5-notes.md
GOA TSV: present - genes/human/FBXL5/FBXL5-goa.tsv
UniProt record: present - genes/human/FBXL5/FBXL5-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXL5.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXL5.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXL5/FBXL5-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 28; MODIFY: 1

PN Consistency Summary

Consistency: Strong. Deep research, review YAML, PN annotation, and node mapping agree: FBXL5 is the iron/oxygen-sensing SCF substrate receptor for IRP2/IREB2. Rich experimental backbone (PMID:19762596 IMP/IDA, 19762597 IDA/IEP, 17532294 DCTN1, 24157836 SNAI1). No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor MF. The review goes well beyond: it keeps the experimentally validated GO:0005506 iron ion binding (IDA) as a co-core MF — a real function the PN mapping does NOT capture — and MODIFY's the catalytic GO:0004842 (NAS) to GO:1990756. The review also PROPOSES a new term "iron- and oxygen-sensing ubiquitin-ligase substrate adaptor activity" (child of GO:1990756). OLS search returns no existing GO equivalent, so this is a legitimate candidate-new-term, not a duplicate; correctly justified as more precise than GO:1990756. Conclusion: adaptor MF captured; the iron-sensing MF + proposed child are an ADD beyond the PN story (defensible).
Evidence alignment: PN cites only "15340381/rev" (PMID:15340381). The review does not cite it; it uses gene-specific primaries plus falcon. Benign placeholder divergence.
Verdict: CONSISTENT / ACCEPT mapping. No edits needed. Note: proposed_new_term (iron/oxygen-sensing adaptor) is verified as not pre-existing in GO — keep as candidate (unverified existence elsewhere, but no GO clash).

Full Consistency Review

UniProt: Q9UKA1 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group-level mapped / ok_for_propagation_to_go / GO:1990756; class context_only / too_broad / GO:0061630.
Consistency: Strong. Deep research, review YAML, PN annotation, and node mapping agree: FBXL5 is the iron/oxygen-sensing SCF substrate receptor for IRP2/IREB2. Rich experimental backbone (PMID:19762596 IMP/IDA, 19762597 IDA/IEP, 17532294 DCTN1, 24157836 SNAI1). No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor MF. The review goes well beyond: it keeps the experimentally validated GO:0005506 iron ion binding (IDA) as a co-core MF — a real function the PN mapping does NOT capture — and MODIFY's the catalytic GO:0004842 (NAS) to GO:1990756. The review also PROPOSES a new term "iron- and oxygen-sensing ubiquitin-ligase substrate adaptor activity" (child of GO:1990756). OLS search returns no existing GO equivalent, so this is a legitimate candidate-new-term, not a duplicate; correctly justified as more precise than GO:1990756. Conclusion: adaptor MF captured; the iron-sensing MF + proposed child are an ADD beyond the PN story (defensible).
Mapping strategy: Gene does not change the node; group GO:1990756 is appropriate and matches review core_functions. PN scope correct. The metal-sensing layer is gene-specific and rightly stays out of the shared node mapping. Canonical, validated-substrate receptor — no orphan flag.
Evidence alignment: PN cites only "15340381/rev" (PMID:15340381). The review does not cite it; it uses gene-specific primaries plus falcon. Benign placeholder divergence.
Verdict: CONSISTENT / ACCEPT mapping. No edits needed. Note: proposed_new_term (iron/oxygen-sensing adaptor) is verified as not pre-existing in GO — keep as candidate (unverified existence elsewhere, but no GO clash).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXL5/FBXL5-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR

UniProt: Q9UKA1
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR001611, IPR032675
PN references (titles):
- 15340381 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

FBXL5

Gene Description

Proposed New Ontology Terms

iron- and oxygen-sensing ubiquitin-ligase substrate adaptor activity

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human FBXL5 (UniProt Q9UKA1) — Functional Annotation and Current Understanding

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 FBXL5 as a substrate receptor in an SCF E3 ubiquitin ligase

1.2 IRP/IRE post-transcriptional iron regulation (context for FBXL5 function)

1.3 “Iron/oxygen sensor” concept as applied to FBXL5

2) Molecular function, domains, and mechanism (structure → function)

2.1 Domain architecture (and why it matters)

2.2 Iron-dependent regulation of FBXL5 stability and IRP2 ubiquitination

2.3 Oxygen responsiveness and Fe–S cluster-linked sensing

2.4 Substrates and interaction partners

2.5 Subcellular localization

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2023 JBC perspective on oxygen modulation of iron homeostasis

3.2 2024 PNAS work highlighting FBXL5 as an “iron-sensing” [2Fe–2S] case

3.3 2024 Inorganics review on regulatory/sensing Fe–S clusters

3.4 2024 Molecular Cell context for oxygen-responsive [2Fe–2S] cluster regulation

4) Current applications and real-world implementations

4.1 FBXL5 perturbation as a preclinical model of iron overload–driven ferroptosis and liver injury

4.2 Therapeutic modulation: ferroptosis inhibition (ferrostatin-1)

4.3 Biomarker development: “iFerroptosis” hepatic gene signature and iron/lipid-peroxidation markers

5) Disease relevance, expert analysis, and authoritative perspectives

5.1 Pathophysiological framing: FBXL5 as a “brake” on iron accumulation

5.2 Evidence of clinical or phenotypic association from Open Targets

6) Relevant statistics and quantitative data from recent studies

6.1 Mouse IRI/ferroptosis intervention study: group sizes and significance thresholds

6.2 Human cohort: iron stratification and clinical correlation

7) Summary table (evidence-grounded functional annotation)

8) Key figure (domain architecture and interactions)

9) Limitations of the current evidence set

10) Source URLs and publication dates (from retrieved context)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXL5 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR

Projected GO annotations (1)

Note

📄 View Raw YAML