Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0008270 zinc ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Electronic (InterPro/keyword) assignment of zinc binding based on the N-terminal TRAF-type zinc finger (residues 48-109), which plausibly coordinates zinc as a structural feature. Reason: The TRAF-type zinc finger plausibly binds zinc, but this is a structural attribute of one domain and is subsidiary to the protein's role as an SCF substrate-recognition adaptor; not a standalone core function. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt ZN_FING 48..109
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000002	MODIFY	Summary: Electronic (InterPro) assignment of ubiquitin protein ligase activity. As an F-box protein, FBXO30 is the substrate-recognition adaptor of the SCF complex and is not the catalytic ligase; the ubiquitin-transfer activity resides in the RBX1/RING subunit. This is a common over-propagation of ligase activity onto F-box adaptors. Reason: F-box proteins are substrate-recognition adaptors, not catalytic ligases; the catalytic activity resides in RBX1/RING. The substrate-adaptor activity term better captures FBXO30's molecular function. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: High-throughput affinity-purification interactome (BioPlex) capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. Reason: Records a real interactor (MYO6) detected in a large-scale interactome, but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Q8TB52; Q9UM54: MYO6
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Cell-specific proteome-scale interactome (BioPlex) again capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. Reason: Records the same MYO6 interaction from a high-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Q8TB52; Q9UM54: MYO6
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-derived electronic assignment of the general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination/ proteasomal degradation process in which FBXO30 participates. Reason: Correct but generic; the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures the biological role. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0019005 SCF ubiquitin ligase complex	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	Summary: ComplexPortal (NAS) assignment that FBXO30 is part of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the core cellular localization for an F-box substrate-recognition protein. A dedicated complex variant (CPX-7968) is annotated. Reason: Core localization; FBXO30 assembles into the SCF complex via its F-box domain binding SKP1, consistent with UniProt and the dedicated ComplexPortal SCF FBXO30 variant. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
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: ComplexPortal (NAS) assignment of the SCF-dependent proteasomal ubiquitin-dependent protein catabolic process, the core biological process for an SCF substrate-recognition receptor that targets substrates for proteasomal degradation. Reason: Core biological process; as the substrate-recognition component of an SCF/CRL1 ligase, FBXO30 directs substrates into SCF-dependent proteasomal degradation. Falcon-sourced literature grounds this with specific reported substrates (human RARG and HIF-1A; mouse Eg5/KIF11 and SLBP), consistent with the functional placement of FBXO30 as an F-box/SCF (CRL1) substrate-recognition receptor; individual substrate-pathway links remain single-study and are not promoted to substrate-specific GO terms here. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXO30/FBXO30-deep-research-falcon.md Human work directly demonstrates FBXO30-mediated ubiquitylation of RARγ and proteasome-dependent regulation of HIF-1α
GO:0005829 cytosol	TAS Reactome:R-HSA-8952618	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/ neddylation pathway reaction (AcM-UBE2M transfers NEDD8 to CRL1). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952620	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/ neddylation pathway reaction (NEDD8:AcM-UBE2M binds CRL1). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (CAND1 binds cytosolic CRL E3 ligases). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956200	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1 complex). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (polyubiquitination of substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	KEEP AS NON CORE	Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation.

Core Functions

Substrate-recognition (substrate-adaptor) component of an SCF (SKP1-CUL1-F-box protein)/CRL1-type E3 ubiquitin ligase complex; via its F-box domain FBXO30 binds SKP1 and, within the assembled SCF complex (with CUL1 and catalytic RBX1/RING), selects substrate proteins for polyubiquitination and SCF-dependent 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:

file:human/FBXO30/FBXO30-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
file:human/FBXO30/FBXO30-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

PMID:28514442

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

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.

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/FBXO30/FBXO30-deep-research-falcon.md

Falcon deep research report for human FBXO30

FBXO30 is a substrate-recognition F-box adaptor of SCF/CUL1-RING ubiquitin ligase complexes, conferring specificity for ubiquitin-dependent proteasomal turnover rather than catalyzing a small-molecule reaction.

"it is not an enzyme that catalyzes a small-molecule reaction; rather, it confers target specificity for **ubiquitylation leading to proteasomal degradation**."
In human cells FBXO30 ubiquitinates RARG, positively regulating BMP signaling, and promotes proteasomal degradation of HIF-1A.

"Human work directly demonstrates FBXO30-mediated ubiquitylation of **RARγ** and proteasome-dependent regulation of **HIF-1α**"
FBXO30 is predominantly cytoplasmic in human cells and colocalizes with its RARG substrate.

"A human study reports FBXO30 is **predominantly cytoplasmic**, and FBXO30 and RARγ show **cytoplasmic colocalization** by immunofluorescence"
In the mouse ortholog FBXO30 binds SKP1 and CUL1 and ubiquitinates the mitotic kinesin Eg5/KIF11 and the stem-loop binding protein SLBP.

"Fbxo30 physically associates with **Skp1 and Cul1** and targets the mitotic kinesin **Eg5/KIF11** for ubiquitin-dependent regulation."

Suggested Experiments

Experiment: Identify FBXO30 SCF substrates by affinity purification or proximity labeling coupled to quantitative proteomics, comparing wild-type versus F-box-deleted FBXO30 and proteasome-inhibited cells to enrich for stabilized substrates, and test the reported substrates (RARG, HIF-1A, Eg5/KIF11, SLBP) for direct, F-box/SKP1-dependent ubiquitination.

Experiment: Validate physical incorporation of FBXO30 into the SCF complex by co-immunoprecipitation / reconstitution of SKP1, CUL1 and RBX1 binding, and test F-box-domain mutants to confirm the SKP1-dependent adaptor interaction.

Experiment: Determine FBXO30 subcellular localization across the cell and meiotic cycle (live-cell imaging, fractionation) and correlate cytoplasmic versus spindle/nuclear pools with degradation of specific substrates (e.g. RARG vs Eg5).

Deep Research

Falcon

(FBXO30-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 15 citations 2 artifacts 2026-06-13T06:54:06.469292

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000015 The requested visual information is provided in the following figures and table: - **FBXO30 Domain Architecture & Co-immunoprecipit (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 FBXO30 (UniProt Q8TB52) — functional annotation and current evidence base

0) Target verification (gene/protein identity)

The gene symbol FBXO30 corresponds to F-box only protein 30 (synonym FBX30) in Homo sapiens, consistent with the human experimental literature that explicitly studies “FBXO30/F-box protein 30” as an F-box–containing ubiquitin-ligase component. In a human mechanistic study, FBXO30 was mapped to contain an F-box domain (aa 373–409) and a zinc-finger domain (aa 48–109), matching the domain expectations for an F-box substrate receptor with additional protein–protein interaction motifs (cheng2019fboxproteinfbxo30 pages 4-7).

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF/Cullin-RING E3 ligases

F-box proteins are substrate-recognition modules within SKP1–CUL1–F-box (SCF) E3 ubiquitin ligase complexes. SCF/CRL architecture typically includes a cullin scaffold (e.g., CUL1) and ROC1/RBX1 to recruit the ubiquitin-charged E2 enzyme, while the F-box protein provides substrate specificity (fischer2023identificationofhypertrophymodulating pages 1-2). This conceptual framework is essential for interpreting FBXO30: it is not an enzyme that catalyzes a small-molecule reaction; rather, it confers target specificity for ubiquitylation leading to proteasomal degradation.

1.2 Molecular function of FBXO30 (what it “does”)

Across human and mouse experimental systems, the evidence supports FBXO30 as an SCF-type F-box adaptor/E3 ligase component that promotes ubiquitin-dependent, proteasome-mediated turnover of specific protein substrates in a context- and tissue-dependent manner. Human work directly demonstrates FBXO30-mediated ubiquitylation of RARγ and proteasome-dependent regulation of HIF-1α (cheng2019fboxproteinfbxo30 pages 4-7, yuan2023fbxo30functionsas pages 4-6).

2) Domain architecture and subcellular localization

2.1 Domain architecture

In human cells, FBXO30 contains:
- Zinc finger domain (aa 48–109)
- F-box domain (aa 373–409)
These features were experimentally used for interaction mapping with RARγ (cheng2019fboxproteinfbxo30 pages 4-7) and are also shown in the extracted figure panel(s) (cheng2019fboxproteinfbxo30 media aa47de8f).

2.2 Subcellular localization

A human study reports FBXO30 is predominantly cytoplasmic, and FBXO30 and RARγ show cytoplasmic colocalization by immunofluorescence (cheng2019fboxproteinfbxo30 pages 4-7). In mouse oocytes, Fbxo30 displays dynamic localization: nuclear at GV stage, then cytoplasmic with enrichment around chromosomes after GVBD, and spindle-associated at Pro-MI/MI (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 1-2). These observations are consistent with a protein whose functional localization depends on cellular state and substrate.

3) Experimentally supported substrates, pathways, and mechanisms

Evidence type	Molecular role	Validated substrates	Pathway/process	Subcellular localization	Key quantitative findings	Diseases/phenotypes	Primary reference (year)	DOI URL
Human; in vitro (HEK293, NT2/D1), human fetal tissue	F-box protein functioning as E3 ubiquitin ligase/SCF-type substrate adaptor for proteasomal turnover	RARγ	RA/RARγ-BMP signaling; positive regulation of BMP signaling via RARγ degradation	Predominantly cytoplasmic; cytoplasmic colocalization with RARγ; domains mapped: zinc finger aa48-109, F-box aa373-409	RARγ half-life ~4 h; FBXO30 knockdown RNA-seq: 86 upregulated and 78 downregulated genes; positive correlation with ID2 r=0.672 (p<0.05); negative correlation with chordin r=-0.515 (p<0.05); NanoString n=10; some WB n=3; human NTD retinoid values reported up to ~9.31 ng/mg in anencephaly vs up to ~3.70 ng/mg in controls (cheng2019fboxproteinfbxo30 pages 4-7, cheng2019fboxproteinfbxo30 pages 11-14, cheng2019fboxproteinfbxo30 media aa47de8f)	Neural tube defects; aberrant FBXO30 levels/downregulation in high-retinol NTD samples; reduced BMP target gene expression (cheng2019fboxproteinfbxo30 pages 1-2, cheng2019fboxproteinfbxo30 pages 4-7, cheng2019fboxproteinfbxo30 pages 11-14)	Cheng et al. (2019) (cheng2019fboxproteinfbxo30 pages 1-2, cheng2019fboxproteinfbxo30 pages 4-7)	https://doi.org/10.1038/s41419-019-1783-y
Human; in vitro and in vivo (ccRCC cell lines, xenograft/metastasis models), human tumor cohorts	F-box protein in SCF-type E3 ligase complexes; tumor-suppressive E3 ligase promoting proteasome-dependent HIF-1α degradation in hZIP1/Zn2+-dependent axis	HIF-1α	Hypoxia/HIF-1α regulation; hZIP1/Zn2+/FBXO30/HIF-1α axis	Not established in gathered 2023 ccRCC evidence	TCGA analyses used 533 ccRCC vs 72 adjacent normal tissues in one report; another excerpt reports 253 renal cancer tissues vs 72 normal tissues; clinical validation included 20 paired tumors for WB and 24 paired tumors for RT-qPCR; xenograft n=5/group; lung metastasis assay n=3/group; higher FBXO30 associated with better overall survival using 50% cutoff (yuan2023fbxo30functionsas pages 3-4, yuan2023fbxo30functionsas pages 4-6, yuan2023fbxo30functionsas pages 1-2)	Clear cell renal cell carcinoma; FBXO30 downregulated with higher grade/stage; FBXO30 overexpression suppresses proliferation, invasion, EMT, tumorigenesis, metastasis (yuan2023fbxo30functionsas pages 3-4, yuan2023fbxo30functionsas pages 4-6)	Yuan et al. (2023) (yuan2023fbxo30functionsas pages 3-4, yuan2023fbxo30functionsas pages 4-6, yuan2023fbxo30functionsas pages 1-2)	https://doi.org/10.3892/ijo.2023.5488
Mouse; in vivo mammary gland plus biochemical/cell-based assays	SCF adaptor/E3 ligase component; binds SKP1 and CUL1 and ubiquitinates substrate	Eg5/KIF11	Mitosis, centrosome homeostasis, spindle assembly, mammopoiesis	Not established in gathered excerpts	Mass spectrometry identified 7 unique EG5 peptides; co-IP recovered EG5, SKP1, CUL1; Eg5-binding region mapped to C-terminus likely aa812-1052; rescue of Fbxo30-/- defects by shRNA or EG5 inhibitor demonstrated functional specificity (liu2016fbxo30regulatesmammopoiesis pages 1-3, liu2016fbxo30regulatesmammopoiesis pages 3-4, liu2016fbxo30regulatesmammopoiesis pages 16-20)	Mammary gland developmental defects; impaired mammary stem/progenitor function; centrosome and spindle abnormalities when Fbxo30 lost (liu2016fbxo30regulatesmammopoiesis pages 1-3, liu2016fbxo30regulatesmammopoiesis pages 16-20)	Liu et al. (2016) (liu2016fbxo30regulatesmammopoiesis pages 1-3, liu2016fbxo30regulatesmammopoiesis pages 3-4, liu2016fbxo30regulatesmammopoiesis pages 16-20)	https://doi.org/10.1016/j.celrep.2016.03.083
Mouse; oocyte RNAi, proteomics, immunofluorescence, transfected cells	F-box protein/SCF-family substrate selector promoting ubiquitin-proteasome turnover	SLBP	Oocyte meiosis; chromosome condensation/segregation via SLBP-histone H3 control	Nuclear at GV; cytoplasmic after GVBD with enrichment around chromosomes; spindle-associated at Pro-MI/MI; minimal at MII (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 1-2)	iTRAQ used 3000 MI oocytes/group; 238 Fbxo30-associated proteins identified; 13 unique SLBP peptides detected; MG132 4 μM for 6 h used in ubiquitination/proteasome assays (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 2-4)	Meiotic arrest, failure of polar body extrusion, chromosome overcondensation and segregation defects after Fbxo30 depletion; rescue by SLBP knockdown (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 2-4, jin2019fbxo30regulateschromosome pages 1-2)	Jin et al. (2019) (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 2-4, jin2019fbxo30regulateschromosome pages 1-2)	https://doi.org/10.1007/s00018-019-03038-z
Cross-source synthesis: human primary evidence plus mouse functional orthology	Overall current annotation: substrate-recognition F-box protein in SCF/CUL1-RING ubiquitin ligase complexes, with context-dependent substrates rather than enzymatic small-molecule catalysis	Human: RARγ, HIF-1α; Mouse: Eg5/KIF11, SLBP	Developmental signaling (RA/BMP), hypoxia signaling, mitotic control, chromosome segregation	Context-dependent; cytoplasmic in human RARγ study; spindle/chromosome-associated in mouse oocytes (cheng2019fboxproteinfbxo30 pages 4-7, jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 1-2)	Recent review notes many F-box proteins in spermatogenesis remain incompletely defined; for FBXO30, mechanistic evidence is still substrate- and tissue-specific rather than system-wide (OpenTargets Search: -FBXO30)	Disease links supported in Open Targets include neural tube defect and nonpapillary renal cell carcinoma, but evidence base is limited and literature-driven rather than genetically definitive (OpenTargets Search: -FBXO30)	Open Targets / literature-supported synthesis (2024 update context) (OpenTargets Search: -FBXO30)	https://platform.opentargets.org/target/ENSG00000118496

Table: This table summarizes experimentally supported functional annotation for human FBXO30 (UniProt Q8TB52) and the most relevant orthologous mouse evidence. It organizes validated substrates, pathways, localization, quantitative findings, and disease links so the evidence base can be assessed at a glance.

3.1 FBXO30 → RARγ ubiquitylation links retinoic acid signaling to BMP pathway control (development/NTD)

Mechanism (human cells): FBXO30 interacts with retinoic acid receptor γ (RARγ) (identified by IP/MS and validated by co-IP) and promotes ubiquitylation of RARγ (cheng2019fboxproteinfbxo30 pages 4-7). Truncation mapping indicates the F-box domain is necessary/sufficient for the FBXO30–RARγ interaction (cheng2019fboxproteinfbxo30 pages 4-7); the domain schematic and mapping are visible in the extracted figure region (cheng2019fboxproteinfbxo30 media aa47de8f).

Pathway consequence: The study positions FBXO30 as a positive regulator of BMP signaling by destabilizing RARγ, thereby modulating RA-mediated suppression of BMP outputs (cheng2019fboxproteinfbxo30 pages 4-7, cheng2019fboxproteinfbxo30 pages 1-2). BMP pathway readouts (e.g., BRE reporter activity, p-Smad1/5) and RARγ ubiquitylation assays are shown in the extracted figures (cheng2019fboxproteinfbxo30 media aa47de8f, cheng2019fboxproteinfbxo30 media 665338cd, cheng2019fboxproteinfbxo30 media 0fad8d55).

Quantitative data: RARγ is described as a short-lived protein with ~4 h half-life (cheng2019fboxproteinfbxo30 pages 4-7). RNA-seq after FBXO30 depletion identified 86 upregulated and 78 downregulated genes (cheng2019fboxproteinfbxo30 pages 4-7). In NTD-associated tissue analyses, correlations with BMP-related genes included FBXO30–ID2 r = 0.672 (p < 0.05) and FBXO30–chordin r = −0.515 (p < 0.05) (cheng2019fboxproteinfbxo30 pages 11-14).

Human disease/tissue evidence: FBXO30 protein was reported as significantly downregulated in human fetal brain tissue from neural tube defect (NTD) cases relative to controls (cheng2019fboxproteinfbxo30 pages 4-7). A clinical table in the same study reports higher retinoid values in anencephaly samples (up to ~9.31 ng/mg) compared with controls (up to ~3.70 ng/mg) (cheng2019fboxproteinfbxo30 pages 11-14), and this table is present in the extracted visual content (cheng2019fboxproteinfbxo30 media aa47de8f, cheng2019fboxproteinfbxo30 media eab6c99f).

Interpretation: The most direct mechanistic chain supported by experimental evidence is: retinoid/RA exposure → reduced FBXO30 levels → altered RARγ stability → altered BMP signaling outputs, which provides a plausible molecular link between environmental vitamin A derivatives and developmental signaling defects (cheng2019fboxproteinfbxo30 pages 1-2, cheng2019fboxproteinfbxo30 pages 11-14).

3.2 FBXO30 → HIF-1α degradation axis in clear cell renal cell carcinoma (2023)

A 2023 study in clear cell renal cell carcinoma (ccRCC) reports that FBXO30 mediates ubiquitination and proteasomal degradation of HIF‑1α under normoxia, functioning as a tumor suppressor in their models (yuan2023fbxo30functionsas pages 4-6, yuan2023fbxo30functionsas pages 1-2).

Cohorts and models (quantitative details):
- TCGA-level comparisons described include 533 ccRCC vs 72 adjacent normal tissues in one excerpted analysis (yuan2023fbxo30functionsas pages 3-4) and 253 renal cancer tissues vs 72 normal tissues in another excerpt (yuan2023fbxo30functionsas pages 4-6).
- Clinical validation included 20 paired ccRCC/adjacent tissues by western blot and 24 paired samples by RT-qPCR (yuan2023fbxo30functionsas pages 4-6).
- In vivo assays reported n=5 mice/group for subcutaneous xenografts and n=3 mice/group for lung metastasis models (yuan2023fbxo30functionsas pages 3-4).

Mechanistic evidence: FBXO30 altered HIF‑1α at the protein (not mRNA) level, and the proteasome inhibitor MG132 reversed FBXO30’s negative regulation, consistent with proteasome-dependent turnover (yuan2023fbxo30functionsas pages 4-6). The paper proposes an upstream hZIP1/Zn2+ regulation of FBXO30 and HIF‑1α (yuan2023fbxo30functionsas pages 1-2).

Interpretation and limitations: The study provides a coherent E3-ligase mechanism in a specific tumor context but, in the retrieved excerpts, does not provide hazard ratios or detailed effect-size statistics beyond survival stratification and experimental sample sizes (yuan2023fbxo30functionsas pages 4-6).

3.3 Cross-species mechanistic substrates informing conserved biology (mouse evidence)

Although the user’s target is the human protein, mechanistic studies of the mouse ortholog provide strong biochemical evidence for SCF assembly and substrate specificity that plausibly generalizes to the human protein family member.

Eg5/KIF11 (mitosis; mammopoiesis): In a mouse study, Fbxo30 physically associates with Skp1 and Cul1 and targets the mitotic kinesin Eg5/KIF11 for ubiquitin-dependent regulation. Mass spectrometry recovered SCF components and Eg5 peptides; co-IPs and in vitro ubiquitination assays support Eg5 as a substrate; and genetic/chemical normalization of Eg5 activity rescued mammary epithelial proliferation and mammopoiesis defects in Fbxo30−/− mice (liu2016fbxo30regulatesmammopoiesis pages 3-4, liu2016fbxo30regulatesmammopoiesis pages 16-20).

SLBP (chromosome segregation; oocyte meiosis): Another mouse study identified SLBP as an Fbxo30-associated protein by IP-MS, with 13 unique peptides detected; depletion of Fbxo30 caused meiotic arrest and chromosome segregation defects that were rescued by SLBP knockdown, consistent with SLBP being a functional substrate (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 2-4, jin2019fbxo30regulateschromosome pages 1-2).

4) Recent developments (prioritizing 2023–2024)

4.1 2023: FBXO30 as a putative tumor suppressor E3 ligase in ccRCC via HIF‑1α turnover

The clearest 2023 advance specific to FBXO30 is the ccRCC mechanism implicating FBXO30 in HIF‑1α degradation and tumor suppression phenotypes across in vitro assays and mouse xenograft/metastasis models, supported by patient-tissue comparisons (yuan2023fbxo30functionsas pages 3-4, yuan2023fbxo30functionsas pages 4-6).

4.2 2023: Phenotypic screening implicates Fbxo30 in cardiomyocyte hypertrophy modulation

A 2023 functional genomics screen of Cullin-RING ligase components in neonatal rat cardiomyocytes identified Fbxo30 as a hit where siRNA depletion increased cardiomyocyte cell size under basal conditions, suggesting a negative regulatory role in hypertrophy pathways (fischer2023identificationofhypertrophymodulating pages 1-2, fischer2023identificationofhypertrophymodulating pages 6-8). The paper provides expert caveats common to CRL screens (e.g., limited mechanistic data for many F-box proteins and expression–function disconnects), which is relevant for interpreting FBXO30 as under-characterized outside a few substrate-defined contexts (fischer2023identificationofhypertrophymodulating pages 6-8).

4.3 2024: Continued emphasis on tissue-specific roles of F-box proteins; limited direct FBXO30 review coverage

A 2024 review of F-box proteins in spermatogenesis provides broader SCF context and highlights that many F-box proteins remain incompletely characterized at the substrate level; however, in the retrieved excerpt it does not directly discuss FBXO30 (xuan2024theemergingand pages 11-12). This underscores a field-wide gap: FBXO30 currently has few well-validated substrates compared with prominent F-box proteins (xuan2024theemergingand pages 11-12).

5) Current applications and real-world implementations

5.1 Biomarker/target hypotheses in cancer and developmental disorders

Cancer: The ccRCC study positions FBXO30 expression and its regulation of HIF‑1α as potentially relevant for prognosis/therapeutic targeting, though the retrieved excerpt does not provide complete clinical performance statistics (yuan2023fbxo30functionsas pages 4-6).
Developmental biology/NTD: The RARγ/BMP mechanism suggests FBXO30 could be considered in mechanistic interpretations of retinoid-associated teratogenicity and BMP pathway dysregulation, including in human fetal tissue contexts (cheng2019fboxproteinfbxo30 pages 4-7, cheng2019fboxproteinfbxo30 pages 11-14).

5.2 Translational strategy context: targeting ubiquitin ligase pathways

In general, SCF-type E3 ligase components are increasingly viewed as druggable nodes (e.g., via ligase-substrate interaction disruption or targeted protein degradation approaches). However, no direct FBXO30-targeting therapeutic modality was identified in the retrieved 2023–2024 literature set; current evidence best supports FBXO30 as a biologically relevant node with context-dependent substrates rather than an established drug target.

6) Expert opinion / authoritative synthesis (from sources retrieved here)

The cardiomyocyte CRL screening study provides an “expert-methods” lens: F-box proteins are interchangeable substrate receptors within CRLs/SCFs, and phenotypic screens can identify candidate regulators (including FBXO30), but many hits lack deep mechanistic characterization and require substrate identification follow-up (fischer2023identificationofhypertrophymodulating pages 6-8).
Open Targets provides a synthesis of genetics and literature that places FBXO30 among modestly supported associations with neoplasm, nonpapillary renal cell carcinoma, and neural tube defect, emphasizing that current human disease linkage is largely literature-driven with relatively modest association scores (OpenTargets Search: -FBXO30).

7) Disease associations and supporting statistics (Open Targets and primary literature)

Open Targets (target ENSG00000118496) lists associations (each showing 3 evidences in the extract) with neoplasm, nonpapillary renal cell carcinoma, neural tube defect, hair color, and abnormality of the skeletal system, supported by literature (Europe PMC) and GWAS credible sets. Two key supporting references in the Open Targets extract are PubMed 31320612 (2019; PMCID PMC6639381) and PubMed 36799168 (2023; PMCID PMC9946804), corresponding to the mechanistic NTD and ccRCC evidence base; the association scores shown are modest (e.g., neoplasm ~0.088; nonpapillary RCC ~0.074; neural tube defect ~0.058; skeletal system abnormality ~0.133) (OpenTargets Search: -FBXO30).

8) Summary: primary functional annotation (best-supported)

The best-supported primary function of human FBXO30 (Q8TB52) is as an F-box substrate-recognition component of an SCF/CUL1-type E3 ubiquitin ligase, mediating ubiquitylation and proteasome-dependent degradation of specific substrates. Two human substrates have direct mechanistic evidence in the retrieved corpus: RARγ (linking retinoic acid signaling to BMP pathway outputs in development/NTD) and HIF‑1α (tumor biology in ccRCC, including a proposed hZIP1/Zn2+ upstream axis). Mouse ortholog studies extend mechanistic breadth, identifying Eg5/KIF11 and SLBP as context-specific substrates involved in mitosis/mammopoiesis and oocyte chromosome segregation, respectively, and provide direct biochemical evidence for SCF assembly (cheng2019fboxproteinfbxo30 pages 4-7, yuan2023fbxo30functionsas pages 4-6, liu2016fbxo30regulatesmammopoiesis pages 16-20, jin2019fbxo30regulateschromosome pages 2-4).

Key sources (publication dates and URLs)

Yuan et al. “FBXO30 functions as a tumor suppressor and an E3 ubiquitin ligase for hZIP1-mediated HIF-1α degradation in renal cell carcinoma.” International Journal of Oncology (Feb 2023). https://doi.org/10.3892/ijo.2023.5488 (yuan2023fbxo30functionsas pages 3-4, yuan2023fbxo30functionsas pages 4-6)
Fischer et al. “Identification of hypertrophy-modulating Cullin-RING ubiquitin ligases in primary cardiomyocytes.” Frontiers in Physiology (Mar 2023). https://doi.org/10.3389/fphys.2023.1134339 (fischer2023identificationofhypertrophymodulating pages 1-2, fischer2023identificationofhypertrophymodulating pages 6-8)
Cheng et al. “F-box protein FBXO30 mediates retinoic acid receptor γ ubiquitination and regulates BMP signaling in neural tube defects.” Cell Death & Disease (Jul 2019). https://doi.org/10.1038/s41419-019-1783-y (cheng2019fboxproteinfbxo30 pages 4-7, cheng2019fboxproteinfbxo30 pages 11-14)
Liu et al. “Fbxo30 Regulates Mammopoiesis by Targeting the Bipolar Mitotic Kinesin Eg5.” Cell Reports (May 2016). https://doi.org/10.1016/j.celrep.2016.03.083 (liu2016fbxo30regulatesmammopoiesis pages 3-4, liu2016fbxo30regulatesmammopoiesis pages 16-20)
Jin et al. “Fbxo30 regulates chromosome segregation of oocyte meiosis.” Cellular and Molecular Life Sciences (Apr 2019). https://doi.org/10.1007/s00018-019-03038-z (jin2019fbxo30regulateschromosome pages 4-6, jin2019fbxo30regulateschromosome pages 2-4)
Open Targets Platform: FBXO30 (ENSG00000118496) disease associations (accessed via tool; platform reference cited in extract). https://platform.opentargets.org/target/ENSG00000118496 (OpenTargets Search: -FBXO30)

References

(cheng2019fboxproteinfbxo30 pages 4-7): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(fischer2023identificationofhypertrophymodulating pages 1-2): Maximillian Fischer, Moritz Jakab, Marc N. Hirt, Tessa R. Werner, Stefan Engelhardt, and Antonio Sarikas. Identification of hypertrophy-modulating cullin-ring ubiquitin ligases in primary cardiomyocytes. Frontiers in Physiology, Mar 2023. URL: https://doi.org/10.3389/fphys.2023.1134339, doi:10.3389/fphys.2023.1134339. This article has 5 citations.
(yuan2023fbxo30functionsas pages 4-6): Yulin Yuan, Zimeng Liu, Bohan Li, Zheng Gong, Chiyuan Piao, Zhuonan Liu, Zhe Zhang, and Xiao Dong. Fbxo30 functions as a tumor suppressor and an e3 ubiquitin ligase for hzip1-mediated hif-1α degradation in renal cell carcinoma. International Journal of Oncology, Feb 2023. URL: https://doi.org/10.3892/ijo.2023.5488, doi:10.3892/ijo.2023.5488. This article has 8 citations and is from a peer-reviewed journal.
(cheng2019fboxproteinfbxo30 media aa47de8f): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(jin2019fbxo30regulateschromosome pages 4-6): Yimei Jin, Mo Yang, Chang Gao, Wei Yue, Xiaoling Liang, Bingteng Xie, Xiaohui Zhu, Shangrong Fan, Rong Li, and Mo Li. Fbxo30 regulates chromosome segregation of oocyte meiosis. Cellular and Molecular Life Sciences, 76:2217-2229, Apr 2019. URL: https://doi.org/10.1007/s00018-019-03038-z, doi:10.1007/s00018-019-03038-z. This article has 26 citations and is from a domain leading peer-reviewed journal.
(jin2019fbxo30regulateschromosome pages 1-2): Yimei Jin, Mo Yang, Chang Gao, Wei Yue, Xiaoling Liang, Bingteng Xie, Xiaohui Zhu, Shangrong Fan, Rong Li, and Mo Li. Fbxo30 regulates chromosome segregation of oocyte meiosis. Cellular and Molecular Life Sciences, 76:2217-2229, Apr 2019. URL: https://doi.org/10.1007/s00018-019-03038-z, doi:10.1007/s00018-019-03038-z. This article has 26 citations and is from a domain leading peer-reviewed journal.
(cheng2019fboxproteinfbxo30 pages 11-14): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(cheng2019fboxproteinfbxo30 pages 1-2): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(yuan2023fbxo30functionsas pages 3-4): Yulin Yuan, Zimeng Liu, Bohan Li, Zheng Gong, Chiyuan Piao, Zhuonan Liu, Zhe Zhang, and Xiao Dong. Fbxo30 functions as a tumor suppressor and an e3 ubiquitin ligase for hzip1-mediated hif-1α degradation in renal cell carcinoma. International Journal of Oncology, Feb 2023. URL: https://doi.org/10.3892/ijo.2023.5488, doi:10.3892/ijo.2023.5488. This article has 8 citations and is from a peer-reviewed journal.
(yuan2023fbxo30functionsas pages 1-2): Yulin Yuan, Zimeng Liu, Bohan Li, Zheng Gong, Chiyuan Piao, Zhuonan Liu, Zhe Zhang, and Xiao Dong. Fbxo30 functions as a tumor suppressor and an e3 ubiquitin ligase for hzip1-mediated hif-1α degradation in renal cell carcinoma. International Journal of Oncology, Feb 2023. URL: https://doi.org/10.3892/ijo.2023.5488, doi:10.3892/ijo.2023.5488. This article has 8 citations and is from a peer-reviewed journal.
(liu2016fbxo30regulatesmammopoiesis pages 1-3): Yan Liu, Yin Wang, Zhanwen Du, Xiaoli Yan, Pan Zheng, and Yang Liu. Fbxo30 regulates mammopoiesis by targeting the bipolar mitotic kinesin eg5. Cell reports, 15 5:1111-1122, May 2016. URL: https://doi.org/10.1016/j.celrep.2016.03.083, doi:10.1016/j.celrep.2016.03.083. This article has 15 citations and is from a highest quality peer-reviewed journal.
(liu2016fbxo30regulatesmammopoiesis pages 3-4): Yan Liu, Yin Wang, Zhanwen Du, Xiaoli Yan, Pan Zheng, and Yang Liu. Fbxo30 regulates mammopoiesis by targeting the bipolar mitotic kinesin eg5. Cell reports, 15 5:1111-1122, May 2016. URL: https://doi.org/10.1016/j.celrep.2016.03.083, doi:10.1016/j.celrep.2016.03.083. This article has 15 citations and is from a highest quality peer-reviewed journal.
(liu2016fbxo30regulatesmammopoiesis pages 16-20): Yan Liu, Yin Wang, Zhanwen Du, Xiaoli Yan, Pan Zheng, and Yang Liu. Fbxo30 regulates mammopoiesis by targeting the bipolar mitotic kinesin eg5. Cell reports, 15 5:1111-1122, May 2016. URL: https://doi.org/10.1016/j.celrep.2016.03.083, doi:10.1016/j.celrep.2016.03.083. This article has 15 citations and is from a highest quality peer-reviewed journal.
(jin2019fbxo30regulateschromosome pages 2-4): Yimei Jin, Mo Yang, Chang Gao, Wei Yue, Xiaoling Liang, Bingteng Xie, Xiaohui Zhu, Shangrong Fan, Rong Li, and Mo Li. Fbxo30 regulates chromosome segregation of oocyte meiosis. Cellular and Molecular Life Sciences, 76:2217-2229, Apr 2019. URL: https://doi.org/10.1007/s00018-019-03038-z, doi:10.1007/s00018-019-03038-z. This article has 26 citations and is from a domain leading peer-reviewed journal.
(OpenTargets Search: -FBXO30): Open Targets Query (-FBXO30, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(cheng2019fboxproteinfbxo30 media 665338cd): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(cheng2019fboxproteinfbxo30 media 0fad8d55): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(cheng2019fboxproteinfbxo30 media eab6c99f): Xiyue Cheng, Pei Pei, Juan Yu, Qin Zhang, Dan Li, Xiaolu Xie, Jianxin Wu, Shan Wang, and Ting Zhang. F-box protein fbxo30 mediates retinoic acid receptor γ ubiquitination and regulates bmp signaling in neural tube defects. Cell Death & Disease, Jul 2019. URL: https://doi.org/10.1038/s41419-019-1783-y, doi:10.1038/s41419-019-1783-y. This article has 30 citations and is from a peer-reviewed journal.
(fischer2023identificationofhypertrophymodulating pages 6-8): Maximillian Fischer, Moritz Jakab, Marc N. Hirt, Tessa R. Werner, Stefan Engelhardt, and Antonio Sarikas. Identification of hypertrophy-modulating cullin-ring ubiquitin ligases in primary cardiomyocytes. Frontiers in Physiology, Mar 2023. URL: https://doi.org/10.3389/fphys.2023.1134339, doi:10.3389/fphys.2023.1134339. This article has 5 citations.
(xuan2024theemergingand pages 11-12): Zhuang Xuan, Jun Ruan, Canquan Zhou, and Zhi-ming Li. The emerging and diverse roles of f-box proteins in spermatogenesis and male infertility. Cell Regeneration, Jun 2024. URL: https://doi.org/10.1186/s13619-024-00196-9, doi:10.1186/s13619-024-00196-9. This article has 5 citations.

Artifacts

Edison artifact artifact-00

Citations

fischer2023identificationofhypertrophymodulating pages 1-2
fischer2023identificationofhypertrophymodulating pages 6-8
xuan2024theemergingand pages 11-12
https://doi.org/10.1038/s41419-019-1783-y
https://doi.org/10.3892/ijo.2023.5488
https://doi.org/10.1016/j.celrep.2016.03.083
https://doi.org/10.1007/s00018-019-03038-z
https://platform.opentargets.org/target/ENSG00000118496
https://doi.org/10.3389/fphys.2023.1134339
https://doi.org/10.1038/s41419-019-1783-y,
https://doi.org/10.3389/fphys.2023.1134339,
https://doi.org/10.3892/ijo.2023.5488,
https://doi.org/10.1007/s00018-019-03038-z,
https://doi.org/10.1016/j.celrep.2016.03.083,
https://doi.org/10.1186/s13619-024-00196-9,

📚 Additional Documentation

Pn Notes

(FBXO30-pn-notes.md)

FBXO30 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8TB52
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO30/FBXO30-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO30/FBXO30-ai-review.html
Gene notes: missing - genes/human/FBXO30/FBXO30-notes.md
GOA TSV: present - genes/human/FBXO30/FBXO30-goa.tsv
UniProt record: present - genes/human/FBXO30/FBXO30-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO30.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO30.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXO30/FBXO30-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXO30 (F-box only protein 30) is a 745-residue F-box "other" (FBXO) protein that serves as a substrate-recognition component of an SCF (SKP1-CUL1-F-box protein)-type, cullin-RING ligase 1 (CRL1) E3 ubiquitin ligase complex. Its C-terminal F-box domain (residues 610-658) docks onto SKP1, which together with CUL1 and the RING protein RBX1/ROC1 assembles the catalytic ligase; the catalytic ubiquitin-transfer activity resides in the RBX1/RING subunit rather than in FBXO30 itself. The N-terminal region carries a TRAF-type zinc finger (residues 48-109) whose solution structure has been determined and which is predicted to coordinate zinc as a structural feature. Within the assembled SCF complex FBXO30 selects specific substrate proteins for polyubiquitination and subsequent proteasomal degradation, with substrates that appear strongly context- and tissue-dependent. In human cells FBXO30 is predominantly cytoplasmic and has been reported to ubiquitinate retinoic acid receptor gamma (RARG), linking retinoic-acid signaling to positive regulation of BMP signaling in neural-tube development, and to promote proteasomal degradation of HIF-1A under normoxia, acting as a candidate tumor suppressor in clear-cell renal cell carcinoma. Studies of the rodent ortholog identify additional substrates, including the mitotic kinesin Eg5/KIF11 (mammary epithelial proliferation and spindle/centrosome homeostasis) and the stem-loop binding protein SLBP (oocyte meiotic chromosome condensation and segregation), and show dynamic nuclear/cytoplasmic/spindle-associated localization through the cell and meiotic cycle. By similarity, FBXO30 has also been implicated in muscle atrophy following denervation. The protein is widely but lowly expressed, is itself subject to auto-ubiquitination and possible neddylation, and a dedicated SCF complex variant (ComplexPortal CPX-7968) is annotated. Although several candidate substrates have now been reported, individual substrate-pathway links remain based on single studies and FBXO30 is still relatively poorly characterized.
Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 14; MODIFY: 1

PN Consistency Summary

Consistency: Strong. Deep research (Falcon → RARG, HIF-1A human; Eg5/KIF11, SLBP mouse), UniProt and GOA concordant on SCF/CRL1 substrate-receptor role. Review MODIFY of GO:0061630 (InterPro IEA ubiquitin protein ligase activity) → GO:1990756 matches the PN group target precisely. TRAF-type ZnF GO:0008270 zinc binding kept non-core (structural). No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor MF, already captured (core_function MF = GO:1990756, verified). Falcon substrates (RARG/HIF-1A/Eg5/SLBP) are single-study leads; review correctly does NOT promote them to substrate-specific GO terms (proposed_new_terms empty). Conclusion: PN adaptor claim ALREADY CAPTURED; no defensible NEW term.
Evidence alignment: PN cites only "15340381 / rev" (not in review refs). Review anchored on Falcon-sourced primary studies (Cheng 2019, Yuan 2023, Liu 2016, Jin 2019 — author-year, UNVERIFIED), the BioPlex interactome PMIDs (MYO6), and PMID:34445249. Divergence: PN reference disjoint; review's substrate evidence is lead-grade (Falcon DOIs not re-verified) but consistent with adaptor framing.
Verdict: CONSISTENT — no changes needed.

Full Consistency Review

UniProt: Q8TB52 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE (well-developed; relatively poorly characterized gene)
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|TRAF-type ZnF (aux domain IPR001293) ; PN-node mapping: group=mapped GO:1990756; subtype/type/branch=no_mapping; class=context_only (GO:0061630).
Consistency: Strong. Deep research (Falcon → RARG, HIF-1A human; Eg5/KIF11, SLBP mouse), UniProt and GOA concordant on SCF/CRL1 substrate-receptor role. Review MODIFY of GO:0061630 (InterPro IEA ubiquitin protein ligase activity) → GO:1990756 matches the PN group target precisely. TRAF-type ZnF GO:0008270 zinc binding kept non-core (structural). No contradictions.
PN story / NEW pressure: PN asserts only the generic adaptor MF, already captured (core_function MF = GO:1990756, verified). Falcon substrates (RARG/HIF-1A/Eg5/SLBP) are single-study leads; review correctly does NOT promote them to substrate-specific GO terms (proposed_new_terms empty). Conclusion: PN adaptor claim ALREADY CAPTURED; no defensible NEW term.
Mapping strategy: Correct; gene does not change the node. GO:1990756 equals the review's core MF. The catalytic-ligase IEA (GO:0061630) is exactly the over-propagation the F-box pattern predicts, correctly MODIFIED here. Note GO:0061630 also appears as the class-level context_only target — at the gene level it is properly demoted, not propagated.
Evidence alignment: PN cites only "15340381 / rev" (not in review refs). Review anchored on Falcon-sourced primary studies (Cheng 2019, Yuan 2023, Liu 2016, Jin 2019 — author-year, UNVERIFIED), the BioPlex interactome PMIDs (MYO6), and PMID:34445249. Divergence: PN reference disjoint; review's substrate evidence is lead-grade (Falcon DOIs not re-verified) but consistent with adaptor framing.
Verdict: CONSISTENT — no changes needed.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO30/FBXO30-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q8TB52
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR001293
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|TRAF-type ZnF
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

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

Note

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

📄 View Raw YAML

id: Q8TB52
gene_symbol: FBXO30
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO30 (F-box only protein 30) is a 745-residue F-box "other" (FBXO) protein
  that serves as a substrate-recognition component of an SCF (SKP1-CUL1-F-box
  protein)-type, cullin-RING ligase 1 (CRL1) E3 ubiquitin ligase complex. Its
  C-terminal F-box domain (residues 610-658) docks onto SKP1, which together
  with CUL1 and the RING protein RBX1/ROC1 assembles the catalytic ligase; the
  catalytic ubiquitin-transfer activity resides in the RBX1/RING subunit rather
  than in FBXO30 itself. The N-terminal region carries a TRAF-type zinc finger
  (residues 48-109) whose solution structure has been determined and which is
  predicted to coordinate zinc as a structural feature. Within the assembled SCF
  complex FBXO30 selects specific substrate proteins for polyubiquitination and
  subsequent proteasomal degradation, with substrates that appear strongly
  context- and tissue-dependent. In human cells FBXO30 is predominantly
  cytoplasmic and has been reported to ubiquitinate retinoic acid receptor gamma
  (RARG), linking retinoic-acid signaling to positive regulation of BMP signaling
  in neural-tube development, and to promote proteasomal degradation of HIF-1A
  under normoxia, acting as a candidate tumor suppressor in clear-cell renal cell
  carcinoma. Studies of the rodent ortholog identify additional substrates,
  including the mitotic kinesin Eg5/KIF11 (mammary epithelial proliferation and
  spindle/centrosome homeostasis) and the stem-loop binding protein SLBP (oocyte
  meiotic chromosome condensation and segregation), and show dynamic
  nuclear/cytoplasmic/spindle-associated localization through the cell and meiotic
  cycle. By similarity, FBXO30 has also been implicated in muscle atrophy
  following denervation. The protein is widely but lowly expressed, is itself
  subject to auto-ubiquitination and possible neddylation, and a dedicated SCF
  complex variant (ComplexPortal CPX-7968) is annotated. Although several
  candidate substrates have now been reported, individual substrate-pathway links
  remain based on single studies and FBXO30 is still relatively poorly
  characterized.
existing_annotations:
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic (InterPro/keyword) assignment of zinc binding based on the
      N-terminal TRAF-type zinc finger (residues 48-109), which plausibly coordinates
      zinc as a structural feature.
    action: KEEP_AS_NON_CORE
    reason: The TRAF-type zinc finger plausibly binds zinc, but this is a structural
      attribute of one domain and is subsidiary to the protein's role as an SCF
      substrate-recognition adaptor; not a standalone core function.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: ZN_FING         48..109
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic (InterPro) assignment of ubiquitin protein ligase activity.
      As an F-box protein, FBXO30 is the substrate-recognition adaptor of the SCF
      complex and is not the catalytic ligase; the ubiquitin-transfer activity
      resides in the RBX1/RING subunit. This is a common over-propagation of ligase
      activity onto F-box adaptors.
    action: MODIFY
    reason: F-box proteins are substrate-recognition adaptors, not catalytic ligases;
      the catalytic activity resides in RBX1/RING. The substrate-adaptor activity
      term better captures FBXO30's molecular function.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box
        protein)-type E3 ubiquitin ligase complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput affinity-purification interactome (BioPlex) capturing
      the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation
      guidelines.
    action: KEEP_AS_NON_CORE
    reason: Records a real interactor (MYO6) detected in a large-scale interactome,
      but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: 'Q8TB52; Q9UM54: MYO6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific proteome-scale interactome (BioPlex) again capturing the
      FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation
      guidelines.
    action: KEEP_AS_NON_CORE
    reason: Records the same MYO6 interaction from a high-throughput interactome;
      bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: 'Q8TB52; Q9UM54: MYO6'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived electronic assignment of the general protein
      ubiquitination process, a parent of the specific SCF-dependent ubiquitination/
      proteasomal degradation process in which FBXO30 participates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific GO:0031146 (SCF-dependent
      proteasomal ubiquitin-dependent protein catabolic process) better captures
      the biological role.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal (NAS) assignment that FBXO30 is part of an SCF
      (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the core cellular localization
      for an F-box substrate-recognition protein. A dedicated complex variant
      (CPX-7968) is annotated.
    action: ACCEPT
    reason: Core localization; FBXO30 assembles into the SCF complex via its F-box
      domain binding SKP1, consistent with UniProt and the dedicated ComplexPortal
      SCF FBXO30 variant.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
- 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: ComplexPortal (NAS) assignment of the SCF-dependent proteasomal
      ubiquitin-dependent protein catabolic process, the core biological process
      for an SCF substrate-recognition receptor that targets substrates for
      proteasomal degradation.
    action: ACCEPT
    reason: Core biological process; as the substrate-recognition component of an
      SCF/CRL1 ligase, FBXO30 directs substrates into SCF-dependent proteasomal
      degradation. Falcon-sourced literature grounds this with specific reported
      substrates (human RARG and HIF-1A; mouse Eg5/KIF11 and SLBP), consistent with
      the functional placement of FBXO30 as an F-box/SCF (CRL1) substrate-recognition
      receptor; individual substrate-pathway links remain single-study and are not
      promoted to substrate-specific GO terms here.
    supported_by:
    - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box
        protein)-type E3 ubiquitin ligase complex.
    - reference_id: file:human/FBXO30/FBXO30-deep-research-falcon.md
      supporting_text: Human work directly demonstrates FBXO30-mediated ubiquitylation
        of **RARγ** and proteasome-dependent regulation of **HIF-1α**
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/
      neddylation pathway reaction (AcM-UBE2M transfers NEDD8 to CRL1). Plausible
      but generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/
      neddylation pathway reaction (NEDD8:AcM-UBE2M binds CRL1). Plausible but
      generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle
      reaction (CAND1 binds cytosolic CRL E3 ligases). Plausible but generic
      pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle
      reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Plausible but
      generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle
      reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Plausible
      but generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic CRL1
      reaction (MyrG-DCUN1D3 binds CRL1 complex). Plausible but generic
      pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic
      ubiquitination reaction (transfer of Ub from E2 to substrate). Plausible but
      generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic
      ubiquitination reaction (release of E3 from polyubiquitinated substrate).
      Plausible but generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic
      ubiquitination reaction (polyubiquitination of substrate). Plausible but
      generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome (TAS) cytosolic localization derived from a generic
      ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex).
      Plausible but generic pathway-context localization.
    action: KEEP_AS_NON_CORE
    reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible
      cytosolic localization but not specific to FBXO30 and subsidiary to the SCF
      complex annotation.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: 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 affinity-purification interactome (BioPlex);
      source of the bare protein binding annotation (FBXO30-MYO6, MYO6=Q9UM54).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific proteome-scale interactome (BioPlex); source of the
      bare protein binding annotation (FBXO30-MYO6, MYO6=Q9UM54).
- 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 (Int J Mol Sci 2021, PMC8395177); abstract-only in
      cache. General review of SCF/CRL1 complex biology used by ComplexPortal as the
      NAS basis for the SCF-complex (GO:0019005) and SCF-dependent catabolic-process
      (GO:0031146) annotations. Supports the family-level SCF framing rather than
      FBXO30-specific function.
- 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/FBXO30/FBXO30-deep-research-falcon.md
  title: Falcon deep research report for human FBXO30
  findings:
  - statement: FBXO30 is a substrate-recognition F-box adaptor of SCF/CUL1-RING
      ubiquitin ligase complexes, conferring specificity for ubiquitin-dependent
      proteasomal turnover rather than catalyzing a small-molecule reaction.
    supporting_text: it is not an enzyme that catalyzes a small-molecule reaction;
      rather, it confers target specificity for **ubiquitylation leading to
      proteasomal degradation**.
  - statement: In human cells FBXO30 ubiquitinates RARG, positively regulating BMP
      signaling, and promotes proteasomal degradation of HIF-1A.
    supporting_text: Human work directly demonstrates FBXO30-mediated ubiquitylation
      of **RARγ** and proteasome-dependent regulation of **HIF-1α**
  - statement: FBXO30 is predominantly cytoplasmic in human cells and colocalizes
      with its RARG substrate.
    supporting_text: A human study reports FBXO30 is **predominantly cytoplasmic**,
      and FBXO30 and RARγ show **cytoplasmic colocalization** by immunofluorescence
  - statement: In the mouse ortholog FBXO30 binds SKP1 and CUL1 and ubiquitinates
      the mitotic kinesin Eg5/KIF11 and the stem-loop binding protein SLBP.
    supporting_text: Fbxo30 physically associates with **Skp1 and Cul1** and targets
      the mitotic kinesin **Eg5/KIF11** for ubiquitin-dependent regulation.
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Edison/Falcon LLM-generated synthesis citing author-year/DOIs
      (Cheng 2019 Cell Death Dis; Yuan 2023 Int J Oncol; Liu 2016 Cell Rep; Jin
      2019 Cell Mol Life Sci). Substrate claims (RARG, HIF-1A human; Eg5/KIF11,
      SLBP mouse) are leads consistent with UniProt SCF-adaptor framing but were
      not independently re-verified against full text here; treat as
      hypothesis-grounding, not as basis for new substrate-specific GO terms.
core_functions:
- description: Substrate-recognition (substrate-adaptor) component of an SCF
    (SKP1-CUL1-F-box protein)/CRL1-type E3 ubiquitin ligase complex; via its F-box
    domain FBXO30 binds SKP1 and, within the assembled SCF complex (with CUL1 and
    catalytic RBX1/RING), selects substrate proteins for polyubiquitination and
    SCF-dependent proteasomal degradation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
    supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box
      protein)-type E3 ubiquitin ligase complex.
  - reference_id: file:human/FBXO30/FBXO30-uniprot.txt
    supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: Are the reported FBXO30 substrates (human RARG and HIF-1A; mouse Eg5/KIF11
    and SLBP) bona fide direct SCF(FBXO30) substrates in human cells, and do they
    reflect a unified molecular activity or genuinely context- and tissue-dependent
    substrate repertoires? Is the high-throughput interactor MYO6 a substrate?
- question: Does the same substrate-recognition activity underlie FBXO30's distinct
    reported roles (BMP/retinoic-acid signaling in neural-tube development, HIF-1A
    turnover and tumor suppression in renal carcinoma, mitotic/meiotic spindle and
    chromosome homeostasis), and how is its dynamic nuclear/cytoplasmic/spindle
    localization regulated through the cell and meiotic cycle?
- question: Is the reported role of FBXO30 in muscle atrophy following denervation a
    direct consequence of its SCF substrate-recognition activity, and which substrate
    mediates it?
suggested_experiments:
- description: Identify FBXO30 SCF substrates by affinity purification or proximity
    labeling coupled to quantitative proteomics, comparing wild-type versus F-box-deleted
    FBXO30 and proteasome-inhibited cells to enrich for stabilized substrates, and
    test the reported substrates (RARG, HIF-1A, Eg5/KIF11, SLBP) for direct,
    F-box/SKP1-dependent ubiquitination.
- description: Validate physical incorporation of FBXO30 into the SCF complex by
    co-immunoprecipitation / reconstitution of SKP1, CUL1 and RBX1 binding, and test
    F-box-domain mutants to confirm the SKP1-dependent adaptor interaction.
- description: Determine FBXO30 subcellular localization across the cell and meiotic
    cycle (live-cell imaging, fractionation) and correlate cytoplasmic versus
    spindle/nuclear pools with degradation of specific substrates (e.g. RARG vs Eg5).

FBXO30

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXO30 (UniProt Q8TB52) — functional annotation and current evidence base

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF/Cullin-RING E3 ligases

1.2 Molecular function of FBXO30 (what it “does”)

2) Domain architecture and subcellular localization

2.1 Domain architecture

2.2 Subcellular localization

3) Experimentally supported substrates, pathways, and mechanisms

3.1 FBXO30 → RARγ ubiquitylation links retinoic acid signaling to BMP pathway control (development/NTD)

3.2 FBXO30 → HIF-1α degradation axis in clear cell renal cell carcinoma (2023)

3.3 Cross-species mechanistic substrates informing conserved biology (mouse evidence)

4) Recent developments (prioritizing 2023–2024)

4.1 2023: FBXO30 as a putative tumor suppressor E3 ligase in ccRCC via HIF‑1α turnover

4.2 2023: Phenotypic screening implicates Fbxo30 in cardiomyocyte hypertrophy modulation

4.3 2024: Continued emphasis on tissue-specific roles of F-box proteins; limited direct FBXO30 review coverage

5) Current applications and real-world implementations

5.1 Biomarker/target hypotheses in cancer and developmental disorders

5.2 Translational strategy context: targeting ubiquitin ligase pathways

6) Expert opinion / authoritative synthesis (from sources retrieved here)

7) Disease associations and supporting statistics (Open Targets and primary literature)

8) Summary: primary functional annotation (best-supported)

Key sources (publication dates and URLs)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXO30 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (1)

Note

📄 View Raw YAML