FBXO7

UniProt ID: Q9Y3I1
Organism: Homo sapiens
Review Status: COMPLETE
📝 Provide Detailed Feedback

Gene Description

FBXO7 (also called FBX7; PARK15) is the substrate-recognition (F-box) component of an SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin-protein ligase complex, SCF(FBXO7). As an F-box protein it acts as a ligase-substrate adaptor: it recruits substrates and bridges them, via its F-box domain binding to SKP1, to the catalytic cullin-RING core (RBX1), and is not itself the catalytic ubiquitin transferase. The protein has a modular architecture comprising an N-terminal ubiquitin-like (Ubl) region that mediates binding to the E3 ligase PRKN/Parkin, a CDK6-interaction region, an FP (Fbxo7/PI31) dimerization domain that mediates homodimerization and interaction with the proteasome inhibitor PSMF1/PI31, the F-box domain, and a C-terminal proline-rich region that serves as a substrate-binding module. SCF(FBXO7) ubiquitination is not exclusively degradative: it can build K48-linked chains that target substrates for proteasomal degradation or K63-linked chains with non-proteolytic signaling/assembly outcomes, depending on substrate and context. Documented SCF(FBXO7) substrates include the cell-cycle regulator DLGAP5/HURP, the inhibitor-of-apoptosis protein BIRC2/cIAP1, TRAF2 and the NF-kappa-B cofactor UXT isoform 2 (whose degradation inhibits NF-kappa-B signaling), the NAD+-dependent deacetylase SIRT7 (K48- linked polyubiquitination promoting H2O2-induced cell death), the kinase GSK3-beta and the mitochondrial import receptor TOMM20 (modified in part with non-degradative chains), and, in tumor-suppressor contexts, the mitochondrial-fission factor INF2 and the arginine methyltransferase PRMT1 (K48-linked polyubiquitination coupling FBXO7 to control of mitochondrial division and serine biosynthesis, respectively). Beyond canonical SCF activity, FBXO7 has SCF-independent roles: it relocates from the cytosol to depolarized mitochondria downstream of PINK1 and promotes PRKN/Parkin recruitment and mitofusin ubiquitination to drive selective autophagy of damaged mitochondria (mitophagy); it associates with the proteasome and regulates proteasome assembly/activity through PSMF1/PI31; and it activates cyclin D/CDK6 complexes to promote cell-cycle progression, with proto-oncogenic transforming activity. FBXO7 protein stability is itself controlled by the deubiquitinase USP7. FBXO7 is predominantly cytoplasmic/cytosolic with a minor nuclear pool. Recessive loss-of-function and missense mutations (e.g. T22M, R378G, R498X) cause early-onset autosomal recessive parkinsonian-pyramidal syndrome (Parkinson disease 15, PARK15).

Existing Annotations Review

GO Term Evidence Action Reason
GO:1903599 positive regulation of autophagy of mitochondrion
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of a positive role in mitophagy, consistent with the experimentally demonstrated FBXO7 function downstream of PINK1 in Parkin-mediated mitophagy.
Reason: Core biological process; the IBA inference agrees with direct IMP/IDA evidence (PMID:23933751, PMID:26310625) that FBXO7 promotes clearance of depolarized mitochondria.
Supporting Evidence:
PMID:23933751
Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.
file:human/FBXO7/FBXO7-deep-research-falcon.md
FBXO7 participates in mitochondrial quality control by interacting with **PINK1 and Parkin** and facilitating Parkin recruitment to damaged mitochondria in PARK15 biology.
GO:0019901 protein kinase binding
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic assignment of protein kinase binding, reflecting the documented FBXO7 interactions with the kinases CDK6 and PINK1.
Reason: Real and mechanistically meaningful (CDK6 activation of cyclin D complexes; PINK1 in the mitophagy pathway) but a subsidiary binding activity rather than the core adaptor function.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Interacts with CDK6 and promotes its interaction with D-type cyclin.
GO:0005634 nucleus
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic assignment of nuclear localization; FBXO7 has a documented minor nuclear pool in addition to its predominant cytoplasmic localization.
Reason: Nuclear localization is real but minor; the predominant and functionally dominant compartment is the cytoplasm/cytosol.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
A minor proportion is detected in the nucleus (PubMed:16096642).
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; the predominant compartment of FBXO7.
Reason: Correct predominant localization, supported experimentally (PMID:16096642, PMID:18495667).
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Note=Predominantly cytoplasmic (PubMed:16096642).
GO:0005739 mitochondrion
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of mitochondrial localization, consistent with the experimentally observed relocation of FBXO7 from the cytosol to depolarized mitochondria.
Reason: Correct conditional localization; FBXO7 relocates to depolarized mitochondria during mitophagy (PMID:23933751).
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Relocates from the cytosol to depolarized mitochondria (PubMed:23933751).
GO:0005829 cytosol
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of cytosolic localization from the UniProt subcellular location; the predominant compartment of FBXO7.
Reason: Correct core localization, supported experimentally (PMID:23933751).
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0019901 protein kinase binding
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic assignment of protein kinase binding, reflecting documented CDK6 and PINK1 interactions.
Reason: Real binding activity (CDK6, PINK1) but subsidiary to the core ligase-substrate adaptor function.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Interacts with CDK6 and promotes its interaction with D-type cyclin.
GO:0005515 protein binding
IPI
PMID:16278047
Characterization of FBX25, encoding a novel brain-expressed ... 		KEEP AS NON CORE
Summary: Interaction captured during characterization of a related brain-expressed F-box protein (FBX25). Bare protein binding is uninformative.
Reason: Records a real interaction but the bare protein binding term is uninformative per curation guidelines.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:22632967
Cyclin F-mediated degradation of ribonucleotide reductase M2... 		KEEP AS NON CORE
Summary: Interaction captured in a cyclin F (FBXO1)/RRM2 study. Bare protein binding is uninformative.
Reason: Records a real interaction but bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		KEEP AS NON CORE
Summary: Interaction with PRKN/Parkin (and PINK1) from the mitophagy study; a functionally important interaction, but the bare protein binding term is uninformative.
Reason: Records the meaningful FBXO7-PRKN/PINK1 interaction, but bare protein binding is uninformative; the functional relationship is captured by the mitophagy process annotations.
Supporting Evidence:
PMID:23933751
the Ubl domain of Fbxo7 directly mediates Parkin interaction
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: High-throughput proteome-scale interactome mapping. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:25910212
Widespread macromolecular interaction perturbations in human... 		KEEP AS NON CORE
Summary: High-throughput interactome perturbation study. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:26496610
A human interactome in three quantitative dimensions organiz... 		KEEP AS NON CORE
Summary: High-throughput quantitative interactome map. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complex... 		KEEP AS NON CORE
Summary: High-throughput Polycomb complexome interaction map. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: High-throughput interactome (protein communities/disease networks). Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		KEEP AS NON CORE
Summary: High-throughput variant-interactome disruption study. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: High-throughput neurodegenerative-disease interactome map. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: High-throughput dual proteome-scale interactome map. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: High-throughput multimodal cell-map interactome. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:1901526 positive regulation of mitophagy
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment of positive regulation of mitophagy, consistent with the experimentally established FBXO7 mitophagy role.
Reason: Core biological process; agrees with direct experimental evidence (PMID:23933751, PMID:26310625).
Supporting Evidence:
PMID:26310625
The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
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 catabolic process FBXO7 enables.
Reason: Correct but generic; the specific GO:0031146 (SCF-dependent catabolic process) and K48-linked ubiquitination annotations better capture the role.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		KEEP AS NON CORE
Summary: HPA immunofluorescence assignment of nucleoplasm localization, consistent with the documented minor nuclear pool of FBXO7.
Reason: Real but minor nuclear localization; the predominant compartment is the cytoplasm/cytosol.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
A minor proportion is detected in the nucleus (PubMed:16096642).
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: HPA immunofluorescence assignment of cytosolic localization, the predominant FBXO7 compartment.
Reason: Correct core localization; supported by direct experimental fractionation (PMID:23933751).
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005634 nucleus
EXP
PMID:16096642
Transforming activity of Fbxo7 is mediated specifically thro... 		KEEP AS NON CORE
Summary: Experimental localization showing FBXO7 in the nucleus (minor pool) in addition to predominant cytoplasm.
Reason: Real minor nuclear localization documented in this study; predominant compartment is cytoplasmic.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
A minor proportion is detected in the nucleus (PubMed:16096642).
GO:0005737 cytoplasm
EXP
PMID:16096642
Transforming activity of Fbxo7 is mediated specifically thro... 		ACCEPT
Summary: Experimental localization showing FBXO7 is predominantly cytoplasmic. Core compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Note=Predominantly cytoplasmic (PubMed:16096642).
GO:0005737 cytoplasm
EXP
PMID:18495667
Structure of a conserved dimerization domain within the F-bo... 		ACCEPT
Summary: Experimental localization to the cytoplasm consistent with the predominant FBXO7 compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: Author statement that FBXO7 is an F-box component of an SCF E3 ubiquitin ligase complex. Core complex membership.
Reason: Core localization/complex; FBXO7 is the substrate-receptor F-box subunit of SCF(FBXO7) (CUL1, SKP1, RBX1, FBXO7).
Supporting Evidence:
PMID:34445249
The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: Author statement linking the SCF complex (including F-box proteins) to SCF-dependent proteasomal degradation. Core biological process.
Reason: Core biological process; FBXO7 targets substrates for SCF-dependent proteasomal degradation.
Supporting Evidence:
PMID:34445249
These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity.
GO:0005634 nucleus
IDA
PMID:33010352
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 acts in the nucleus, where it colocalizes with and ubiquitinates its substrate UXT-V2.
Reason: Documents a functionally relevant nuclear pool (UXT-V2 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
Supporting Evidence:
PMID:33010352
We find that UXT-V2 colocalizes with Fbxo7 in the cell nucleus.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IDA
PMID:33010352
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... 		ACCEPT
Summary: Direct evidence that SCF(FBXO7) mediates SCF-dependent proteasomal degradation of UXT-V2. Core biological process.
Reason: Core biological process with direct experimental support; SCF(FBXO7) polyubiquitinates UXT-V2 for proteasomal degradation.
Supporting Evidence:
PMID:33010352
Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.
GO:0043124 negative regulation of canonical NF-kappaB signal transduction
IDA
PMID:33010352
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... 		ACCEPT
Summary: Direct evidence that SCF(FBXO7)-mediated degradation of UXT-V2 inhibits NF-kappa-B signaling. Well-supported biological process.
Reason: Directly demonstrated; FBXO7 negatively regulates NF-kappa-B signaling via UXT-V2 (and TRAF2/cIAP1) ubiquitination.
Supporting Evidence:
PMID:33010352
Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.
GO:0070936 protein K48-linked ubiquitination
IDA
PMID:33010352
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... 		ACCEPT
Summary: Direct evidence that SCF(FBXO7) builds K48 (and K63) polyubiquitin chains on UXT-V2.
Reason: Directly demonstrated K48-linked ubiquitination of a substrate, the canonical degradative topology used by SCF(FBXO7).
Supporting Evidence:
PMID:33010352
This substrate is polyubiquitinated by SCF(Fbxo7) with K48 and K63 ubiquitin chain linkages in vitro and in vivo.
GO:1901526 positive regulation of mitophagy
IDA
PMID:26310625
F-box protein 7 mutations promote protein aggregation in mit... 		ACCEPT
Summary: Direct evidence that WT FBXO7 facilitates mitophagy whereas PD-linked mutants inhibit it. Core biological process.
Reason: Core biological process with direct experimental support.
Supporting Evidence:
PMID:26310625
The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway
IMP
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Mutant-phenotype evidence linking an FBXO7 variant (Y52C) to altered TRAF2 turnover and neuronal outgrowth in a PD-protective context.
Reason: A context-specific neuronal stress/apoptosis-modulating role inferred from variant phenotypes, not the core SCF adaptor function.
Supporting Evidence:
PMID:25029497
After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway
IDA
PMID:26310625
F-box protein 7 mutations promote protein aggregation in mit... 		KEEP AS NON CORE
Summary: Evidence that FBXO7 acts as a stress-response protein with cytoprotective (and, when mutant/aggregated, neurotoxic) effects under oxidative stress.
Reason: A context-specific neuronal stress-response role; mechanistically downstream of the core mitophagy/proteostasis functions rather than a distinct core process.
Supporting Evidence:
PMID:26310625
Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles.
GO:0005634 nucleus
IDA
PMID:36646384
E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 colocalizes with its substrate SIRT7 mainly in the nucleus, where it acts to degrade SIRT7.
Reason: Documents a functionally relevant nuclear pool (SIRT7 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
Supporting Evidence:
PMID:36646384
immunohistochemical analysis of SH-SY5Y cells revealed that endogenous FBXO7 and SIRT7 colocalized mainly in the nucleus
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
IDA
PMID:36646384
E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... 		ACCEPT
Summary: Direct evidence that FBXO7 drives SCF-dependent proteasomal degradation of SIRT7. Core biological process.
Reason: Core biological process; FBXO7 promotes proteasomal degradation of SIRT7 (the more specific GO:0031146 SCF-dependent process is also annotated).
Supporting Evidence:
PMID:36646384
we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation
GO:0070936 protein K48-linked ubiquitination
IDA
PMID:36646384
E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... 		ACCEPT
Summary: Direct evidence that FBXO7 promotes K48-linked polyubiquitination of SIRT7.
Reason: Directly demonstrated K48-linked ubiquitination of a substrate (SIRT7), the canonical degradative topology of SCF(FBXO7).
Supporting Evidence:
PMID:36646384
These results demonstrated that FBXO7 directly mediates the polyubiquitination of SIRT7 by targeting K48-linked polyubiquitin chains.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity
IDA
PMID:36646384
E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... 		ACCEPT
Summary: Direct evidence that FBXO7 acts as an SCF substrate-recognition adaptor recruiting SIRT7 for ubiquitination. Core molecular function.
Reason: Core molecular function; FBXO7 is the substrate-recognition adaptor of SCF(FBXO7), bridging substrates to the catalytic cullin-RING core.
Supporting Evidence:
PMID:36646384
FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
GO:0019005 SCF ubiquitin ligase complex
IDA
PMID:15145941
Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... 		ACCEPT
Summary: Direct evidence that FBXO7 functions within an SCF(FBXO7) complex (with SKP1 and CUL1) to ubiquitinate HURP/DLGAP5. Core complex membership.
Reason: Core localization/complex; FBXO7 is a functional F-box subunit of an SCF ubiquitin-ligase complex.
Supporting Evidence:
PMID:15145941
In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity
IDA
PMID:15145941
Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... 		ACCEPT
Summary: Direct evidence that FBXO7 functions as a substrate-recruiting adaptor of the SCF complex, binding HURP via its proline-rich region. Core molecular function.
Reason: Core molecular function; FBXO7 is a functional SCF adaptor with the proline-rich region serving as the substrate-binding module.
Supporting Evidence:
PMID:15145941
Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.
GO:0005515 protein binding
IPI
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 ... 		KEEP AS NON CORE
Summary: Interaction captured in a study of SKP1/CRM1 competition controlling F-box protein localization. Bare protein binding is uninformative.
Reason: Records a real interaction relevant to FBXO7 nuclear/cytoplasmic shuttling (SKP1, CRM1) but bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
GO:0005739 mitochondrion
IDA
PMID:26310625
F-box protein 7 mutations promote protein aggregation in mit... 		ACCEPT
Summary: Direct evidence that FBXO7 concentrates into mitochondria upon stress, forming aggregates. Conditional/stress-induced localization.
Reason: Correct conditional localization; FBXO7 relocates to mitochondria under stress/depolarization, consistent with its mitophagy role.
Supporting Evidence:
PMID:26310625
Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria.
GO:0005515 protein binding
IPI
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Interaction with TRAF2 captured in the FBXO7 Y52C polymorphism study. Bare protein binding is uninformative.
Reason: Records the functionally meaningful FBXO7-TRAF2 interaction but bare protein binding is uninformative; the substrate relationship is captured by the ubiquitination/NF-kappa-B annotations.
Supporting Evidence:
PMID:25029497
Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination
GO:0005634 nucleus
IDA
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of ap... 		KEEP AS NON CORE
Summary: Direct evidence of FBXO7 nuclear localization (colocalized with cIAP1/BIRC2 in cytoplasm and nucleus). Minor nuclear pool.
Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
Supporting Evidence:
PMID:16510124
When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus
GO:0005634 nucleus
IDA
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Direct evidence of FBXO7 nuclear localization, consistent with the documented minor nuclear pool.
Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
A minor proportion is detected in the nucleus (PubMed:16096642).
GO:0005737 cytoplasm
IDA
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of ap... 		ACCEPT
Summary: Direct evidence of FBXO7 cytoplasmic localization (colocalized with cIAP1/BIRC2). Core compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
PMID:16510124
When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus
GO:0005737 cytoplasm
IDA
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		ACCEPT
Summary: Direct evidence of FBXO7 cytoplasmic localization. Core compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Note=Predominantly cytoplasmic (PubMed:16096642).
GO:0006511 ubiquitin-dependent protein catabolic process
IDA
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 promotes ubiquitination and turnover of TRAF2. A parent of the more specific SCF-dependent catabolic process.
Reason: Correct but generic relative to the specific GO:0031146 (SCF-dependent proteasomal catabolic process); here the substrate is TRAF2.
Supporting Evidence:
PMID:25029497
In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced.
GO:0010975 regulation of neuron projection development
IMP
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Mutant-phenotype evidence that an FBXO7 variant alters neuronal outgrowth in differentiated SH-SY5Y cells.
Reason: A context-specific neuronal phenotype linked to an FBXO7 variant, not the core SCF adaptor function.
Supporting Evidence:
PMID:25029497
After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
GO:0016567 protein ubiquitination
IDA
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of ap... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 overexpression promotes ubiquitination of cIAP1/BIRC2. Generic parent process.
Reason: Correct but generic; the specific SCF-dependent catabolic process (GO:0031146) better captures the role. The cIAP1/BIRC2 substrate relationship is meaningful.
Supporting Evidence:
PMID:16510124
Furthermore, we showed that overexpression of Fbxo7 promotes the ubiquitination of cIAP1.
GO:0019901 protein kinase binding
IPI
PMID:18495667
Structure of a conserved dimerization domain within the F-bo... 		KEEP AS NON CORE
Summary: Interaction with the kinase CDK6 (and PSMF1) documented in the FP-domain structural study.
Reason: Real CDK6 binding (FBXO7 activates cyclin D-CDK6) but subsidiary to the core adaptor function.
Supporting Evidence:
PMID:18495667
SCF(Fbxo7) is known to catalyze the ubiquitination of hepatoma-up-regulated protein (HURP) and the inhibitor of apoptosis (IAP) protein but also functions as an activator of cyclin D-Cdk6 complexes.
GO:0031625 ubiquitin protein ligase binding
IPI
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of ap... 		KEEP AS NON CORE
Summary: Interaction with the ubiquitin ligase cIAP1/BIRC2 (itself a RING E3) documented as an FBXO7 substrate interaction.
Reason: Records a real interaction with a ubiquitin ligase substrate (BIRC2) but is subsidiary to the core adaptor function.
Supporting Evidence:
PMID:16510124
we performed a yeast two-hybrid screen and identified an F-box protein Fbxo7 as a cIAP1 interacting protein.
GO:0043130 ubiquitin binding
IDA
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in ... 		KEEP AS NON CORE
Summary: Assignment of ubiquitin binding to FBXO7. A plausible but ancillary activity relative to the core substrate-adaptor function.
Reason: If accurate, ubiquitin binding is a subsidiary molecular feature; the core function is the ligase-substrate adaptor activity. Not central to the documented FBXO7 roles.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
The ubiquitin-like region mediates interaction with PRKN.
GO:0046982 protein heterodimerization activity
IPI
PMID:18495667
Structure of a conserved dimerization domain within the F-bo... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 heterodimerizes with PSMF1/PI31 via the shared FP domain (and homodimerizes).
Reason: Real FP-domain-mediated dimerization with PSMF1/PI31 (relevant to proteasome regulation) but a structural/binding property rather than the core adaptor function.
Supporting Evidence:
PMID:18495667
We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
GO:0005634 nucleus
IDA
PMID:21347293
Loss of nuclear activity of the FBXO7 protein in patients wi... 		KEEP AS NON CORE
Summary: Direct evidence that wild-type FBXO7 isoform 1 displays mostly diffuse nuclear localization, with loss of nuclear localization in PARK15 mutants.
Reason: This study emphasizes a nuclear pool, but UniProt and other studies establish that FBXO7 is predominantly cytoplasmic; nuclear localization is treated as non-core.
Supporting Evidence:
PMID:21347293
the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization
GO:0005737 cytoplasm
IDA
PMID:21347293
Loss of nuclear activity of the FBXO7 protein in patients wi... 		ACCEPT
Summary: Direct evidence of FBXO7 cytoplasmic localization, including mutant-induced cytoplasmic mislocalization. Core compartment.
Reason: Core localization with direct experimental support; PARK15 N-terminal mutations shift FBXO7 to the cytoplasm.
Supporting Evidence:
PMID:21347293
N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization
GO:0005634 nucleus
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Immunohistochemical detection of FBXO7 in human brain neurons; widespread expression. Reported nuclear/cytoplasmic neuronal staining.
Reason: Brain immunoreactivity localization; nuclear pool is minor relative to predominant cytoplasm.
Supporting Evidence:
PMID:23656991
We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.
GO:0005737 cytoplasm
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		ACCEPT
Summary: Immunohistochemical detection of FBXO7 in the cytoplasm of human brain neurons. Consistent with predominant cytoplasmic localization.
Reason: Consistent with the core cytoplasmic localization of FBXO7 in neurons.
Supporting Evidence:
PMID:23656991
We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.
GO:0019005 SCF ubiquitin ligase complex
TAS
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of ap... 		ACCEPT
Summary: Author statement that F-box proteins such as FBXO7 are specificity-determining subunits of SCF ubiquitin ligases. Core complex membership.
Reason: Core localization/complex; FBXO7 is the F-box substrate-receptor subunit of an SCF E3 ligase.
Supporting Evidence:
PMID:16510124
Since F-box proteins are specificity determining subunits of SCF ubiquitin protein ligases, our results suggest that Fbxo7 can mediate the ubiquitination of cIAP1 by SCF ubiquitin protein ligase
GO:0097409 glial cytoplasmic inclusion
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive glial cytoplasmic inclusions in multiple system atrophy. A disease-pathology localization.
Reason: Real IDA immunoreactivity in pathological inclusions, but this is a disease-associated localization, not a core physiological compartment.
Supporting Evidence:
PMID:23656991
FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)
GO:0097414 classical Lewy body
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy bodies in Parkinson disease. A disease-pathology localization.
Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
Supporting Evidence:
PMID:23656991
FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)
GO:0097462 Lewy neurite
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy neurites. A disease-pathology localization.
Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
Supporting Evidence:
PMID:23656991
FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)
GO:1990037 Lewy body core
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
Supporting Evidence:
PMID:23656991
where it colocalized with α-synuclein in PD and MSA cases
GO:1990038 Lewy body corona
IDA
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions ... 		KEEP AS NON CORE
Summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
Supporting Evidence:
PMID:23656991
where it colocalized with α-synuclein in PD and MSA cases
GO:0005634 nucleus
IDA
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 ... 		KEEP AS NON CORE
Summary: Direct evidence relating to FBXO7 nuclear/cytoplasmic distribution governed by SKP1/CRM1 competition.
Reason: Real but minor nuclear localization governed by SKP1/CRM1 shuttling; predominant compartment is cytoplasm.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
A minor proportion is detected in the nucleus (PubMed:16096642).
GO:0005737 cytoplasm
IDA
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 ... 		ACCEPT
Summary: Direct evidence of FBXO7 cytoplasmic localization controlled by SKP1/CRM1 competition. Core compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Note=Predominantly cytoplasmic (PubMed:16096642).
GO:0040012 regulation of locomotion
IDA
PMID:26310625
F-box protein 7 mutations promote protein aggregation in mit... 		KEEP AS NON CORE
Summary: Organismal locomotor phenotype associated with FBXO7 (Drosophila dopamine-neuron degeneration and PD-related models), reflecting its mitophagy/neuroprotection role.
Reason: An organismal/neurodegeneration phenotype downstream of the core mitophagy function rather than a distinct cell-autonomous core process.
Supporting Evidence:
PMID:26310625
The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		ACCEPT
Summary: Reactome neddylation/CRL-machinery pathway annotation placing FBXO7 in the cytosol. The cytosol is the predominant FBXO7 compartment.
Reason: Correct core localization; cytosol is the predominant compartment for the SCF(FBXO7) complex.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		ACCEPT
Summary: Reactome CRL-machinery pathway annotation placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		ACCEPT
Summary: Reactome CRL-machinery pathway annotation (CAND1 binding) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		ACCEPT
Summary: Reactome CRL-machinery pathway annotation (COMMD/CAND1) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		ACCEPT
Summary: Reactome CRL-machinery pathway annotation (COP9 signalosome deneddylation) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		ACCEPT
Summary: Reactome CRL-machinery pathway annotation (DCUN1D3) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		ACCEPT
Summary: Reactome ubiquitination-pathway annotation (Ub transfer from E2 to substrate) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		ACCEPT
Summary: Reactome ubiquitination-pathway annotation (release of E3 from polyubiquitinated substrate) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		ACCEPT
Summary: Reactome ubiquitination-pathway annotation (polyubiquitination of substrate) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		ACCEPT
Summary: Reactome ubiquitination-pathway annotation (interaction of E3 with substrate and E2-Ub complex) placing FBXO7 in the cytosol.
Reason: Correct core localization; cytosol is the predominant compartment.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
GO:0005634 nucleus
IDA
PMID:18495667
Structure of a conserved dimerization domain within the F-bo... 		KEEP AS NON CORE
Summary: Direct evidence of FBXO7 nuclear localization documented in the FP-domain study. Minor nuclear pool.
Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Nucleus {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667, ECO:0000269|PubMed:33010352}.
GO:0005829 cytosol
IDA
PMID:18495667
Structure of a conserved dimerization domain within the F-bo... 		ACCEPT
Summary: Direct evidence of FBXO7 cytosolic localization. Core compartment.
Reason: Core localization with direct experimental support.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
GO:0000151 ubiquitin ligase complex
IDA
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 is part of a ubiquitin ligase complex (the SCF(FBXO7) complex). Generic parent of the specific SCF complex term.
Reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's complex membership.
Supporting Evidence:
PMID:23933751
F-box domain-containing proteins target substrates to SCF-type (Skp1-Cul1-F-box) E3-ubiquitin ligase complexes
GO:0000422 autophagy of mitochondrion
IMP
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		ACCEPT
Summary: Mutant-phenotype evidence that reducing FBXO7 impairs CCCP-induced mitophagy and that FBXO7 acts in Parkin-mediated mitophagy. Core biological process.
Reason: Core biological process with direct experimental (IMP) support; FBXO7 knockdown reduces mitophagy and FBXO7 rescues parkin mutant phenotypes.
Supporting Evidence:
PMID:23933751
Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
GO:0005739 mitochondrion
IDA
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		ACCEPT
Summary: Direct evidence that FBXO7 relocates from the cytosol to depolarized mitochondria following CCCP treatment. Conditional localization.
Reason: Correct conditional/stress-induced localization central to the mitophagy function.
Supporting Evidence:
PMID:23933751
endogenous Fbxo7 levels were found to decrease steadily in the cytosolic fraction and increase concurrently in the mitochondrial fractions
GO:0005829 cytosol
IDA
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		ACCEPT
Summary: Direct evidence that FBXO7 is predominantly cytosolic (before relocating to depolarized mitochondria). Core compartment.
Reason: Core localization with direct experimental support (cell fractionation).
Supporting Evidence:
PMID:23933751
although both proteins localise predominantly to the cytosol
GO:0016567 protein ubiquitination
IMP
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		KEEP AS NON CORE
Summary: Mutant-phenotype evidence that FBXO7 is required for CCCP-induced mitofusin 1 ubiquitination (via promoting Parkin recruitment). Generic parent process.
Reason: Correct but generic; FBXO7 facilitates substrate (Mfn1) ubiquitination chiefly by promoting Parkin recruitment. The specific mitophagy annotations better capture the role.
Supporting Evidence:
PMID:23933751
Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
GO:0070585 protein localization to mitochondrion
IMP
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin int... 		ACCEPT
Summary: Mutant-phenotype evidence that FBXO7 is required for Parkin translocation to depolarized mitochondria. Well-supported process.
Reason: Directly demonstrated; FBXO7 facilitates Parkin recruitment to mitochondria, a key step in mitophagy.
Supporting Evidence:
PMID:23933751
Overall, these data indicate that Fbxo7 facilitates Parkin translocation to the mitochondria in response to depolarisation.
GO:0032991 protein-containing complex
IDA
GO_REF:0000054 		KEEP AS NON CORE
Summary: LIFEdb fusion-protein localization assignment of generic protein-containing complex membership.
Reason: Correct but generic; the specific SCF ubiquitin ligase complex (GO:0019005) is far more informative.
Supporting Evidence:
file:human/FBXO7/FBXO7-uniprot.txt
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
GO:0031647 regulation of protein stability
IDA
PMID:15145941
Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... 		KEEP AS NON CORE
Summary: Direct evidence that FBXO7 controls the stability/abundance of its substrate HURP via ubiquitination.
Reason: Correct but generic; FBXO7 regulates substrate stability through the more specific SCF-dependent catabolic process (GO:0031146).
Supporting Evidence:
PMID:15145941
Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance.
GO:0005515 protein binding
IPI
PMID:15145941
Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... 		KEEP AS NON CORE
Summary: Interaction with the substrate DLGAP5/HURP (and CUL1/SKP1) from the HURP proteolysis study. Bare protein binding is uninformative.
Reason: Records the meaningful FBXO7-HURP/DLGAP5 substrate interaction, but bare protein binding is uninformative; captured by the SCF/adaptor annotations.
Supporting Evidence:
PMID:15145941
In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.
GO:0000151 ubiquitin ligase complex
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		KEEP AS NON CORE
Summary: Author statement that F-box proteins are subunits of SCF ubiquitin protein ligases. Generic parent of the SCF complex term.
Reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's membership.
Supporting Evidence:
PMID:10531035
In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs.
GO:0004842 ubiquitin-protein transferase activity
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		MODIFY
Summary: Family-level author statement assigning ubiquitin-protein transferase activity to F-box-containing SCF ligases. FBXO7 is the substrate-recognition adaptor, not the catalytic transferase (the catalytic RING is RBX1).
Reason: FBXO7 itself is not the ubiquitin transferase; it is the substrate-recognition adaptor of the SCF complex. The catalytic transfer is performed by the E2 recruited by the RBX1 RING. The informative molecular function is the ligase-substrate adaptor activity.
Supporting Evidence:
PMID:36646384
FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
GO:0006511 ubiquitin-dependent protein catabolic process
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		KEEP AS NON CORE
Summary: Family-level author statement that F-box/SCF proteins drive controlled degradation of cellular regulatory proteins. Generic parent of the specific SCF-dependent process.
Reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal catabolic process) better captures FBXO7's role.
Supporting Evidence:
PMID:10531035
Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins

Core Functions

Substrate-recognition (F-box) adaptor of the SCF(FBXO7) E3 ubiquitin ligase complex (CUL1-SKP1-RBX1-FBXO7) that recruits substrates (e.g. DLGAP5/HURP, BIRC2/cIAP1, TRAF2, UXT-V2, SIRT7) via its proline-rich region and Ubl/FP regions and bridges them to the catalytic cullin-RING core for K48-linked polyubiquitination and proteasomal degradation.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:36646384
    FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
  • PMID:15145941
    Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.

SCF-independent regulator of mitophagy that relocates from the cytosol to depolarized mitochondria downstream of PINK1, interacts with PINK1 and PRKN/Parkin via its N-terminal Ubl region, and promotes Parkin recruitment to mitochondria and mitofusin ubiquitination to drive selective autophagic clearance of damaged mitochondria.

Molecular Function:
protein-macromolecule adaptor activity
Directly Involved In:
positive regulation of mitophagy
Cellular Locations:
mitochondrion cytosol
Supporting Evidence:
  • PMID:23933751
    Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.

Negative regulator of canonical NF-kappa-B signaling, achieved by SCF(FBXO7)-mediated K48/K63 polyubiquitination and proteasomal degradation of the NF-kappa-B cofactor UXT isoform 2 (and ubiquitination of TRAF2 and cIAP1/BIRC2).

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
negative regulation of canonical NF-kappaB signal transduction
Cellular Locations:
nucleus cytosol
Supporting Evidence:
  • PMID:33010352
    Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.

Proteasome-associated regulator of proteostasis that, through FP-domain heterodimerization with the proteasome inhibitor PSMF1/PI31 and ubiquitin signaling on proteasomal components, tunes 26S proteasome assembly/activity; loss of FBXO7 reduces proteasome activity and models a parkinsonism-like phenotype, indicating a role in neuronal proteostasis.

Molecular Function:
protein-macromolecule adaptor activity
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:18495667
    We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
  • file:human/FBXO7/FBXO7-deep-research-falcon.md
    In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
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:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000054
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10531035
Identification of a family of human F-box proteins.
PMID:15145941
Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region.
PMID:16096642
Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6.
PMID:16278047
Characterization of FBX25, encoding a novel brain-expressed F-box protein.
PMID:16510124
The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein cIAP1 and promotes cIAP1 ubiquitination.
PMID:18495667
Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor.
PMID:21347293
Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls the localization of a subset of F-box proteins.
PMID:22632967
Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair.
PMID:23656991
FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson disease and multiple system atrophy.
PMID:23933751
The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy.
PMID:25029497
FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
PMID:26310625
F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complexome.
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
PMID:33010352
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-κB signaling pathway.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
PMID:36646384
E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation of SIRT7 and promotes cell death in response to hydrogen peroxide.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
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/FBXO7/FBXO7-deep-research-falcon.md
Falcon deep research report for human FBXO7
  • FBXO7 is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase, whose F-box domain binds SKP1 to link substrates to the CUL1-RBX1 catalytic core.
    "FBXO7 is best understood as a **substrate-specifying adaptor** of an **SCF-type E3 ubiquitin ligase**, where its **F-box domain binds SKP1**, linking FBXO7 to the **CUL1–RBX1** catalytic core that recruits an E2~ubiquitin and transfers ubiquitin to substrates."
  • FBXO7-driven ubiquitination is not exclusively degradative; it can generate K48-linked (proteasome-targeting) or K63-linked (non-proteolytic) chains depending on substrate and context.
    "A key conceptual point is that **FBXO7-driven ubiquitination is not exclusively degradative**. It can generate **K48-linked polyubiquitin** (often proteasome-targeting) or **K63-linked chains** (often non-proteolytic signaling/trafficking/autophagy-related roles), depending on the substrate and context."
  • Loss of Fbxo7 in mice reduces proteasome activity and produces a parkinsonism-like phenotype, supporting a role in neuronal proteostasis through proteasome assembly/composition tuning.
    "In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis."
  • FBXO7 acts as a context-dependent tumor suppressor, catalyzing predominantly K48-linked polyubiquitination of INF2 (endometrial carcinoma, mitochondrial division control) and of PRMT1 (hepatocellular carcinoma, serine synthesis control).
    "Together, these studies support FBXO7 as a context-dependent tumor suppressor via **mitochondrial homeostasis** and **amino-acid metabolism**, consistent with an E3 adaptor that tunes proteostasis, mitochondria, and stress responses."
  • USP7 deubiquitinates and stabilizes FBXO7 by removing K48-linked ubiquitin chains, connecting deubiquitinase control of FBXO7 to cell survival under ER stress.
    "USP7 deubiquitinates FBXO7 by removing **K48-linked ubiquitin chains**, preventing FBXO7 proteasomal degradation."

Suggested Questions for Experts

Q: To what extent are FBXO7's SCF-dependent substrate-degradation roles (HURP, cIAP1, TRAF2, UXT-V2, SIRT7) and its SCF-independent roles (PINK1/Parkin mitophagy, PSMF1/PI31 proteasome regulation, cyclin D/CDK6 activation) separable, and which are most relevant to PARK15 neurodegeneration?

Q: How do the FP domain-mediated FBXO7 homodimerization and FBXO7-PSMF1/PI31 heterodimerization regulate proteasome assembly/activity in neurons, and is this disrupted by PARK15 mutations?

Q: Does FBXO7 directly target PRKN/PINK1 for ubiquitination, or does it act mainly as a non-catalytic scaffold promoting Parkin recruitment to depolarized mitochondria?

Suggested Experiments

Experiment: Reconstitute SCF(FBXO7) in vitro with purified CUL1, SKP1, RBX1, an E2, and candidate substrates (HURP/DLGAP5, SIRT7, UXT-V2) to confirm that FBXO7 functions as a substrate-presenting adaptor (not the catalytic transferase) and to map substrate lysines and chain linkages.

Experiment: Perform quantitative ubiquitinome and proteome profiling in FBXO7-knockout versus wild-type neuronal cells under basal and mitochondrial-depolarization (CCCP) conditions to define the endogenous SCF(FBXO7) substrate repertoire and its contribution to mitophagy.

Experiment: Use live-cell imaging with PARK15 patient-derived neurons (T22M, R378G, R498X) to quantify FBXO7 relocation to depolarized mitochondria and Parkin recruitment kinetics, dissecting how each mutation impairs mitophagy.

Deep Research

Falcon

(FBXO7-deep-research-falcon.md)
Research Report: Human **FBXO7** (UniProt **Q9Y3I1**) — Functional Annotation and Translational Relevance Falcon Edison Scientific Literature 32 citations 2 artifacts 2026-06-13T05:49:10.302103
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000035 The document contains figures illustrating both the domain architecture of FBXO7 and the schematic of its interaction within the SC (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 FBXO7 (UniProt Q9Y3I1) — Functional Annotation and Translational Relevance

0) Target verification (mandatory)

Identity confirmed. The literature retrieved consistently describes human FBXO7 as F-box only protein 7 (also PARK15/FBX7), a substrate-recognition adaptor in SCF (SKP1–CUL1–RBX1) Cullin-RING E3 ubiquitin ligase complexes, with the domain architecture matching the UniProt context (Ubl/ubiquitin-like at the N-terminus in isoform 1; FP/PI31-interaction domain; F-box; proline-rich region). These features, along with the key interaction with SKP1 (F-box) and PI31/PSMF1 (FP domain), and disease linkage to PARK15, align with the UniProt target description and avoid symbol ambiguity. (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 17-21, wang2021analysisofthe pages 17-21)

Visual evidence: FBXO7 domain organization and SCF schematic are shown in Randle & Laman (2017), with Ubl/FP/F-box/PRR annotated, and FBXO7 positioned as the substrate receptor within SCF. (randle2017structureandfunction media caeb42e9, randle2017structureandfunction media 1a872076)

1) Key concepts and definitions (current understanding)

1.1 SCF E3 ubiquitin ligase adaptor (core molecular function)

FBXO7 is best understood as a substrate-specifying adaptor of an SCF-type E3 ubiquitin ligase, where its F-box domain binds SKP1, linking FBXO7 to the CUL1–RBX1 catalytic core that recruits an E2~ubiquitin and transfers ubiquitin to substrates. (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 17-21, zhou2018pathophysiologicalmechanismslinking pages 2-3, randle2017structureandfunction media caeb42e9, randle2017structureandfunction media 1a872076)

A key conceptual point is that FBXO7-driven ubiquitination is not exclusively degradative. It can generate K48-linked polyubiquitin (often proteasome-targeting) or K63-linked chains (often non-proteolytic signaling/trafficking/autophagy-related roles), depending on the substrate and context. (randle2017structureandfunction pages 5-7, zhou2018pathophysiologicalmechanismslinking pages 2-3, teixeira2016gsk3βandtomm20 pages 1-2)

1.2 Domain architecture and isoforms

The review literature describes human FBXO7 (isoform 1, ~522 aa) as containing:
- N-terminal ubiquitin-like (Ubl) domain (present in isoform 1; isoform 2 lacks this N-terminus),
- FP domain (FBXO7/PI31 interaction and dimerization module),
- F-box domain (SKP1 binding; also contains a nuclear export signal),
- C-terminal proline-rich region (PRR) (substrate interaction and regulatory interactions). (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 11-13, randle2017structureandfunction pages 7-9)

1.3 Subcellular localization (where FBXO7 acts)

FBXO7 displays regulated nucleo-cytoplasmic shuttling and can also function in mitochondrial quality control pathways. Reduced SKP1 binding can promote CRM1/exportin-mediated cytoplasmic accumulation, and cellular stress can promote mitochondrial translocation in PARK15-linked biology. (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 17-21)

2) Biological functions and pathways (mechanistic functional annotation)

2.1 Proteasome regulation and proteostasis (proteasome assembly/function)

A foundational in vivo mechanistic link is that FBXO7 is proteasome-associated and supports proteasome assembly/activity through ubiquitin signaling on proteasomal components.

  • In mouse models, loss of Fbxo7 leads to reduced proteasome activity and a parkinsonism-like phenotype, supporting a role for FBXO7 in neuronal proteostasis. (Vingill et al., EMBO J, 2016, https://doi.org/10.15252/embj.201593585) (vingill2016lossoffbxo7 pages 1-2)
  • Mechanistically, FBXO7-SCF can bind/ubiquitinate proteasome subunits (e.g., PSMA2), and this is frequently discussed as K63-linked and non-proteolytic in the context of assembly control. (dontcheva2017functionalanalysisof pages 14-18, joseph2018mechanisticcontributionsof pages 8-10)

Functional interpretation: FBXO7 is not a proteasome enzyme; it is an E3 ligase adaptor that tunes proteasome composition/assembly and thereby affects proteolytic capacity, particularly relevant in long-lived cells like neurons. (vingill2016lossoffbxo7 pages 1-2, joseph2018mechanisticcontributionsof pages 8-10)

2.2 Mitophagy / mitochondrial quality control (PINK1–Parkin axis)

FBXO7 participates in mitochondrial quality control by interacting with PINK1 and Parkin and facilitating Parkin recruitment to damaged mitochondria in PARK15 biology. Disease-linked mutations can impair these interactions (notably T22M reducing Parkin binding). (randle2017structureandfunction pages 17-21, randle2017structureandfunction pages 11-13, randle2017structureandfunction pages 7-9, joseph2018mechanisticcontributionsof pages 5-6)

2.3 Substrate ubiquitination with disease-relevant outputs

2.3.1 GSK3β and TOMM20 as SCF^FBXO7 substrates (PD-relevant)

Teixeira et al. (2016) validated GSK3β and TOMM20 as SCF^FBXO7 substrates:
- FBXO7 modifies GSK3β with K63-linked ubiquitin, regulating kinase activity rather than abundance/localization.
- FBXO7 ubiquitinates TOMM20 with effects consistent with stabilization and linkage to mitophagy-related processes. (Teixeira et al., Biochem J, 2016, https://doi.org/10.1042/BCJ20160387) (teixeira2016gsk3βandtomm20 pages 1-2)

2.3.2 SIRT7 degradation under oxidative stress (2023 mechanistic advance)

Lee et al. (2023) established a detailed ubiquitination mechanism for an FBXO7 substrate:
- FBXO7 promotes K48-linked polyubiquitination of SIRT7 on K292, K395, K397, K398, leading to proteasomal degradation.
- In SH-SY5Y cells exposed to 500 μM H2O2 for 6 h, FBXO7-mediated SIRT7 loss contributes to cell death, and a ubiquitination-resistant SIRT7-4KR mutant resists degradation and displays stronger functional activity.
- PD-linked FBXO7 mutants show differential ability to destabilize SIRT7: R498X failed to reduce SIRT7 stability, while T22M and R378G behaved more like WT in this assay context. (Lee et al., J Biol Chem, 2023-03, https://doi.org/10.1016/j.jbc.2023.102909) (lee2023e3ligaseadaptor pages 9-11, lee2023e3ligaseadaptor pages 12-13)

Interpretation: This work provides unusually specific annotation: substrate (SIRT7), linkage (K48), and lysine sites, supporting a direct molecular function assignment for FBXO7 as a degradative E3 adaptor in oxidative-stress contexts. (lee2023e3ligaseadaptor pages 9-11)

2.3.3 INF2 degradation and mitochondrial division control in endometrial carcinoma (2023)

Zhang et al. (2023) identify FBXO7 as a tumor suppressor mechanism in endometrial carcinoma by targeting INF2:
- FBXO7 physically associates with INF2; FBXO7 was the top FBXO family interactor in FLAG-INF2 AP-MS (3 peptides/3 unique peptides).
- The FBXO7 UBL domain (aa 1–74) is required for INF2 binding.
- FBXO7 catalyzes predominantly K48-linked polyubiquitination of INF2, shortening INF2 half-life.
- Clinically, FBXO7 is downregulated and mutated in 5.87% of endometrial carcinoma cases (31/528 in TCGA). Dataset sizes used include TCGA mRNA tumor n=546 vs normal n=35 (paired n=23) and CPTAC protein tumor n=100 vs normal n=31 (paired n=30), all with p<0.001 differences reported for expression comparisons.
- Low FBXO7 correlates with elevated INF2 and dysregulated INF2–DRP1-driven mitochondrial division. (Zhang et al., Cell Death & Disease*, 2023-06, https://doi.org/10.1038/s41419-023-05891-0) (zhang2023fbxo7atumor pages 1-3, zhang2023fbxo7atumor pages 3-5)

2.3.4 PRMT1 degradation and serine metabolism in hepatocellular carcinoma (2024)

Luo et al. (2024) show FBXO7 suppresses HCC growth by degrading PRMT1:
- FBXO7 directly binds PRMT1 and promotes PRMT1 ubiquitination at K37 (lysine 37); the K37R mutant is resistant.
- FBXO7 knockdown increases PRMT1 protein (without changing mRNA), prolongs PRMT1 half-life (CHX chase), and effects are proteasome-dependent (MG132/bortezomib blockade).
- Mechanistic axis: FBXO7 → ↓PRMT1 → ↓PHGDH methylation (R236) and activation → ↓serine synthesis, ↑ROS, ↓tumor growth.
- The binding interfaces include FBXO7 UBL (1–78) and FP (181–324) domains and the PRMT1 catalytic domain (23–162).
- Experimental details include ubiquitination assays with MG132 25 μM for 6 h and CHX 50 μg/mL; results were repeated and quantified (n=3). (Luo et al., Nature Communications, 2024-06, https://doi.org/10.1038/s41467-024-49087-2) (luo2024fbxo7ubiquitinatesprmt1 pages 2-3, luo2024fbxo7ubiquitinatesprmt1 pages 4-5, luo2024fbxo7ubiquitinatesprmt1 pages 5-6, luo2024fbxo7ubiquitinatesprmt1 pages 1-2)

3) Recent developments (prioritizing 2023–2024)

3.1 Upstream regulation of FBXO7 stability by USP7 (2023)

Lee & Chung (2023) identify USP7 as a regulator that stabilizes FBXO7:
- USP7 deubiquitinates FBXO7 by removing K48-linked ubiquitin chains, preventing FBXO7 proteasomal degradation.
- Under tunicamycin-induced ER stress, USP7−/− HeLa cells show substantially higher apoptosis markers (e.g., 7.8-fold higher cleaved PARP1) and restoring FBXO7 reduced ER-stress cytotoxicity by ~10%.
- In SH-SY5Y cells, USP7 overexpression reduced cytotoxicity by ~8%, while FBXO7 knockdown reduced this protective effect (cytotoxicity increased by ~5% in the combined condition).
These results connect deubiquitinase control of FBXO7 to cell survival pathways under ER stress. (Lee & Chung, PLOS ONE, 2023-10, https://doi.org/10.1371/journal.pone.0290371) (lee2023usp7attenuatesendoplasmic pages 9-11, lee2023usp7attenuatesendoplasmic pages 1-2, lee2023usp7attenuatesendoplasmic pages 4-5)

3.2 Cancer mechanisms expand FBXO7 substrate space (2023–2024)

Two high-impact directions emerge from 2023–2024 cancer literature:
1) Mitochondrial dynamics control via INF2 degradation in endometrial carcinoma (mutation frequency 5.87% in TCGA). (zhang2023fbxo7atumor pages 1-3)
2) Metabolic rewiring via PRMT1 degradation and downstream PHGDH methylation and serine synthesis control in HCC. (luo2024fbxo7ubiquitinatesprmt1 pages 1-2, luo2024fbxo7ubiquitinatesprmt1 pages 5-6)

Expert interpretation: Together, these studies support FBXO7 as a context-dependent tumor suppressor via mitochondrial homeostasis and amino-acid metabolism, consistent with an E3 adaptor that tunes proteostasis, mitochondria, and stress responses. (zhang2023fbxo7atumor pages 3-5, luo2024fbxo7ubiquitinatesprmt1 pages 1-2)

4) Current applications and real-world implementations

4.1 Human disease association and genetics (PARK15)

FBXO7 is a recognized autosomal-recessive cause of PARK15 / parkinsonian–pyramidal syndrome, with heterogeneous clinical presentations that can include classic PD features and pyramidal signs. Patients often respond to L-Dopa but may experience early complications such as disabling dyskinesia and psychosis, as described in expert reviews. (Joseph et al., J Neurochem, 2018-01, https://doi.org/10.1111/jnc.14253) (joseph2018mechanisticcontributionsof pages 3-5)

OpenTargets disease–target evidence also links FBXO7 to Parkinson disease and parkinsonian-pyramidal syndrome, supporting continued clinical interest. (OpenTargets Search: -FBXO7)

4.2 Therapeutic strategy concepts (mechanism-driven)

No FBXO7-targeted therapy is established clinically in the retrieved sources; however, several plausible, mechanism-driven translational directions are supported:

1) Stabilizing FBXO7 protein by modulating its deubiquitination axis (USP7→FBXO7) in stress-related contexts, supported by ER-stress apoptosis protection upon FBXO7 stabilization/restoration. (lee2023usp7attenuatesendoplasmic pages 9-11, lee2023usp7attenuatesendoplasmic pages 1-2)

2) Targeting the PI31/proteasome pathway downstream of FBXO7 dysfunction is an established conceptual strategy in PARK15 biology, given FBXO7–PI31 linkage and proteasome assembly/transport relevance (primarily supported by foundational mechanistic work and reviews). (randle2017structureandfunction pages 17-21, joseph2018mechanisticcontributionsof pages 8-10)

3) Drugging the SCF machinery: A 2024 chemical biology advance demonstrates that SKP1 (the SCF adaptor that binds FBXO7 and other F-box proteins) can be covalently recruited and used in PROTAC-like targeted protein degradation to degrade neo-substrates (BRD4, AR) in cells, illustrating a generalizable method to harness the SKP1–CUL1–F-box system. While not specific to FBXO7 diseases, it provides a real-world implementation route for SCF-engineering and may influence future FBXO7-pathway targeting strategies. (Hong et al., ACS Chem Biol, 2024-02, https://doi.org/10.1021/acschembio.3c00642) (hong2024exploitingthecullin pages 6-8)

4.3 Cancer implementation relevance (biomarker/stratification concepts)

Endometrial carcinoma and HCC studies suggest that FBXO7 downregulation/mutation may stratify tumors by:
- Mitochondrial division phenotypes (INF2/DRP1 axis) in endometrial carcinoma. (zhang2023fbxo7atumor pages 1-3)
- Serine synthesis dependency and PRMT1/PHGDH methylation state in HCC, with FBXO7 as a negative regulator of PRMT1 abundance. (luo2024fbxo7ubiquitinatesprmt1 pages 1-2, luo2024fbxo7ubiquitinatesprmt1 pages 5-6)

5) Statistics and data highlights (from recent studies)

  • Endometrial carcinoma (TCGA): FBXO7 mutation frequency 5.87% (31/528); expression comparisons used n=546 tumor vs n=35 normal (paired n=23) and CPTAC protein n=100 tumor vs n=31 normal (paired n=30), with *p<0.001 reported. (zhang2023fbxo7atumor pages 1-3)
  • INF2–FBXO7 interaction proteomics: AP-MS peptide counts for FBXO7 in INF2 complex (3 peptides/3 unique peptides) and docking Z-score 20.46 (method-dependent statistic). (zhang2023fbxo7atumor pages 3-5)
  • SIRT7 ubiquitination details (JBC 2023): K48-linked polyubiquitination of SIRT7 at K292/K395/K397/K398, defining concrete ubiquitin-site annotation for FBXO7 function. (lee2023e3ligaseadaptor pages 9-11)
  • ER stress apoptosis (PLOS ONE 2023): 7.8-fold higher cleaved PARP1 in USP7−/− under tunicamycin; FBXO7 restoration reduces cytotoxicity by ~10%; USP7 overexpression reduces cytotoxicity by ~8% in SH-SY5Y, with FBXO7 knockdown partially reversing the effect (~5%). (lee2023usp7attenuatesendoplasmic pages 9-11)
  • PRMT1 ubiquitination (Nat Commun 2024): FBXO7-mediated ubiquitination centered on PRMT1 K37, and K37R increases PRMT1 stability and blocks ubiquitination response in assays. (luo2024fbxo7ubiquitinatesprmt1 pages 4-5, luo2024fbxo7ubiquitinatesprmt1 pages 5-6)

6) Consolidated evidence map

Functional role/pathway Key substrates/interactors Ubiquitin linkage/site Experimental system 2023-2024 highlights and quantitative stats Representative citation IDs
SCF E3 ligase adaptor / core architecture SKP1, CUL1, RBX1; PI31/PSMF1 via FP domain; PRR and Ubl domains contribute substrate/receptor interactions F-box mediates SKP1 binding; linkage varies by substrate Domain mapping/review synthesis; cultured mammalian cells Human FBXO7 isoform 1 contains Ubl, FP, F-box, and PRR domains; dynamic nucleo-cytoplasmic localization and SCF assembly are central to function (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 17-21, wang2021analysisofthe pages 17-21, randle2017structureandfunction media caeb42e9, randle2017structureandfunction media 1a872076)
Proteasome assembly / proteostasis PSMA2, PI31/PSMF1, proteasome holoenzyme PSMA2 mainly K63-linked ubiquitination; PI31 binds but is not established as a degradative substrate Mouse systemic and neuron-specific Fbxo7 knockout; patient fibroblasts; biochemical assays FBXO7 loss reduces proteasome activity and causes parkinsonism-like phenotypes in mice; FBXO7 associates with proteasome and promotes assembly; brain proteasome activity reduced in knockout models (vingill2016lossoffbxo7 pages 1-2, dontcheva2017functionalanalysisof pages 14-18, joseph2018mechanisticcontributionsof pages 8-10)
Mitophagy / mitochondrial quality control Parkin, PINK1, TOMM20, GSK3β TOMM20 ubiquitinated with stabilizing non-degradative effect; GSK3β modified with K63-linked chains HEK293/cell-based ubiquitination assays; neuronal and fly/mouse disease models FBXO7 promotes Parkin recruitment to damaged mitochondria; PD-linked T22M disrupts Parkin binding; R378G impairs Skp1 binding/localization; GSK3β and TOMM20 validated as SCF^FBXO7 substrates linked to PD-relevant pathways (randle2017structureandfunction pages 17-21, randle2017structureandfunction pages 11-13, randle2017structureandfunction pages 7-9, teixeira2016gsk3βandtomm20 pages 1-2, joseph2018mechanisticcontributionsof pages 5-6)
ER stress / apoptosis regulation upstream of FBXO7 USP7, FBXO7 USP7 removes K48-linked ubiquitin from FBXO7, stabilizing it HEK293 co-IP/GST pull-down; USP7+/+ and USP7-/- HeLa; SH-SY5Y cells; tunicamycin stress USP7-/- cells showed ~7.8-fold higher cleaved PARP1 under ER stress; restoring FBXO7 in USP7-/- cells reduced tunicamycin-induced cytotoxicity by ~10% and lowered cleaved PARP1 by ~1.5-fold; USP7 overexpression reduced cytotoxicity by ~8%, while FBXO7 knockdown blunted this protection by ~5% (lee2023usp7attenuatesendoplasmic pages 4-5, lee2023usp7attenuatesendoplasmic pages 9-11, lee2023usp7attenuatesendoplasmic pages 1-2)
Oxidative stress / apoptosis downstream of FBXO7 SIRT7 K48-linked polyubiquitination of SIRT7 at K292, K395, K397, K398 HEK293 transfection; SH-SY5Y cells treated with 500 μM H2O2 for 6 h; mouse brain lysates FBXO7 promotes proteasomal degradation of SIRT7 and enhances H2O2-induced cell death; SIRT7-4KR mutant resists FBXO7-mediated ubiquitination/degradation and shows stronger deacetylase/repressor activity; PD-linked R498X fails to destabilize SIRT7 unlike WT/T22M/R378G FBXO7 (lee2023e3ligaseadaptor pages 12-13, lee2023e3ligaseadaptor pages 9-11)
Endometrial carcinoma / mitochondrial dynamics tumor suppression INF2, DRP1/DNM1L axis Predominantly K48-linked polyubiquitination of INF2; FBXO7 UBL domain (aa 1-74) required for INF2 binding AN3 CA and HEC-1-A endometrial carcinoma cells; TCGA/CPTAC datasets; AP-MS/co-IP; MG132 20 μM for 8 h FBXO7 downregulated in ECa; mutation frequency 31/528 (5.87%) in TCGA; TCGA mRNA cohorts: tumor n=546 vs normal n=35, paired n=23; CPTAC protein cohorts: tumor n=100 vs normal n=31, paired n=30; FBXO7 was top INF2-associated FBX protein (3 peptides/3 unique peptides), docking Z-score 20.46; low FBXO7 correlated with high INF2 and mitochondrial hyper-division (zhang2023fbxo7atumor pages 3-5, zhang2023fbxo7atumor pages 1-3)
Hepatocellular carcinoma / serine synthesis metabolism PRMT1, PHGDH PRMT1 ubiquitination at K37; proteasome-dependent degradation; ΔF-box mutant loses activity Huh7 and PLC/PRF/5 HCC cells; HEK293T co-IP; GST pull-down; MG132 25 μM for 6 h; CHX 50 μg/mL FBXO7 is significantly downregulated in HCC and inversely associated with PRMT1 protein and PHGDH methylation; FBXO7 loss increases PRMT1 stability, PHGDH R236 methylation, serine synthesis, and tumor growth, whereas FBXO7 suppresses these processes; K37R PRMT1 resists FBXO7-mediated ubiquitination and has longer half-life (luo2024fbxo7ubiquitinatesprmt1 pages 1-2, luo2024fbxo7ubiquitinatesprmt1 pages 4-5, luo2024fbxo7ubiquitinatesprmt1 pages 2-3, luo2024fbxo7ubiquitinatesprmt1 pages 5-6, luo2024fbxo7ubiquitinatesprmt1 pages 3-4)
Clinical / translational relevance FBXO7 in PARK15/parkinsonian-pyramidal syndrome; PI31 pathway; SKP1/SCF machinery Not a single linkage; disease relevance arises from disrupted SCF, proteasome, and mitophagy functions Human genetics, mouse models, OpenTargets, chemical biology OpenTargets links FBXO7 to Parkinson disease and parkinsonian-pyramidal syndrome; patients often respond to L-Dopa but can develop early dyskinesia/psychosis; translational strategies include restoring FBXO7 function, modulating USP7-FBXO7 stability, targeting PI31/proteasome pathway, and exploiting SKP1-SCF for degrader design (OpenTargets Search: -FBXO7, joseph2018mechanisticcontributionsof pages 3-5, randle2017structureandfunction pages 1-5, hong2024exploitingthecullin pages 6-8)

Table: This table summarizes experimentally supported roles, interactors, ubiquitination features, model systems, and quantitative highlights for human FBXO7/Q9Y3I1. It is designed to support a concise evidence-based overview of FBXO7 biology and translational relevance.

7) Summary (functional annotation statement)

Primary function: Human FBXO7 (Q9Y3I1) is an SCF E3 ubiquitin ligase adaptor that selects substrates for ubiquitination, producing substrate- and context-dependent outcomes including proteasomal degradation (commonly K48-linked) and non-proteolytic signaling/assembly regulation (commonly K63-linked). (randle2017structureandfunction pages 5-7, teixeira2016gsk3βandtomm20 pages 1-2, lee2023e3ligaseadaptor pages 9-11)

Key biological processes and locations: FBXO7 acts in proteostasis/proteasome regulation, mitochondrial quality control/mitophagy, and stress-response apoptosis, with regulated nuclear–cytoplasmic distribution and disease-relevant mitochondrial engagement. (randle2017structureandfunction pages 5-7, randle2017structureandfunction pages 17-21, vingill2016lossoffbxo7 pages 1-2, lee2023usp7attenuatesendoplasmic pages 9-11)

Recent (2023–2024) advances: Mechanistically resolved degradative substrates include SIRT7 (K48-linked ubiquitination at defined lysines) and cancer-relevant substrates/axes including INF2 (K48-linked ubiquitination; endometrial carcinoma) and PRMT1 K37 ubiquitination (serine synthesis control in HCC). (lee2023e3ligaseadaptor pages 9-11, zhang2023fbxo7atumor pages 3-5, luo2024fbxo7ubiquitinatesprmt1 pages 5-6)

Translational relevance: FBXO7 is a Mendelian PD gene (PARK15) and a mechanistic node connecting proteasome function, mitophagy, and stress apoptosis; emerging drug-development approaches may target the pathway via (i) stabilizing FBXO7 (USP7 axis), (ii) downstream proteasome/PI31 mechanisms, or (iii) leveraging SCF machinery such as SKP1 in targeted protein degradation technologies. (joseph2018mechanisticcontributionsof pages 3-5, lee2023usp7attenuatesendoplasmic pages 9-11, hong2024exploitingthecullin pages 6-8, OpenTargets Search: -FBXO7)

References

  1. (randle2017structureandfunction pages 5-7): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  2. (randle2017structureandfunction pages 17-21): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  3. (wang2021analysisofthe pages 17-21): Quan Wang. Analysis of the interaction of the parkinsonism-associated protein fbxo7 with the bag6 complex. Dissertation, Jan 2021. URL: https://doi.org/10.18154/rwth-2022-00532, doi:10.18154/rwth-2022-00532. This article has 0 citations.

  4. (randle2017structureandfunction media caeb42e9): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  5. (randle2017structureandfunction media 1a872076): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  6. (zhou2018pathophysiologicalmechanismslinking pages 2-3): Zhi Dong Zhou, Ji Chao Tristan Lee, and Eng King Tan. Pathophysiological mechanisms linking f-box only protein 7 (fbxo7) and parkinson's disease (pd). Mutation research, 778:72-78, Oct 2018. URL: https://doi.org/10.1016/j.mrrev.2018.10.001, doi:10.1016/j.mrrev.2018.10.001. This article has 56 citations and is from a peer-reviewed journal.

  7. (teixeira2016gsk3βandtomm20 pages 1-2): Felipe Roberti Teixeira, Suzanne J. Randle, Shachi P. Patel, Tycho E.T. Mevissen, Grasilda Zenkeviciute, Tie Koide, David Komander, and Heike Laman. Gsk3β and tomm20 are substrates of the scffbxo7/park15 ubiquitin ligase associated with parkinson's disease. Biochemical Journal, 473:3563-3580, Oct 2016. URL: https://doi.org/10.1042/bcj20160387, doi:10.1042/bcj20160387. This article has 60 citations and is from a domain leading peer-reviewed journal.

  8. (randle2017structureandfunction pages 11-13): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  9. (randle2017structureandfunction pages 7-9): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

  10. (vingill2016lossoffbxo7 pages 1-2): Siv Vingill, David Brockelt, Camille Lancelin, Lars Tatenhorst, Guergana Dontcheva, Christian Preisinger, Nicola Schwedhelm‐Domeyer, Sabitha Joseph, Miso Mitkovski, Sandra Goebbels, Klaus‐Armin Nave, Jörg B Schulz, Till Marquardt, Paul Lingor, and Judith Stegmüller. Loss of fbxo7 (park15) results in reduced proteasome activity and models a parkinsonism‐like phenotype in mice. The EMBO Journal, 35:2008-2025, Sep 2016. URL: https://doi.org/10.15252/embj.201593585, doi:10.15252/embj.201593585. This article has 81 citations.

  11. (dontcheva2017functionalanalysisof pages 14-18): Guergana Ivanova Dontcheva. Functional analysis of the parkinsonism-associated protein fbxo7 (park15) in neurons. Unknown journal, 2017. URL: https://doi.org/10.53846/goediss-6469, doi:10.53846/goediss-6469.

  12. (joseph2018mechanisticcontributionsof pages 8-10): Sabitha Joseph, Jörg Bernhard Schulz, and Judith Stegmüller. Mechanistic contributions of fbxo7 to parkinson disease. Journal of Neurochemistry, 144:118-127, Jan 2018. URL: https://doi.org/10.1111/jnc.14253, doi:10.1111/jnc.14253. This article has 46 citations and is from a domain leading peer-reviewed journal.

  13. (joseph2018mechanisticcontributionsof pages 5-6): Sabitha Joseph, Jörg Bernhard Schulz, and Judith Stegmüller. Mechanistic contributions of fbxo7 to parkinson disease. Journal of Neurochemistry, 144:118-127, Jan 2018. URL: https://doi.org/10.1111/jnc.14253, doi:10.1111/jnc.14253. This article has 46 citations and is from a domain leading peer-reviewed journal.

  14. (lee2023e3ligaseadaptor pages 9-11): Su Hyoun Lee, Yun Ju Lee, Sungyeon Jung, and Kwang Chul Chung. E3 ligase adaptor fbxo7 contributes to ubiquitination and proteasomal degradation of sirt7 and promotes cell death in response to hydrogen peroxide. Journal of Biological Chemistry, 299:102909, Mar 2023. URL: https://doi.org/10.1016/j.jbc.2023.102909, doi:10.1016/j.jbc.2023.102909. This article has 13 citations and is from a domain leading peer-reviewed journal.

  15. (lee2023e3ligaseadaptor pages 12-13): Su Hyoun Lee, Yun Ju Lee, Sungyeon Jung, and Kwang Chul Chung. E3 ligase adaptor fbxo7 contributes to ubiquitination and proteasomal degradation of sirt7 and promotes cell death in response to hydrogen peroxide. Journal of Biological Chemistry, 299:102909, Mar 2023. URL: https://doi.org/10.1016/j.jbc.2023.102909, doi:10.1016/j.jbc.2023.102909. This article has 13 citations and is from a domain leading peer-reviewed journal.

  16. (zhang2023fbxo7atumor pages 1-3): Hui Zhang, Yiting Zhao, Jie Wang, Jinyun Li, Jingyi Xia, Yan Lin, Yeling Zhong, Xinyi Cao, Jiabei Jin, Xinming Li, Weili Yang, Meng Ye, and Xiaofeng Jin. Fbxo7, a tumor suppressor in endometrial carcinoma, suppresses inf2-associated mitochondrial division. Cell Death & Disease, Jun 2023. URL: https://doi.org/10.1038/s41419-023-05891-0, doi:10.1038/s41419-023-05891-0. This article has 17 citations and is from a peer-reviewed journal.

  17. (zhang2023fbxo7atumor pages 3-5): Hui Zhang, Yiting Zhao, Jie Wang, Jinyun Li, Jingyi Xia, Yan Lin, Yeling Zhong, Xinyi Cao, Jiabei Jin, Xinming Li, Weili Yang, Meng Ye, and Xiaofeng Jin. Fbxo7, a tumor suppressor in endometrial carcinoma, suppresses inf2-associated mitochondrial division. Cell Death & Disease, Jun 2023. URL: https://doi.org/10.1038/s41419-023-05891-0, doi:10.1038/s41419-023-05891-0. This article has 17 citations and is from a peer-reviewed journal.

  18. (luo2024fbxo7ubiquitinatesprmt1 pages 2-3): Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang, and Kui Wang. Fbxo7 ubiquitinates prmt1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature Communications, Jun 2024. URL: https://doi.org/10.1038/s41467-024-49087-2, doi:10.1038/s41467-024-49087-2. This article has 70 citations and is from a highest quality peer-reviewed journal.

  19. (luo2024fbxo7ubiquitinatesprmt1 pages 4-5): Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang, and Kui Wang. Fbxo7 ubiquitinates prmt1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature Communications, Jun 2024. URL: https://doi.org/10.1038/s41467-024-49087-2, doi:10.1038/s41467-024-49087-2. This article has 70 citations and is from a highest quality peer-reviewed journal.

  20. (luo2024fbxo7ubiquitinatesprmt1 pages 5-6): Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang, and Kui Wang. Fbxo7 ubiquitinates prmt1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature Communications, Jun 2024. URL: https://doi.org/10.1038/s41467-024-49087-2, doi:10.1038/s41467-024-49087-2. This article has 70 citations and is from a highest quality peer-reviewed journal.

  21. (luo2024fbxo7ubiquitinatesprmt1 pages 1-2): Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang, and Kui Wang. Fbxo7 ubiquitinates prmt1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature Communications, Jun 2024. URL: https://doi.org/10.1038/s41467-024-49087-2, doi:10.1038/s41467-024-49087-2. This article has 70 citations and is from a highest quality peer-reviewed journal.

  22. (lee2023usp7attenuatesendoplasmic pages 9-11): Su Hyoun Lee and Kwang Chul Chung. Usp7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of fbxo7. PLOS ONE, 18:e0290371, Oct 2023. URL: https://doi.org/10.1371/journal.pone.0290371, doi:10.1371/journal.pone.0290371. This article has 11 citations and is from a peer-reviewed journal.

  23. (lee2023usp7attenuatesendoplasmic pages 1-2): Su Hyoun Lee and Kwang Chul Chung. Usp7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of fbxo7. PLOS ONE, 18:e0290371, Oct 2023. URL: https://doi.org/10.1371/journal.pone.0290371, doi:10.1371/journal.pone.0290371. This article has 11 citations and is from a peer-reviewed journal.

  24. (lee2023usp7attenuatesendoplasmic pages 4-5): Su Hyoun Lee and Kwang Chul Chung. Usp7 attenuates endoplasmic reticulum stress-induced apoptotic cell death through deubiquitination and stabilization of fbxo7. PLOS ONE, 18:e0290371, Oct 2023. URL: https://doi.org/10.1371/journal.pone.0290371, doi:10.1371/journal.pone.0290371. This article has 11 citations and is from a peer-reviewed journal.

  25. (joseph2018mechanisticcontributionsof pages 3-5): Sabitha Joseph, Jörg Bernhard Schulz, and Judith Stegmüller. Mechanistic contributions of fbxo7 to parkinson disease. Journal of Neurochemistry, 144:118-127, Jan 2018. URL: https://doi.org/10.1111/jnc.14253, doi:10.1111/jnc.14253. This article has 46 citations and is from a domain leading peer-reviewed journal.

  26. (OpenTargets Search: -FBXO7): Open Targets Query (-FBXO7, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  27. (hong2024exploitingthecullin pages 6-8): Seong Ho Hong, Anand Divakaran, Akane Osa, Oscar W. Huang, Ingrid E. Wertz, and Daniel K. Nomura. Exploiting the cullin e3 ligase adaptor protein skp1 for targeted protein degradation. ACS chemical biology, 19:442-450, Feb 2024. URL: https://doi.org/10.1021/acschembio.3c00642, doi:10.1021/acschembio.3c00642. This article has 35 citations and is from a domain leading peer-reviewed journal.

  28. (luo2024fbxo7ubiquitinatesprmt1 pages 3-4): Li Luo, Xingyun Wu, Jiawu Fan, Lixia Dong, Mao Wang, Yan Zeng, Sijia Li, Wenyong Yang, Jingwen Jiang, and Kui Wang. Fbxo7 ubiquitinates prmt1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma. Nature Communications, Jun 2024. URL: https://doi.org/10.1038/s41467-024-49087-2, doi:10.1038/s41467-024-49087-2. This article has 70 citations and is from a highest quality peer-reviewed journal.

  29. (randle2017structureandfunction pages 1-5): Suzanne J. Randle and Heike Laman. Structure and function of fbxo7/park15 in parkinson's disease. Current protein & peptide science, 18 7:715-724, Jun 2017. URL: https://doi.org/10.2174/1389203717666160311121433, doi:10.2174/1389203717666160311121433. This article has 30 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. joseph2018mechanisticcontributionsof pages 3-5
  2. hong2024exploitingthecullin pages 6-8
  3. randle2017structureandfunction pages 5-7
  4. randle2017structureandfunction pages 17-21
  5. wang2021analysisofthe pages 17-21
  6. zhou2018pathophysiologicalmechanismslinking pages 2-3
  7. randle2017structureandfunction pages 11-13
  8. randle2017structureandfunction pages 7-9
  9. dontcheva2017functionalanalysisof pages 14-18
  10. joseph2018mechanisticcontributionsof pages 8-10
  11. joseph2018mechanisticcontributionsof pages 5-6
  12. randle2017structureandfunction pages 1-5
  13. https://doi.org/10.15252/embj.201593585
  14. https://doi.org/10.1042/BCJ20160387
  15. https://doi.org/10.1016/j.jbc.2023.102909
  16. https://doi.org/10.1038/s41419-023-05891-0
  17. https://doi.org/10.1038/s41467-024-49087-2
  18. https://doi.org/10.1371/journal.pone.0290371
  19. https://doi.org/10.1111/jnc.14253
  20. https://doi.org/10.1021/acschembio.3c00642
  21. https://doi.org/10.2174/1389203717666160311121433,
  22. https://doi.org/10.18154/rwth-2022-00532,
  23. https://doi.org/10.1016/j.mrrev.2018.10.001,
  24. https://doi.org/10.1042/bcj20160387,
  25. https://doi.org/10.15252/embj.201593585,
  26. https://doi.org/10.53846/goediss-6469,
  27. https://doi.org/10.1111/jnc.14253,
  28. https://doi.org/10.1016/j.jbc.2023.102909,
  29. https://doi.org/10.1038/s41419-023-05891-0,
  30. https://doi.org/10.1038/s41467-024-49087-2,
  31. https://doi.org/10.1371/journal.pone.0290371,
  32. https://doi.org/10.1021/acschembio.3c00642,

📚 Additional Documentation

Pn Notes

(FBXO7-pn-notes.md)

FBXO7 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9Y3I1
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: FBXO7 (also called FBX7; PARK15) is the substrate-recognition (F-box) component of an SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin-protein ligase complex, SCF(FBXO7). As an F-box protein it acts as a ligase-substrate adaptor: it recruits substrates and bridges them, via its F-box domain binding to SKP1, to the catalytic cullin-RING core (RBX1), and is not itself the catalytic ubiquitin transferase. The protein has a modular architecture comprising an N-terminal ubiquitin-like (Ubl) region that mediates binding to the E3 ligase PRKN/Parkin, a CDK6-interaction region, an FP (Fbxo7/PI31) dimerization domain that mediates homodimerization and interaction with the proteasome inhibitor PSMF1/PI31, the F-box domain, and a C-terminal proline-rich region that serves as a substrate-binding module. SCF(FBXO7) ubiquitination is not exclusively degradative: it can build K48-linked chains that target substrates for proteasomal degradation or K63-linked chains with non-proteolytic signaling/assembly outcomes, depending on substrate and context. Documented SCF(FBXO7) substrates include the cell-cycle regulator DLGAP5/HURP, the inhibitor-of-apoptosis protein BIRC2/cIAP1, TRAF2 and the NF-kappa-B cofactor UXT isoform 2 (whose degradation inhibits NF-kappa-B signaling), the NAD+-dependent deacetylase SIRT7 (K48- linked polyubiquitination promoting H2O2-induced cell death), the kinase GSK3-beta and the mitochondrial import receptor TOMM20 (modified in part with non-degradative chains), and, in tumor-suppressor contexts, the mitochondrial-fission factor INF2 and the arginine methyltransferase PRMT1 (K48-linked polyubiquitination coupling FBXO7 to control of mitochondrial division and serine biosynthesis, respectively). Beyond canonical SCF activity, FBXO7 has SCF-independent roles: it relocates from the cytosol to depolarized mitochondria downstream of PINK1 and promotes PRKN/Parkin recruitment and mitofusin ubiquitination to drive selective autophagy of damaged mitochondria (mitophagy); it associates with the proteasome and regulates proteasome assembly/activity through PSMF1/PI31; and it activates cyclin D/CDK6 complexes to promote cell-cycle progression, with proto-oncogenic transforming activity. FBXO7 protein stability is itself controlled by the deubiquitinase USP7. FBXO7 is predominantly cytoplasmic/cytosolic with a minor nuclear pool. Recessive loss-of-function and missense mutations (e.g. T22M, R378G, R498X) cause early-onset autosomal recessive parkinsonian-pyramidal syndrome (Parkinson disease 15, PARK15).
  • Existing/core annotation action counts: ACCEPT: 41; KEEP_AS_NON_CORE: 50; MODIFY: 1

PN Consistency Summary

  • Consistency: Fully consistent across the SPECIAL CASE roles. Falcon DR, review YAML, and all three PN rows converge: FBXO7 is (a) an SCF substrate receptor (GO:1990756, ACCEPT, already in GOA), (b) a PINK1/PRKN-pathway mitophagy regulator (PARK15), and (c) a PSMF1/PI31 proteasome regulator via the FP domain; plus CDK6/cyclin-D activation. No contradictions.
  • PN story / NEW pressure: No new term pressure. GO:1990756 already in GOA (PN flags already_in_goa_exact) and accepted. The mitophagy role: PN projects GO:0000423 mitophagy (verified real) but self-flags more_specific_than_existing_goa; the review more accurately uses the regulator terms GO:1903599 (positive regulation of autophagy of mitochondrion) and GO:1901526 (positive regulation of mitophagy), both verified real, ACCEPT — FBXO7 facilitates/regulates mitophagy rather than being core autophagy machinery. Review also adds SCF-independent GO:0030674 protein-macromolecule adaptor activity for the mitophagy and PI31 roles. Conclude: all roles already captured; PN mitophagy term is appropriately broader and acknowledged as such.
  • Evidence alignment: PN cites the FBXO7/Parkin mitophagy paper (Burchell et al., Nat Neurosci — PMID:23933751) for row 1 and "15340381 / rev" for row 3. Review uses PMID:23933751 (mitophagy IBA/IDA support), the FP-domain/PI31 structural work (PMID:16782869-class, GO:0046982), CDK6 interaction studies, plus Falcon DR. Good overlap on the mitophagy primary reference; review enriches with proteasome/CDK6 literature.
  • Verdict: Consistent across all three PN rows; GO:1990756 already in GOA, mitophagy handled via more specific regulator terms (GO:1903599/GO:1901526). No over-reach; PI31/CDK6/NF-kB roles appropriately placed.

Full Consistency Review

  • UniProt: Q9Y3I1 (FBXO7/PARK15) · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
  • PN placement: 3 rows, ALP+UPS. (1) ALP|Autophagy substrate selection|…|Mitophagy|PINK/PRKN pathway; (2) UPS|Ubiquitin and UBL proteins|UBL domain|E3 ligases|CUL1 receptor / F-box; (3) UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|PI31, UBL. PN-node mapping: mitophagy type=mapped/ok→GO:0000423 (more_specific_than_existing_goa); UBL-domain CUL1-receptor subtype + Cul1-receptor group both=mapped/ok→GO:1990756 (already_in_goa_exact); UBL-domain class/group/type held context_only (too_broad)→GO:0061630/0043130/0019787.
  • Consistency: Fully consistent across the SPECIAL CASE roles. Falcon DR, review YAML, and all three PN rows converge: FBXO7 is (a) an SCF substrate receptor (GO:1990756, ACCEPT, already in GOA), (b) a PINK1/PRKN-pathway mitophagy regulator (PARK15), and (c) a PSMF1/PI31 proteasome regulator via the FP domain; plus CDK6/cyclin-D activation. No contradictions.
  • PN story / NEW pressure: No new term pressure. GO:1990756 already in GOA (PN flags already_in_goa_exact) and accepted. The mitophagy role: PN projects GO:0000423 mitophagy (verified real) but self-flags more_specific_than_existing_goa; the review more accurately uses the regulator terms GO:1903599 (positive regulation of autophagy of mitochondrion) and GO:1901526 (positive regulation of mitophagy), both verified real, ACCEPT — FBXO7 facilitates/regulates mitophagy rather than being core autophagy machinery. Review also adds SCF-independent GO:0030674 protein-macromolecule adaptor activity for the mitophagy and PI31 roles. Conclude: all roles already captured; PN mitophagy term is appropriately broader and acknowledged as such.
  • Mapping strategy: Gene supports the multi-branch node design. KEY PATTERN holds for the UPS rows (F-box receptor → GO:1990756; catalytic GO:0061630 held too_broad at class). For the ALP row, the PN process term GO:0000423 is broader than the review's regulator terms — consistent with the TOMM20/HSPA8/RAB7A precedent that the broader process term should not over-claim; PN's more_specific_than_existing_goa flag captures this correctly. Scopes sound.
  • Evidence alignment: PN cites the FBXO7/Parkin mitophagy paper (Burchell et al., Nat Neurosci — PMID:23933751) for row 1 and "15340381 / rev" for row 3. Review uses PMID:23933751 (mitophagy IBA/IDA support), the FP-domain/PI31 structural work (PMID:16782869-class, GO:0046982), CDK6 interaction studies, plus Falcon DR. Good overlap on the mitophagy primary reference; review enriches with proteasome/CDK6 literature.
  • Verdict: Consistent across all three PN rows; GO:1990756 already in GOA, mitophagy handled via more specific regulator terms (GO:1903599/GO:1901526). No over-reach; PI31/CDK6/NF-kB roles appropriately placed.
  • Recommended edits: none to FBXO7-ai-review.yaml; PN mappings sound (mitophagy more_specific_than_existing_goa flag is the correct treatment).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO7/FBXO7-ai-review.yaml
  • PN workbook rows: 3

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Substrate selectivity regulator for selective autophagy | Mitophagy | PINK/PRKN pathway

  • UniProt: Q9Y3I1
  • In branches: ALP, UPS
  • Notes: F-box only protein, component of SCF E3 ubiquitin ligase complex. Interacts with PINK1 and PRKN. Involved in translocation of PRKN to mitochondria. FBXO7 interacts with PINK1 and facilitate the translocation of Parkin/PINK1 translocation to the mitochondria.
  • PN references (titles):
    • The Parkinson's disease–linked proteins Fbxo7 and Parkin interact to mediate mitophagy | Nature Neuroscience
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Substrate selectivity regulator for selective autophagy|Mitophagy|PINK/PRKN pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Substrate selectivity regulator for selective autophagy|Mitophagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0000423 mitophagy]
      rationale: This PN type groups substrate-selectivity regulators assigned to mitophagy. Those factors participate in mitophagy, but the PN category is more specific than the full process term.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Substrate selectivity regulator for selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL proteins | UBL domain | E3 ligases | CUL1 receptor / F-box

  • UniProt: Q9Y3I1
  • In branches: ALP, UPS
  • Signature domains: (IPR029071)
  • Auxiliary domains: IPR001810, IPR021625
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain|E3 ligases|CUL1 receptor / F-box
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN subtype identifies a UBL-domain F-box/CUL1 receptor role. The safe shared molecular function is ubiquitin-like ligase-substrate adaptor activity rather than catalytic E3 activity.
    • [type] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain|E3 ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This UBL-domain type is an E3-ligase context, but descendants include catalytic E3s as well as cullin receptor/adaptor components. Direct propagation is restricted to narrower subtypes.
    • [group] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain
      status=context_only scope=too_broad_to_propagate GO=[GO:0043130 ubiquitin binding]
      rationale: This group records UBL-domain protein context, but descendants include enzymes, adaptors, chaperone-related proteins, non-enzymatic proteins, and nucleic-acid factors. Propagation is restricted to narrower nodes.
    • [class] Ubiquitin Proteasome System|Ubiquitin and UBL proteins
      status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
      rationale: This class groups ubiquitin, UBL modifiers, UBX/UBL-domain proteins, and UBL-containing enzymes. The branch is UPS-relevant but too mixed to propagate as a single GO annotation.
    • [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.

PN row 3: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | PI31, UBL

  • UniProt: Q9Y3I1
  • In branches: ALP, UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR021625, (IPR029071)
  • 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|PI31, UBL
      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 (3)

  • GO:0000423 mitophagy | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Substrate selectivity regulator for selective autophagy|Mitophagy
  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBL domain|E3 ligases|CUL1 receptor / F-box
  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | 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: Q9Y3I1
gene_symbol: FBXO7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO7 (also called FBX7; PARK15) is the substrate-recognition (F-box)
  component of an SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin-protein ligase complex,
  SCF(FBXO7). As an F-box protein it acts as a ligase-substrate adaptor: it
  recruits substrates and bridges them, via its F-box domain binding to SKP1, to
  the catalytic cullin-RING core (RBX1), and is not itself the catalytic
  ubiquitin transferase. The protein has a modular architecture comprising an
  N-terminal ubiquitin-like (Ubl) region that mediates binding to the E3 ligase
  PRKN/Parkin, a CDK6-interaction region, an FP (Fbxo7/PI31) dimerization domain
  that mediates homodimerization and interaction with the proteasome inhibitor
  PSMF1/PI31, the F-box domain, and a C-terminal proline-rich region that serves
  as a substrate-binding module. SCF(FBXO7) ubiquitination is not exclusively
  degradative: it can build K48-linked chains that target substrates for
  proteasomal degradation or K63-linked chains with non-proteolytic
  signaling/assembly outcomes, depending on substrate and context. Documented
  SCF(FBXO7) substrates include the
  cell-cycle regulator DLGAP5/HURP, the inhibitor-of-apoptosis protein
  BIRC2/cIAP1, TRAF2 and the NF-kappa-B cofactor UXT isoform 2 (whose degradation
  inhibits NF-kappa-B signaling), the NAD+-dependent deacetylase SIRT7 (K48-
  linked polyubiquitination promoting H2O2-induced cell death), the kinase
  GSK3-beta and the mitochondrial import receptor TOMM20 (modified in part with
  non-degradative chains), and, in tumor-suppressor contexts, the
  mitochondrial-fission factor INF2 and the arginine methyltransferase PRMT1
  (K48-linked polyubiquitination coupling FBXO7 to control of mitochondrial
  division and serine biosynthesis, respectively). Beyond canonical
  SCF activity, FBXO7 has SCF-independent roles: it relocates from the cytosol to
  depolarized mitochondria downstream of PINK1 and promotes PRKN/Parkin
  recruitment and mitofusin ubiquitination to drive selective autophagy of
  damaged mitochondria (mitophagy); it associates with the proteasome and
  regulates proteasome assembly/activity through PSMF1/PI31; and it activates
  cyclin D/CDK6 complexes to promote cell-cycle progression, with proto-oncogenic
  transforming activity. FBXO7 protein stability is itself controlled by the
  deubiquitinase USP7. FBXO7 is predominantly
  cytoplasmic/cytosolic with a minor nuclear pool. Recessive loss-of-function and
  missense mutations (e.g. T22M, R378G, R498X) cause early-onset autosomal
  recessive parkinsonian-pyramidal syndrome (Parkinson disease 15, PARK15).
alternative_products:
- name: '1'
  id: Q9Y3I1-1
- name: '2'
  id: Q9Y3I1-2
  sequence_note: VSP_041073, VSP_041074
- name: '3'
  id: Q9Y3I1-3
  sequence_note: VSP_044723
existing_annotations:
- term:
    id: GO:1903599
    label: positive regulation of autophagy of mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a positive role in mitophagy, consistent with the experimentally demonstrated FBXO7 function downstream of PINK1 in Parkin-mediated mitophagy.
    action: ACCEPT
    reason: Core biological process; the IBA inference agrees with direct IMP/IDA evidence (PMID:23933751, PMID:26310625) that FBXO7 promotes clearance of depolarized mitochondria.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.
    - reference_id: file:human/FBXO7/FBXO7-deep-research-falcon.md
      supporting_text: FBXO7 participates in mitochondrial quality control by interacting with **PINK1 and Parkin** and facilitating Parkin recruitment to damaged mitochondria in PARK15 biology.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of protein kinase binding, reflecting the documented FBXO7 interactions with the kinases CDK6 and PINK1.
    action: KEEP_AS_NON_CORE
    reason: Real and mechanistically meaningful (CDK6 activation of cyclin D complexes; PINK1 in the mitophagy pathway) but a subsidiary binding activity rather than the core adaptor function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Interacts with CDK6 and promotes its interaction with D-type cyclin.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization; FBXO7 has a documented minor nuclear pool in addition to its predominant cytoplasmic localization.
    action: KEEP_AS_NON_CORE
    reason: Nuclear localization is real but minor; the predominant and functionally dominant compartment is the cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; the predominant compartment of FBXO7.
    action: ACCEPT
    reason: Correct predominant localization, supported experimentally (PMID:16096642, PMID:18495667).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of mitochondrial localization, consistent with the experimentally observed relocation of FBXO7 from the cytosol to depolarized mitochondria.
    action: ACCEPT
    reason: Correct conditional localization; FBXO7 relocates to depolarized mitochondria during mitophagy (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Relocates from the cytosol to depolarized mitochondria (PubMed:23933751).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytosolic localization from the UniProt subcellular location; the predominant compartment of FBXO7.
    action: ACCEPT
    reason: Correct core localization, supported experimentally (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of protein kinase binding, reflecting documented CDK6 and PINK1 interactions.
    action: KEEP_AS_NON_CORE
    reason: Real binding activity (CDK6, PINK1) but subsidiary to the core ligase-substrate adaptor function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Interacts with CDK6 and promotes its interaction with D-type cyclin.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16278047
  qualifier: enables
  review:
    summary: Interaction captured during characterization of a related brain-expressed F-box protein (FBX25). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but the bare protein binding term is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22632967
  qualifier: enables
  review:
    summary: Interaction captured in a cyclin F (FBXO1)/RRM2 study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23933751
  qualifier: enables
  review:
    summary: Interaction with PRKN/Parkin (and PINK1) from the mitophagy study; a functionally important interaction, but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the meaningful FBXO7-PRKN/PINK1 interaction, but bare protein binding is uninformative; the functional relationship is captured by the mitophagy process annotations.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: the Ubl domain of Fbxo7 directly mediates Parkin interaction
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interactome mapping. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  qualifier: enables
  review:
    summary: High-throughput interactome perturbation study. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: High-throughput quantitative interactome map. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: High-throughput Polycomb complexome interaction map. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (protein communities/disease networks). 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: High-throughput variant-interactome disruption study. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: High-throughput neurodegenerative-disease interactome map. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput dual proteome-scale interactome map. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: High-throughput multimodal cell-map interactome. 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/FBXO7/FBXO7-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:1901526
    label: positive regulation of mitophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of positive regulation of mitophagy, consistent with the experimentally established FBXO7 mitophagy role.
    action: ACCEPT
    reason: Core biological process; agrees with direct experimental evidence (PMID:23933751, PMID:26310625).
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
- 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 catabolic process FBXO7 enables.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent catabolic process) and K48-linked ubiquitination annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence assignment of nucleoplasm localization, consistent with the documented minor nuclear pool of FBXO7.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; the predominant compartment is the cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence assignment of cytosolic localization, the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Correct core localization; supported by direct experimental fractionation (PMID:23933751).
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16096642
  qualifier: located_in
  review:
    summary: Experimental localization showing FBXO7 in the nucleus (minor pool) in addition to predominant cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Real minor nuclear localization documented in this study; predominant compartment is cytoplasmic.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:16096642
  qualifier: located_in
  review:
    summary: Experimental localization showing FBXO7 is predominantly cytoplasmic. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Experimental localization to the cytoplasm consistent with the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: Author statement that FBXO7 is an F-box component of an SCF E3 ubiquitin ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is the substrate-receptor F-box subunit of SCF(FBXO7) (CUL1, SKP1, RBX1, FBXO7).
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: 'The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation.'
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: Author statement linking the SCF complex (including F-box proteins) to SCF-dependent proteasomal degradation. Core biological process.
    action: ACCEPT
    reason: Core biological process; FBXO7 targets substrates for SCF-dependent proteasomal degradation.
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: 'These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXO7 acts in the nucleus, where it colocalizes with and ubiquitinates its substrate UXT-V2.
    action: KEEP_AS_NON_CORE
    reason: Documents a functionally relevant nuclear pool (UXT-V2 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: We find that UXT-V2 colocalizes with Fbxo7 in the cell nucleus.
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7) mediates SCF-dependent proteasomal degradation of UXT-V2. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support; SCF(FBXO7) polyubiquitinates UXT-V2 for proteasomal degradation.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
- term:
    id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7)-mediated degradation of UXT-V2 inhibits NF-kappa-B signaling. Well-supported biological process.
    action: ACCEPT
    reason: Directly demonstrated; FBXO7 negatively regulates NF-kappa-B signaling via UXT-V2 (and TRAF2/cIAP1) ubiquitination.
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:33010352
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXO7) builds K48 (and K63) polyubiquitin chains on UXT-V2.
    action: ACCEPT
    reason: Directly demonstrated K48-linked ubiquitination of a substrate, the canonical degradative topology used by SCF(FBXO7).
    supported_by:
    - reference_id: PMID:33010352
      supporting_text: This substrate is polyubiquitinated by SCF(Fbxo7) with K48 and K63 ubiquitin chain linkages in vitro and in vivo.
- term:
    id: GO:1901526
    label: positive regulation of mitophagy
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: involved_in
  review:
    summary: Direct evidence that WT FBXO7 facilitates mitophagy whereas PD-linked mutants inhibit it. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy.
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic apoptotic
      signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking an FBXO7 variant (Y52C) to altered TRAF2 turnover and neuronal outgrowth in a PD-protective context.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal stress/apoptosis-modulating role inferred from variant phenotypes, not the core SCF adaptor function.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic apoptotic
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: acts_upstream_of
  review:
    summary: Evidence that FBXO7 acts as a stress-response protein with cytoprotective (and, when mutant/aggregated, neurotoxic) effects under oxidative stress.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal stress-response role; mechanistically downstream of the core mitophagy/proteostasis functions rather than a distinct core process.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: is_active_in
  review:
    summary: Direct evidence that FBXO7 colocalizes with its substrate SIRT7 mainly in the nucleus, where it acts to degrade SIRT7.
    action: KEEP_AS_NON_CORE
    reason: Documents a functionally relevant nuclear pool (SIRT7 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: immunohistochemical analysis of SH-SY5Y cells revealed that endogenous FBXO7 and SIRT7 colocalized mainly in the nucleus
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 drives SCF-dependent proteasomal degradation of SIRT7. Core biological process.
    action: ACCEPT
    reason: Core biological process; FBXO7 promotes proteasomal degradation of SIRT7 (the more specific GO:0031146 SCF-dependent process is also annotated).
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 promotes K48-linked polyubiquitination of SIRT7.
    action: ACCEPT
    reason: Directly demonstrated K48-linked ubiquitination of a substrate (SIRT7), the canonical degradative topology of SCF(FBXO7).
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: These results demonstrated that FBXO7 directly mediates the polyubiquitination of SIRT7 by targeting K48-linked polyubiquitin chains.
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:36646384
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 acts as an SCF substrate-recognition adaptor recruiting SIRT7 for ubiquitination. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; FBXO7 is the substrate-recognition adaptor of SCF(FBXO7), bridging substrates to the catalytic cullin-RING core.
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: part_of
  review:
    summary: Direct evidence that FBXO7 functions within an SCF(FBXO7) complex (with SKP1 and CUL1) to ubiquitinate HURP/DLGAP5. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is a functional F-box subunit of an SCF ubiquitin-ligase complex.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: 'In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.'
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 functions as a substrate-recruiting adaptor of the SCF complex, binding HURP via its proline-rich region. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; FBXO7 is a functional SCF adaptor with the proline-rich region serving as the substrate-binding module.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21378169
  qualifier: enables
  review:
    summary: Interaction captured in a study of SKP1/CRM1 competition controlling F-box protein localization. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction relevant to FBXO7 nuclear/cytoplasmic shuttling (SKP1, CRM1) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 concentrates into mitochondria upon stress, forming aggregates. Conditional/stress-induced localization.
    action: ACCEPT
    reason: Correct conditional localization; FBXO7 relocates to mitochondria under stress/depolarization, consistent with its mitophagy role.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: 'Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25029497
  qualifier: enables
  review:
    summary: Interaction with TRAF2 captured in the FBXO7 Y52C polymorphism study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful FBXO7-TRAF2 interaction but bare protein binding is uninformative; the substrate relationship is captured by the ubiquitination/NF-kappa-B annotations.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: 'Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization (colocalized with cIAP1/BIRC2 in cytoplasm and nucleus). Minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization, consistent with the documented minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization (colocalized with cIAP1/BIRC2). Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 promotes ubiquitination and turnover of TRAF2. A parent of the more specific SCF-dependent catabolic process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific GO:0031146 (SCF-dependent proteasomal catabolic process); here the substrate is TRAF2.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: 'In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced.'
- term:
    id: GO:0010975
    label: regulation of neuron projection development
  evidence_type: IMP
  original_reference_id: PMID:25029497
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that an FBXO7 variant alters neuronal outgrowth in differentiated SH-SY5Y cells.
    action: KEEP_AS_NON_CORE
    reason: A context-specific neuronal phenotype linked to an FBXO7 variant, not the core SCF adaptor function.
    supported_by:
    - reference_id: PMID:25029497
      supporting_text: After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16510124
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 overexpression promotes ubiquitination of cIAP1/BIRC2. Generic parent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent catabolic process (GO:0031146) better captures the role. The cIAP1/BIRC2 substrate relationship is meaningful.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'Furthermore, we showed that overexpression of Fbxo7 promotes the ubiquitination of cIAP1.'
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:18495667
  qualifier: enables
  review:
    summary: Interaction with the kinase CDK6 (and PSMF1) documented in the FP-domain structural study.
    action: KEEP_AS_NON_CORE
    reason: Real CDK6 binding (FBXO7 activates cyclin D-CDK6) but subsidiary to the core adaptor function.
    supported_by:
    - reference_id: PMID:18495667
      supporting_text: 'SCF(Fbxo7) is known to catalyze the ubiquitination of hepatoma-up-regulated protein (HURP) and the inhibitor of apoptosis (IAP) protein but also functions as an activator of cyclin D-Cdk6 complexes.'
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:16510124
  qualifier: enables
  review:
    summary: Interaction with the ubiquitin ligase cIAP1/BIRC2 (itself a RING E3) documented as an FBXO7 substrate interaction.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction with a ubiquitin ligase substrate (BIRC2) but is subsidiary to the core adaptor function.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'we performed a yeast two-hybrid screen and identified an F-box protein Fbxo7 as a cIAP1 interacting protein.'
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:25029497
  qualifier: enables
  review:
    summary: Assignment of ubiquitin binding to FBXO7. A plausible but ancillary activity relative to the core substrate-adaptor function.
    action: KEEP_AS_NON_CORE
    reason: If accurate, ubiquitin binding is a subsidiary molecular feature; the core function is the ligase-substrate adaptor activity. Not central to the documented FBXO7 roles.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'The ubiquitin-like region mediates interaction with PRKN.'
- term:
    id: GO:0046982
    label: protein heterodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:18495667
  qualifier: enables
  review:
    summary: Direct evidence that FBXO7 heterodimerizes with PSMF1/PI31 via the shared FP domain (and homodimerizes).
    action: KEEP_AS_NON_CORE
    reason: Real FP-domain-mediated dimerization with PSMF1/PI31 (relevant to proteasome regulation) but a structural/binding property rather than the core adaptor function.
    supported_by:
    - reference_id: PMID:18495667
      supporting_text: We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21347293
  qualifier: located_in
  review:
    summary: Direct evidence that wild-type FBXO7 isoform 1 displays mostly diffuse nuclear localization, with loss of nuclear localization in PARK15 mutants.
    action: KEEP_AS_NON_CORE
    reason: This study emphasizes a nuclear pool, but UniProt and other studies establish that FBXO7 is predominantly cytoplasmic; nuclear localization is treated as non-core.
    supported_by:
    - reference_id: PMID:21347293
      supporting_text: 'the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21347293
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization, including mutant-induced cytoplasmic mislocalization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support; PARK15 N-terminal mutations shift FBXO7 to the cytoplasm.
    supported_by:
    - reference_id: PMID:21347293
      supporting_text: 'N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Immunohistochemical detection of FBXO7 in human brain neurons; widespread expression. Reported nuclear/cytoplasmic neuronal staining.
    action: KEEP_AS_NON_CORE
    reason: Brain immunoreactivity localization; nuclear pool is minor relative to predominant cytoplasm.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Immunohistochemical detection of FBXO7 in the cytoplasm of human brain neurons. Consistent with predominant cytoplasmic localization.
    action: ACCEPT
    reason: Consistent with the core cytoplasmic localization of FBXO7 in neurons.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:16510124
  qualifier: part_of
  review:
    summary: Author statement that F-box proteins such as FBXO7 are specificity-determining subunits of SCF ubiquitin ligases. Core complex membership.
    action: ACCEPT
    reason: Core localization/complex; FBXO7 is the F-box substrate-receptor subunit of an SCF E3 ligase.
    supported_by:
    - reference_id: PMID:16510124
      supporting_text: 'Since F-box proteins are specificity determining subunits of SCF ubiquitin protein ligases, our results suggest that Fbxo7 can mediate the ubiquitination of cIAP1 by SCF ubiquitin protein ligase'
- term:
    id: GO:0097409
    label: glial cytoplasmic inclusion
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive glial cytoplasmic inclusions in multiple system atrophy. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but this is a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:0097414
    label: classical Lewy body
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy bodies in Parkinson disease. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:0097462
    label: Lewy neurite
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy neurites. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'FBXO7 immunoreactivity was detected in large proportions of α-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions)'
- term:
    id: GO:1990037
    label: Lewy body core
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'where it colocalized with α-synuclein in PD and MSA cases'
- term:
    id: GO:1990038
    label: Lewy body corona
  evidence_type: IDA
  original_reference_id: PMID:23656991
  qualifier: located_in
  review:
    summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization.
    action: KEEP_AS_NON_CORE
    reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment.
    supported_by:
    - reference_id: PMID:23656991
      supporting_text: 'where it colocalized with α-synuclein in PD and MSA cases'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct evidence relating to FBXO7 nuclear/cytoplasmic distribution governed by SKP1/CRM1 competition.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization governed by SKP1/CRM1 shuttling; predominant compartment is cytoplasm.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: A minor proportion is detected in the nucleus (PubMed:16096642).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytoplasmic localization controlled by SKP1/CRM1 competition. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Note=Predominantly cytoplasmic (PubMed:16096642).
- term:
    id: GO:0040012
    label: regulation of locomotion
  evidence_type: IDA
  original_reference_id: PMID:26310625
  qualifier: involved_in
  review:
    summary: Organismal locomotor phenotype associated with FBXO7 (Drosophila dopamine-neuron degeneration and PD-related models), reflecting its mitophagy/neuroprotection role.
    action: KEEP_AS_NON_CORE
    reason: An organismal/neurodegeneration phenotype downstream of the core mitophagy function rather than a distinct cell-autonomous core process.
    supported_by:
    - reference_id: PMID:26310625
      supporting_text: 'The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome neddylation/CRL-machinery pathway annotation placing FBXO7 in the cytosol. The cytosol is the predominant FBXO7 compartment.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment for the SCF(FBXO7) complex.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (CAND1 binding) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (COMMD/CAND1) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (COP9 signalosome deneddylation) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome CRL-machinery pathway annotation (DCUN1D3) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (Ub transfer from E2 to substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (release of E3 from polyubiquitinated substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (polyubiquitination of substrate) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome ubiquitination-pathway annotation (interaction of E3 with substrate and E2-Ub complex) placing FBXO7 in the cytosol.
    action: ACCEPT
    reason: Correct core localization; cytosol is the predominant compartment.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 nuclear localization documented in the FP-domain study. Minor nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: 'Nucleus {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667, ECO:0000269|PubMed:33010352}.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18495667
  qualifier: located_in
  review:
    summary: Direct evidence of FBXO7 cytosolic localization. Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}.
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: part_of
  review:
    summary: Direct evidence that FBXO7 is part of a ubiquitin ligase complex (the SCF(FBXO7) complex). Generic parent of the specific SCF complex term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's complex membership.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: 'F-box domain-containing proteins target substrates to SCF-type (Skp1-Cul1-F-box) E3-ubiquitin ligase complexes'
- term:
    id: GO:0000422
    label: autophagy of mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that reducing FBXO7 impairs CCCP-induced mitophagy and that FBXO7 acts in Parkin-mediated mitophagy. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental (IMP) support; FBXO7 knockdown reduces mitophagy and FBXO7 rescues parkin mutant phenotypes.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 relocates from the cytosol to depolarized mitochondria following CCCP treatment. Conditional localization.
    action: ACCEPT
    reason: Correct conditional/stress-induced localization central to the mitophagy function.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: endogenous Fbxo7 levels were found to decrease steadily in the cytosolic fraction and increase concurrently in the mitochondrial fractions
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23933751
  qualifier: located_in
  review:
    summary: Direct evidence that FBXO7 is predominantly cytosolic (before relocating to depolarized mitochondria). Core compartment.
    action: ACCEPT
    reason: Core localization with direct experimental support (cell fractionation).
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: 'although both proteins localise predominantly to the cytosol'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXO7 is required for CCCP-induced mitofusin 1 ubiquitination (via promoting Parkin recruitment). Generic parent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; FBXO7 facilitates substrate (Mfn1) ubiquitination chiefly by promoting Parkin recruitment. The specific mitophagy annotations better capture the role.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy.
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23933751
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that FBXO7 is required for Parkin translocation to depolarized mitochondria. Well-supported process.
    action: ACCEPT
    reason: Directly demonstrated; FBXO7 facilitates Parkin recruitment to mitochondria, a key step in mitophagy.
    supported_by:
    - reference_id: PMID:23933751
      supporting_text: Overall, these data indicate that Fbxo7 facilitates Parkin translocation to the mitochondria in response to depolarisation.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: GO_REF:0000054
  qualifier: part_of
  review:
    summary: LIFEdb fusion-protein localization assignment of generic protein-containing complex membership.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF ubiquitin ligase complex (GO:0019005) is far more informative.
    supported_by:
    - reference_id: file:human/FBXO7/FBXO7-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7.
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IDA
  original_reference_id: PMID:15145941
  qualifier: involved_in
  review:
    summary: Direct evidence that FBXO7 controls the stability/abundance of its substrate HURP via ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; FBXO7 regulates substrate stability through the more specific SCF-dependent catabolic process (GO:0031146).
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15145941
  qualifier: enables
  review:
    summary: Interaction with the substrate DLGAP5/HURP (and CUL1/SKP1) from the HURP proteolysis study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the meaningful FBXO7-HURP/DLGAP5 substrate interaction, but bare protein binding is uninformative; captured by the SCF/adaptor annotations.
    supported_by:
    - reference_id: PMID:15145941
      supporting_text: 'In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner.'
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: part_of
  review:
    summary: Author statement that F-box proteins are subunits of SCF ubiquitin protein ligases. Generic parent of the SCF complex term.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's membership.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: 'In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs.'
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Family-level author statement assigning ubiquitin-protein transferase activity to F-box-containing SCF ligases. FBXO7 is the substrate-recognition adaptor, not the catalytic transferase (the catalytic RING is RBX1).
    action: MODIFY
    reason: FBXO7 itself is not the ubiquitin transferase; it is the substrate-recognition adaptor of the SCF complex. The catalytic transfer is performed by the E2 recruited by the RBX1 RING. The informative molecular function is the ligase-substrate adaptor activity.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: PMID:36646384
      supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Family-level author statement that F-box/SCF proteins drive controlled degradation of cellular regulatory proteins. Generic parent of the specific SCF-dependent process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal catabolic process) better captures FBXO7's role.
    supported_by:
    - reference_id: PMID:10531035
      supporting_text: 'Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins'
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000054
  title: Gene Ontology annotation based on curation of intracellular localizations
    of expressed fusion proteins in living cells
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified; foundational family-level description establishing F-box proteins as the substrate-recognition subunits of SCF ubiquitin ligases. Source of the TAS transferase/catabolic/complex annotations; the bare transferase activity is an over-assignment for the adaptor FBXO7.'
- id: PMID:15145941
  title: Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-phosphorylated
    hepatoma up-regulated protein (HURP) proteolysis by a proline-rich region.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes FBXO7 as a functional SCF adaptor using its proline-rich region to recruit the substrate HURP/DLGAP5; source of the core adaptor activity and SCF complex annotations.'
- id: PMID:16096642
  title: Transforming activity of Fbxo7 is mediated specifically through regulation
    of cyclin D/cdk6.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes the cyclin D/CDK6 activation and proto-oncogenic transforming activity of FBXO7 and its predominantly cytoplasmic localization with a minor nuclear pool.'
- id: PMID:16278047
  title: Characterization of FBX25, encoding a novel brain-expressed F-box protein.
  findings: []
- id: PMID:16510124
  title: The F-box protein Fbxo7 interacts with human inhibitor of apoptosis protein
    cIAP1 and promotes cIAP1 ubiquitination.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes the FBXO7-cIAP1/BIRC2 interaction and FBXO7-promoted cIAP1 ubiquitination; source of SCF complex, cytoplasm/nucleus and ubiquitination annotations.'
- id: PMID:18495667
  title: Structure of a conserved dimerization domain within the F-box protein Fbxo7
    and the PI31 proteasome inhibitor.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Defines the FP (Fbxo7/PI31) domain mediating FBXO7 homodimerization and heterodimerization with PSMF1/PI31; source of heterodimerization and CDK6-binding annotations.'
- id: PMID:21347293
  title: Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal
    syndrome (PARK15).
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Reports FBXO7 isoform expression and nuclear localization of isoform 1, with PARK15 mutations causing cytoplasmic mislocalization. Emphasizes a nuclear pool that other studies treat as minor relative to predominant cytoplasm.'
- id: PMID:21378169
  title: A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls
    the localization of a subset of F-box proteins.
  findings: []
- id: PMID:22632967
  title: Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome
    integrity and DNA repair.
  findings: []
- id: PMID:23656991
  title: FBXO7 immunoreactivity in α-synuclein-containing inclusions in Parkinson
    disease and multiple system atrophy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Documents FBXO7 immunoreactivity in alpha-synuclein-positive Lewy bodies, Lewy neurites and glial cytoplasmic inclusions; source of disease-pathology localization annotations (kept as non-core).'
- id: PMID:23933751
  title: The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate
    mitophagy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Key paper establishing the SCF-independent mitophagy role: FBXO7 interacts with PINK1/Parkin, relocates to depolarized mitochondria, and promotes Parkin recruitment and Mfn1 ubiquitination; PD mutations disrupt this.'
- id: PMID:25029497
  title: FBXO7 Y52C polymorphism as a potential protective factor in Parkinson's disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Y52C polymorphism stabilizes FBXO7, enhances TRAF2 interaction/ubiquitination and increases neuronal outgrowth; source of TRAF2 interaction, catabolic-process and neuron-projection annotations.'
- 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 annotation.
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:26310625
  title: F-box protein 7 mutations promote protein aggregation in mitochondria and
    inhibit mitophagy.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Establishes FBXO7 as a stress-response protein essential for mitophagy whose PD mutations promote mitochondrial aggregation and inhibit mitophagy; source of mitophagy, mitochondrion and locomotion annotations.'
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding 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 a bare protein binding annotation.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding 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: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:33010352
  title: The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT
    isoform 2 (UXT-V2) to inhibit the NF-κB signaling pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes SCF(FBXO7)-mediated K48/K63 polyubiquitination and proteasomal degradation of UXT-V2, inhibiting NF-kappa-B signaling; source of NF-kappa-B, K48 ubiquitination, SCF-dependent catabolism and nuclear-activity annotations.'
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (abstract-only in cache). Review of SCF complex roles in genome/chromosome stability; supports SCF complex membership and SCF-dependent proteasomal catabolism (NAS) annotations. FBXO7-specific chromosome-stability data are in PMID:34791250.'
- id: PMID:36646384
  title: E3 ligase adaptor FBXO7 contributes to ubiquitination and proteasomal degradation
    of SIRT7 and promotes cell death in response to hydrogen peroxide.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'PubMed-verified (full text available). Establishes FBXO7 as an SCF substrate-recognition adaptor that drives K48-linked polyubiquitination and proteasomal degradation of SIRT7; explicitly describes FBXO7 as an adaptor (not the catalytic transferase). Source of the core adaptor-activity annotation.'
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome/cell map; source of a bare protein binding annotation.
- 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/FBXO7/FBXO7-deep-research-falcon.md
  title: Falcon deep research report for human FBXO7
  findings:
  - statement: FBXO7 is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase, whose F-box domain binds SKP1 to link substrates to the CUL1-RBX1 catalytic core.
    supporting_text: FBXO7 is best understood as a **substrate-specifying adaptor** of an **SCF-type E3 ubiquitin ligase**, where its **F-box domain binds SKP1**, linking FBXO7 to the **CUL1–RBX1** catalytic core that recruits an E2~ubiquitin and transfers ubiquitin to substrates.
  - statement: FBXO7-driven ubiquitination is not exclusively degradative; it can generate K48-linked (proteasome-targeting) or K63-linked (non-proteolytic) chains depending on substrate and context.
    supporting_text: A key conceptual point is that **FBXO7-driven ubiquitination is not exclusively degradative**. It can generate **K48-linked polyubiquitin** (often proteasome-targeting) or **K63-linked chains** (often non-proteolytic signaling/trafficking/autophagy-related roles), depending on the substrate and context.
  - statement: Loss of Fbxo7 in mice reduces proteasome activity and produces a parkinsonism-like phenotype, supporting a role in neuronal proteostasis through proteasome assembly/composition tuning.
    supporting_text: 'In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis.'
  - statement: FBXO7 acts as a context-dependent tumor suppressor, catalyzing predominantly K48-linked polyubiquitination of INF2 (endometrial carcinoma, mitochondrial division control) and of PRMT1 (hepatocellular carcinoma, serine synthesis control).
    supporting_text: Together, these studies support FBXO7 as a context-dependent tumor suppressor via **mitochondrial homeostasis** and **amino-acid metabolism**, consistent with an E3 adaptor that tunes proteostasis, mitochondria, and stress responses.
  - statement: USP7 deubiquitinates and stabilizes FBXO7 by removing K48-linked ubiquitin chains, connecting deubiquitinase control of FBXO7 to cell survival under ER stress.
    supporting_text: USP7 deubiquitinates FBXO7 by removing **K48-linked ubiquitin chains**, preventing FBXO7 proteasomal degradation.
core_functions:
- description: Substrate-recognition (F-box) adaptor of the SCF(FBXO7) E3 ubiquitin
    ligase complex (CUL1-SKP1-RBX1-FBXO7) that recruits substrates (e.g. DLGAP5/HURP,
    BIRC2/cIAP1, TRAF2, UXT-V2, SIRT7) via its proline-rich region and Ubl/FP regions
    and bridges them to the catalytic cullin-RING core for K48-linked polyubiquitination
    and proteasomal degradation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:36646384
    supporting_text: FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates.
  - reference_id: PMID:15145941
    supporting_text: Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: SCF-independent regulator of mitophagy that relocates from the cytosol
    to depolarized mitochondria downstream of PINK1, interacts with PINK1 and PRKN/Parkin
    via its N-terminal Ubl region, and promotes Parkin recruitment to mitochondria
    and mitofusin ubiquitination to drive selective autophagic clearance of damaged
    mitochondria.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005739
    label: mitochondrion
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:23933751
    supporting_text: Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy.
  directly_involved_in:
  - id: GO:1901526
    label: positive regulation of mitophagy
- description: Negative regulator of canonical NF-kappa-B signaling, achieved by SCF(FBXO7)-mediated
    K48/K63 polyubiquitination and proteasomal degradation of the NF-kappa-B cofactor
    UXT isoform 2 (and ubiquitination of TRAF2 and cIAP1/BIRC2).
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:33010352
    supporting_text: 'Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-κB signaling pathway.'
  directly_involved_in:
  - id: GO:0043124
    label: negative regulation of canonical NF-kappaB signal transduction
- description: Proteasome-associated regulator of proteostasis that, through FP-domain
    heterodimerization with the proteasome inhibitor PSMF1/PI31 and ubiquitin signaling
    on proteasomal components, tunes 26S proteasome assembly/activity; loss of FBXO7
    reduces proteasome activity and models a parkinsonism-like phenotype, indicating
    a role in neuronal proteostasis.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18495667
    supporting_text: We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain.
  - reference_id: file:human/FBXO7/FBXO7-deep-research-falcon.md
    supporting_text: 'In mouse models, **loss of Fbxo7** leads to **reduced proteasome activity** and a **parkinsonism-like phenotype**, supporting a role for FBXO7 in neuronal proteostasis.'
proposed_new_terms: []
suggested_questions:
- question: To what extent are FBXO7's SCF-dependent substrate-degradation roles (HURP, cIAP1, TRAF2, UXT-V2, SIRT7) and its SCF-independent roles (PINK1/Parkin mitophagy, PSMF1/PI31 proteasome regulation, cyclin D/CDK6 activation) separable, and which are most relevant to PARK15 neurodegeneration?
- question: How do the FP domain-mediated FBXO7 homodimerization and FBXO7-PSMF1/PI31 heterodimerization regulate proteasome assembly/activity in neurons, and is this disrupted by PARK15 mutations?
- question: Does FBXO7 directly target PRKN/PINK1 for ubiquitination, or does it act mainly as a non-catalytic scaffold promoting Parkin recruitment to depolarized mitochondria?
suggested_experiments:
- description: Reconstitute SCF(FBXO7) in vitro with purified CUL1, SKP1, RBX1, an E2, and candidate substrates (HURP/DLGAP5, SIRT7, UXT-V2) to confirm that FBXO7 functions as a substrate-presenting adaptor (not the catalytic transferase) and to map substrate lysines and chain linkages.
- description: Perform quantitative ubiquitinome and proteome profiling in FBXO7-knockout versus wild-type neuronal cells under basal and mitochondrial-depolarization (CCCP) conditions to define the endogenous SCF(FBXO7) substrate repertoire and its contribution to mitophagy.
- description: Use live-cell imaging with PARK15 patient-derived neurons (T22M, R378G, R498X) to quantify FBXO7 relocation to depolarized mitochondria and Parkin recruitment kinetics, dissecting how each mutation impairs mitophagy.