FBXO25 (F-box only protein 25, FBX25) is a member of the FBXO ("F-box only") class of F-box proteins. It serves as a substrate-recognition (adaptor) subunit of a SKP1-CUL1-F-box (SCF)-type E3 ubiquitin-protein ligase complex, in which it assembles with SKP1, CUL1 and the catalytic RING subunit RBX1. The C-terminal F-box motif mediates binding to SKP1 (an atypical serine in the F-box, Ser244, is required for this interaction), thereby linking specific substrates to the cullin-RING catalytic core for ubiquitination and proteasomal degradation; FBXO25 itself does not possess the catalytic ubiquitin-transfer activity, which resides in the RING/E2 module. FBXO25 is broadly expressed with notable expression in brain and testis, and a region in its N-terminus binds beta-actin. The protein localizes to the nucleus where it concentrates in discrete SKP1-colocalized subnuclear (dot-like) domains termed FBXO25-associated nuclear domains (FANDs) that co-localize with the proteasome and ubiquitinated proteins (their integrity depends on actin polymerization and RNA polymerase I activity), and is excluded from the nucleolus. Its best-validated endogenous substrate is the ETS transcription factor ELK-1: SCF(FBXO25) binds ELK-1 and promotes its ubiquitination and proteasome-dependent degradation, dampening mitogen-induced ELK-1 target genes such as c-fos and egr-1. FBXO25 has also been reported to promote histone H2B K120 monoubiquitination (with downstream H3K4me3 and activation of the osteogenic factor OSX/SP7) during osteogenic differentiation, and other reported substrate/process associations (HAX1, NRF1/NFE2L1, and handling of expanded-polyglutamine huntingtin) point to roles in SCF-dependent protein turnover, but most of these remain thinly characterized. A chromosomal translocation disrupting FBXO25 has been linked to X-linked intellectual disability, and the gene has been associated with ADHD-related phenotypes and cardiomyocyte hypertrophy in model systems.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic assignment of nuclear localization, consistent with the experimentally demonstrated nuclear localization of FBXO25.
Reason: Nuclear localization is directly supported by experimental (IDA) evidence and by the UniProt subcellular location; FBXO25 concentrates in SKP1-colocalized subnuclear domains.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}. Note=In the nucleus, associates with a subnuclear dot-like structure. Colocalized with SKP1.
|
|
GO:0005737
cytoplasm
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic assignment of cytoplasmic localization based on the F-box protein family tree. The experimentally documented localization of human FBXO25 is nuclear, so cytoplasmic localization is plausible (SCF complexes act in both compartments) but not the demonstrated primary site.
Reason: Inferred from orthologs by phylogeny; the experimental evidence for human FBXO25 emphasizes nuclear (subnuclear dot-like) localization. A cytoplasmic pool is plausible but not the core, experimentally established compartment.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.
|
|
GO:0016567
protein ubiquitination
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: Phylogenetic assignment of involvement in protein ubiquitination, the general process to which an SCF substrate-recognition subunit contributes.
Reason: Correct but generic; FBXO25 participates in ubiquitination by providing substrate specificity to the SCF complex. The more specific SCF-dependent catabolic process and substrate-adaptor function better capture the core role.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
FUNCTION: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
|
|
GO:0019005
SCF ubiquitin ligase complex
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic assignment of SCF ubiquitin ligase complex membership, the core cellular-component context for FBXO25 as an F-box protein.
Reason: Core localization/context; FBXO25 was experimentally shown to be part of an SCF complex (FBXO25-SKP1-CUL1-RBX1) and to interact directly with SKP1 and CUL1.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: Electronic transfer of nuclear localization from the UniProt subcellular location vocabulary, redundant with the experimental (IDA) nuclear annotation.
Reason: Correct core localization; matches the experimentally established nuclear localization of FBXO25.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.
|
|
GO:0016567
protein ubiquitination
|
IEA
GO_REF:0000041 |
KEEP AS NON CORE |
Summary: UniPathway-derived electronic assignment of protein ubiquitination, redundant with the IBA/ISS/NAS protein ubiquitination annotations.
Reason: Correct but generic process; captured more specifically by the SCF-dependent proteasomal catabolic process and substrate-adaptor function.
Supporting Evidence:
file:human/FBXO25/FBXO25-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/author-statement assignment of SCF ubiquitin ligase complex membership; FBXO25 is the variable substrate-recognition subunit of one of the ~69 human SCF complexes.
Reason: Core context; consistent with both the experimental SCF identification for FBXO25 and the review describing F-box proteins as the variable, substrate-specifying subunit of SCF complexes.
Supporting Evidence:
PMID:34445249
These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity.
|
|
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 assignment of involvement in SCF-dependent proteasomal degradation, the canonical biological role of an SCF F-box substrate-recognition subunit.
Reason: Represents the core biological process for FBXO25 - directing substrates for SCF-mediated poly-ubiquitination and proteasomal degradation - although the specific endogenous substrate repertoire of FBXO25 remains incompletely defined.
Supporting Evidence:
PMID:34445249
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:0005730
nucleolus
|
IDA
NOT
PMID:16278047 Characterization of FBX25, encoding a novel brain-expressed ... |
ACCEPT |
Summary: Direct-assay negative annotation indicating FBXO25 is NOT located in the nucleolus, refining its nuclear localization to non-nucleolar (subnuclear dot-like) domains.
Reason: Correct NOT annotation; consistent with the UniProt description of nuclear, SKP1-colocalized subnuclear domains rather than nucleolar localization. The cached abstract is abstract-only, so the exact figure is not quotable, but the negation is supported by the documented subnuclear-domain localization.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
Note=In the nucleus, associates with a subnuclear dot-like structure. Colocalized with SKP1.
|
|
GO:0005634
nucleus
|
IDA
PMID:16278047 Characterization of FBX25, encoding a novel brain-expressed ... |
ACCEPT |
Summary: Direct-assay evidence for nuclear localization of FBXO25 from the characterization study, the core experimentally established compartment.
Reason: Core localization with direct experimental support; FBXO25 localizes to the nucleus where it concentrates in SKP1-colocalized subnuclear domains.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.
|
|
GO:0016567
protein ubiquitination
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of involvement in protein ubiquitination.
Reason: Correct but generic; the substrate-recognition role within the SCF complex is captured more specifically by the SCF-dependent catabolic process and adaptor-activity annotations.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
FUNCTION: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of nuclear localization, consistent with the experimental human data.
Reason: Correct core localization; redundant with the IDA/IEA nuclear annotations.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.
|
|
GO:0019005
SCF ubiquitin ligase complex
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of SCF ubiquitin ligase complex membership, the core cellular-component context.
Reason: Core context; redundant with the experimentally supported and IBA/NAS SCF complex annotations.
Supporting Evidence:
file:human/FBXO25/FBXO25-uniprot.txt
Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1.
|
|
GO:0000151
ubiquitin ligase complex
|
NAS
PMID:10531035 Identification of a family of human F-box proteins. |
KEEP AS NON CORE |
Summary: Author-statement assignment of ubiquitin ligase complex membership from the founding F-box family paper, which identified FBXO25/FBX25 as one of a family of human F-box proteins that are subunits of SCF ubiquitin ligases.
Reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) is the parent-refined, accurate cellular-component context for FBXO25.
Supporting Evidence:
PMID:10531035
F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs.
|
|
GO:0004842
ubiquitin-protein transferase activity
|
NAS
PMID:10531035 Identification of a family of human F-box proteins. |
MODIFY |
Summary: Author-statement assignment of ubiquitin-protein transferase activity. As an F-box protein, FBXO25 is the substrate-recognition subunit that recruits substrates to the SCF; the catalytic ubiquitin-transfer activity resides in the RING subunit (RBX1) acting with the E2, not in the F-box protein itself.
Reason: The F-box protein is the substrate receptor, not the catalytic transferase. The ligase-substrate adaptor activity term more accurately captures FBXO25's molecular role of bridging substrates to the catalytic SCF core.
Proposed replacements:
ubiquitin-like ligase-substrate adaptor activity
Supporting Evidence:
PMID:10531035
SCF ligases bring ubiquitin conjugating enzymes (either Ubc3 or Ubc4) to substrates that are specifically recruited by the different F-box proteins.
|
|
GO:0016567
protein ubiquitination
|
NAS
PMID:10531035 Identification of a family of human F-box proteins. |
KEEP AS NON CORE |
Summary: Author-statement assignment of involvement in protein ubiquitination, reflecting FBXO25's role as a substrate-recruiting subunit of an SCF ubiquitin ligase.
Reason: Correct but generic; the substrate-recognition contribution to SCF-dependent ubiquitination/degradation is captured more specifically by other annotations.
Supporting Evidence:
PMID:10531035
Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins
|
Q: Which endogenous substrates does FBXO25 recognize in vivo, and what degron/post-translational features (e.g. phosphodegrons) determine its substrate selectivity?
Q: What is the functional significance of FBXO25 localization to discrete SKP1-colocalized subnuclear domains (FANDs) that co-localize with the proteasome and ubiquitinated proteins, and how does the N-terminal beta-actin interaction (and actin-polymerization/RNA Pol I dependence of FAND integrity) relate to its SCF substrate-targeting function?
Q: Is the reported FBXO25-dependent increase in histone H2B K120 monoubiquitination a direct activity of an FBXO25-containing ligase or an indirect effect on the H2B ubiquitination machinery, and how is it reconciled with FBXO25's canonical role as a degradative SCF substrate adaptor?
Experiment: Perform quantitative ubiquitinome/proteome profiling (e.g. diGly enrichment and TMT proteomics) in FBXO25-knockout versus wild-type cells to define the endogenous substrate repertoire and confirm reported substrates (HAX1, NRF1/NFE2L1, ELK1, polyQ-HTT).
Experiment: Reconstitute the FBXO25-SKP1-CUL1-RBX1 SCF complex in vitro with an E1, E2 and ubiquitin to test substrate-dependent ubiquitination of candidate substrates, including the Ser244Leu F-box mutant to confirm dependence on SKP1 binding for substrate turnover.
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.
The research below is restricted to human FBXO25 encoding F-box only protein 25 (UniProt Q8TCJ0). Primary literature explicitly studies FBXO25 as an F-box substrate-recognition subunit of an SCF/CRL1 ubiquitin ligase, including purification of SCF1(FBXO25) complexes containing SKP1, CUL1, and ROC1/RBX1 in human cells, consistent with UniProt identity and expected F-box protein biology. (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 3-4)
F-box proteins are substrate receptors within SCF (SKP1–CUL1–F-box) complexes (a subset of Cullin-RING ligases, CRL1). In this architecture, the F-box motif mediates binding to SKP1, while other regions of the F-box protein confer substrate recognition, bringing specific targets to the CUL1–RBX1 catalytic core for ubiquitin transfer and often proteasome-dependent degradation. For FBXO25 specifically, Teixeira et al. purified an active SCF1(FBXO25) complex from HEK293T cells that included HA-SKP1, CUL1-FLAG, and Myc-Roc1 (RBX1) together with tagged FBXO25, providing direct biochemical evidence of SCF membership. (teixeira2013thefboxprotein pages 3-4)
Primary molecular function (best supported): FBXO25 acts as the substrate-recognition subunit of an SCF1 E3 ligase that ubiquitinates specific proteins, thereby controlling their abundance and downstream transcriptional programs.
Validated substrate: The transcription factor ELK-1 is the clearest experimentally validated endogenous substrate. FBXO25 physically associates with ELK-1 and promotes ELK-1 ubiquitination and proteasome-dependent degradation in human cells. (teixeira2013thefboxprotein pages 5-6, teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 7-8)
FBXO25 is not merely diffuse in the nucleus; it localizes to discrete nuclear puncta termed FBXO25-associated nuclear domains (FANDs). These FANDs are reported to co-localize with the proteasome and ubiquitinated proteins, suggesting FBXO25 participates in a nuclear proteostasis/ubiquitin signaling compartment. FAND integrity is sensitive to perturbations of actin polymerization and inhibition of RNA polymerase I, indicating regulated assembly and/or dependence on nuclear structural or transcriptional states. (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 4-6)
Discovery/validation strategy: Teixeira et al. used an in-chip ubiquitination screen on a human protein microarray to identify candidate substrates and then validated ELK-1. (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 3-4)
Key experimental evidence for ELK-1 as an SCF1(FBXO25) substrate:
- SCF complex formation: FBXO25 forms SCF1 with SKP1/CUL1/Roc1 (RBX1). (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 3-4)
- Physical interaction: Co-purification/co-IP shows FBXO25 associates with ELK-1; notably, an FBXO25 ΔF-box mutant still binds ELK-1, separating binding from ubiquitination function. (teixeira2013thefboxprotein pages 5-6)
- Ubiquitination: ELK-1 is ubiquitinated by SCF1(FBXO25) in vitro and in cells, with controls demonstrating dependency on intact ubiquitination machinery and the F-box for functional ubiquitination. (teixeira2013thefboxprotein pages 7-8, teixeira2013thefboxprotein pages 3-4)
- Proteasome dependence: ELK-1 turnover is accelerated by FBXO25 and is blocked by epoxomicin, showing proteasome-dependent degradation. (teixeira2013thefboxprotein pages 9-10, teixeira2013thefboxprotein pages 7-8)
- Functional transcriptional consequence: FBXO25 overexpression suppresses induction of ELK-1 target genes c-fos and egr-1 following mitogen stimulation (PMA), consistent with reduced ELK-1 activity due to decreased ELK-1 protein levels. (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 7-8)
Interpretation: This places FBXO25 as a regulator of mitogen-responsive transcriptional output through controlling ELK-1 stability in the nucleus. (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 7-8)
Teixeira et al. combined tandem affinity purification and mass spectrometry with yeast two-hybrid screening to identify an extensive FBXO25 interaction network, reporting 132 novel potential FBXO25-interacting partners. (teixeira2010identificationoffbxo25‐interacting pages 1-2)
A prominent validated interactor is β-actin, reported to bind the N-terminus of FBXO25 and to be enriched in FBXO25 nuclear compartments (FANDs). In the yeast two-hybrid screen, β-actin had 63 hits, suggesting a strong or recurrent interaction signal. (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 21-23)
Interpretation: These results support a model in which FBXO25 participates in a specialized nuclear compartment whose organization may be linked to nuclear actin and proteasome/ubiquitin-associated processes. (teixeira2010identificationoffbxo25‐interacting pages 1-2)
A distinct functional axis implicates FBXO25 in chromatin modification during osteogenesis. In human umbilical cord-derived MSCs (hUC-MSCs), He et al. report that FBXO25 promotes H2B K120 monoubiquitination (H2BK120ub), which is associated with increased H3K4 trimethylation (H3K4me3) and transcriptional activation of the osteogenic transcription factor OSX (osterix/SP7). FBXO25 knockdown decreases H2BK120ub and H3K4me3, consistent with FBXO25 positively regulating this chromatin state. (he2019lncrnaodir1inhibits pages 8-11, he2019lncrnaodir1inhibits pages 15-16)
The lncRNA ODIR1 is reported to bind FBXO25 and facilitate proteasome-dependent degradation of FBXO25 by recruiting CUL3, thereby suppressing the FBXO25→H2BK120ub→H3K4me3→OSX pathway and inhibiting osteogenic differentiation. (he2019lncrnaodir1inhibits pages 8-11)
Interpretation: While FBXO25 is classically framed as a substrate adaptor promoting protein degradation, this study supports a role for FBXO25 in controlling a histone ubiquitination mark and downstream transcriptional programs in a differentiation context. (he2019lncrnaodir1inhibits pages 8-11)
A 2023 study screened Cullin-RING ubiquitin ligases in neonatal rat cardiomyocytes using siRNA and automated microscopy, identifying Fbxo25 depletion as a strong driver of increased basal cardiomyocyte size. Quantitatively, Fbxo25 knockdown increased cardiomyocyte area by ~37% and increased 3H-isoleucine incorporation by ~41%, and it upregulated hypertrophy markers Anp and Bnp. (fischer2023identificationofhypertrophymodulating pages 1-2)
In vivo, after transverse aortic constriction (TAC), Fbxo25 protein concentrations increased by ~4.5-fold compared to control animals. (fischer2023identificationofhypertrophymodulating pages 1-2)
Interpretation: Although performed in rodent systems, these results elevate FBXO25/Fbxo25 as a candidate regulator of cardiac hypertrophy pathways and motivate identification of the relevant cardiac substrates and upstream regulators. (fischer2023identificationofhypertrophymodulating pages 1-2)
A 2023 case report described a previously unreported FBXO25–SEPT14 fusion in a patient with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). The fusion joined FBXO25 exon 4 to SEPT14 exon 10, detected via RNA-based NGS. The patient exhibited persistent suboptimal molecular response (BCR::ABL P210/ABL remained above clinically desirable thresholds across time) and acquired additional cytogenetic abnormalities; the authors suggest the fusion may be associated with TKI resistance, but emphasize the need for functional validation and additional cases. (liao2023ararefbxo25–sept14 pages 1-2, liao2023ararefbxo25–sept14 pages 2-5)
Interpretation: This is an early clinical signal (single-patient) that FBXO25 rearrangements may occur in hematologic malignancy contexts; causality for resistance is unproven. (liao2023ararefbxo25–sept14 pages 1-2)
A 2024 review on epigenetic regulation in bone metabolism was retrieved, but FBXO25-specific mechanistic content was not captured in the scanned segments available here. Consequently, the strongest FBXO25 mechanistic evidence in this corpus remains anchored in 2010/2013 (nuclear localization and ELK-1 substrate) plus 2019 (ODIR1 axis) and 2023 (cardiac phenotype screen). (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2013thefboxprotein pages 1-2, he2019lncrnaodir1inhibits pages 8-11, fischer2023identificationofhypertrophymodulating pages 1-2)
FBXO25 is a good example of how E3 substrate identification is being operationalized using:
- Protein microarray “in-chip ubiquitination” screens to nominate candidate substrates, followed by biochemical validation (e.g., ELK-1). This is a scalable substrate-discovery approach for poorly annotated SCF adaptors. (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 3-4)
- Integrated proteomics (tandem affinity purification + mass spectrometry + yeast two-hybrid) to build an interaction map and discover localization-associated partners (e.g., β-actin; SCF machinery). (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 4-6)
Harich et al. illustrate an integrative workflow: family CNV discovery → large GWAS gene-based analysis → Drosophila overexpression modeling. They report FBXO25 gene-based association with ADHD in a GWAS meta-analysis with n = 55,374, including FBXO25 p = 0.010756, and demonstrate that pan-neuronal overexpression of the fly orthologue increases nocturnal locomotor activity and reduces sleep. Behavioral assay sample sizes include n = 64 and n = 56 for overexpression lines versus n = 63 controls, with significant p-values (e.g., night activity p = 0.0013 and p < 0.0001; sleep p = 0.0076 and p < 0.0001). (harich2020frommanto pages 6-8, harich2020frommanto pages 4-6)
The FBXO25–SEPT14 fusion report reflects real-world implementation of RNA-based next-generation sequencing and fusion calling in oncology. The proposed resistance association is hypothesis-generating rather than actionable at present. (liao2023ararefbxo25–sept14 pages 1-2, liao2023ararefbxo25–sept14 pages 2-5)
Key quantitative observations relevant for functional annotation include:
- 132 novel potential FBXO25 interactors identified by integrated proteomics; β-actin had 63 hits in yeast two-hybrid. (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 21-23)
- 75 putative SCF1(FBXO25) substrates identified by protoarray ubiquitination (candidates; not all validated). (teixeira2013thefboxprotein pages 3-4)
- Cardiomyocyte hypertrophy phenotypes: Fbxo25 knockdown increased cell size by ~37%, increased protein synthesis proxy by ~41%, and TAC increased Fbxo25 protein by ~4.5-fold. (fischer2023identificationofhypertrophymodulating pages 1-2)
- ADHD genetics/modeling: GWAS meta-analysis n = 55,374, FBXO25 gene-based p = 0.010756; fly behavioral assays with n ≈ 56–64 per overexpression line and significant p-values for hyperactivity/sleep phenotypes. (harich2020frommanto pages 6-8, harich2020frommanto pages 4-6)
- CML fusion: single patient; fusion joins FBXO25 exon 4 to SEPT14 exon 10 (hypothesis-generating). (liao2023ararefbxo25–sept14 pages 1-2, liao2023ararefbxo25–sept14 pages 2-5)
The following table consolidates the most supported claims, evidence types, dates, and URLs.
| Category | Key finding | Evidence type | Key citation (author-year) | Publication date | URL/DOI |
|---|---|---|---|---|---|
| Identity/domains | Human FBXO25 corresponds to UniProt Q8TCJ0, “F-box only protein 25,” an F-box substrate-recognition protein in an SCF/CRL1 E3 ligase. Primary literature consistently treats it as a human nuclear F-box protein rather than a different FBXO family member (teixeira2013thefboxprotein pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 1-2). | Primary study, database summary | Teixeira 2013; Teixeira 2010 | 2013-09; 2010-08 | https://doi.org/10.1074/jbc.M113.504308; https://doi.org/10.1002/pmic.200900419 |
| SCF complex | FBXO25 assembles an active SCF1(FBXO25) complex with SKP1, CUL1, and Roc1/RBX1 in HEK293T cells, supporting its core molecular role as the substrate adaptor for ubiquitination. Complex purification used tagged HA-SKP1, CUL1-FLAG, Myc-Roc1, and GST-HA-FBXO25-FLAG (teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 3-4). | Primary study | Teixeira 2013 | 2013-09 | https://doi.org/10.1074/jbc.M113.504308 |
| Localization | FBXO25 localizes to distinct nuclear puncta termed FBXO25-associated nuclear domains (FANDs), which co-localize with proteasomes and ubiquitinated proteins. FAND integrity is disrupted by actin depolymerization and by RNA polymerase I inhibition, supporting a regulated nuclear-compartment function (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 4-6). | Primary study | Teixeira 2010 | 2010-08 | https://doi.org/10.1002/pmic.200900419 |
| Validated substrates | ELK-1 is the best-supported endogenous FBXO25 substrate. FBXO25 binds ELK-1, promotes its ubiquitination, accelerates ELK-1 turnover in methionine-chase assays, and the degradation is blocked by epoxomicin, demonstrating proteasome dependence; FBXO25 overexpression also suppresses ELK-1 target genes c-fos and egr-1 (teixeira2013thefboxprotein pages 9-10, teixeira2013thefboxprotein pages 5-6, teixeira2013thefboxprotein pages 1-2, teixeira2013thefboxprotein pages 7-8). | Primary study | Teixeira 2013 | 2013-09 | https://doi.org/10.1074/jbc.M113.504308 |
| Other reported targets/candidates | A protoarray ubiquitination screen identified 75 putative SCF1(FBXO25) substrates from ~8,000 human proteins; named candidates include GTF2B, ODF2, SAMHD1, RPS10, ADRBK1, CDK9, EGFR, and RABEP2. These are candidates rather than comparably validated substrates, so confidence is lower than for ELK-1 (teixeira2013thefboxprotein pages 7-8, teixeira2013thefboxprotein pages 9-10, teixeira2013thefboxprotein pages 3-4). | Primary study | Teixeira 2013 | 2013-09 | https://doi.org/10.1074/jbc.M113.504308 |
| Regulatory interactions | An integrated proteomics approach identified 132 novel potential FBXO25-interacting partners; β-actin was a validated interactor that binds the N-terminus of FBXO25 and is enriched in FANDs. Proteomics also recovered major SCF-related components, consistent with FBXO25 acting in a broader nuclear interaction network (teixeira2010identificationoffbxo25‐interacting pages 1-2, teixeira2010identificationoffbxo25‐interacting pages 4-6, teixeira2010identificationoffbxo25‐interacting pages 21-23). | Primary study | Teixeira 2010 | 2010-08 | https://doi.org/10.1002/pmic.200900419 |
| Regulatory interactions | In hUC-MSCs, lncRNA ODIR1 binds FBXO25 and promotes its proteasome-dependent degradation by recruiting CUL3; FBXO25 in turn promotes H2BK120 monoubiquitination and downstream H3K4me3, increasing transcription of the osteogenic factor OSX. This places FBXO25 in a chromatin-linked regulatory axis rather than only a classic protein-degradation role (he2019lncrnaodir1inhibits pages 8-11, he2019lncrnaodir1inhibits pages 15-16). | Primary study | He 2019 | 2019-12 | https://doi.org/10.1038/s41419-019-2148-2 |
| Phenotypes/disease links | In neonatal rat cardiomyocytes, Fbxo25 depletion increased cell size by ~37% and 3H-isoleucine incorporation by ~41%, and upregulated Anp/Bnp; in vivo, Fbxo25 protein increased ~4.5-fold after transverse aortic constriction. These data support a conserved antihypertrophic role, but they are from rodent models rather than direct human functional experiments (fischer2023identificationofhypertrophymodulating pages 1-2). | Primary study, model-organism | Fischer 2023 | 2023-03 | https://doi.org/10.3389/fphys.2023.1134339 |
| Phenotypes/disease links | Human genetic and fly-model evidence links FBXO25 to ADHD-related phenotypes. In a large ADHD GWAS meta-analysis (n=55,374), gene-based analysis implicated FBXO25 (reported p=0.010756), and Drosophila pan-neuronal overexpression increased nocturnal locomotor activity and reduced sleep; sample sizes were n=64 and n=56 for two overexpression lines versus n=63 controls, with p-values 0.0013 to <0.0001 depending on assay (harich2020frommanto pages 6-8, harich2020frommanto pages 3-4, OpenTargets Search: -FBXO25, harich2020frommanto pages 4-6, harich2020frommanto pages 1-2). | Primary study, database summary, model-organism | Harich 2020; OpenTargets | 2020-12; OpenTargets accessed in current query | https://doi.org/10.1111/jcpp.13161; https://platform.opentargets.org/target/ENSG00000147364 |
| Phenotypes/disease links | A single-patient case report described a novel FBXO25–SEPT14 fusion in chronic myeloid leukemia, joining FBXO25 exon 4 to SEPT14 exon 10, in a patient with persistent suboptimal molecular response to TKIs. The authors suggest a possible association with TKI resistance, but evidence is limited to one observational case without functional validation (liao2023ararefbxo25–sept14 pages 1-2, liao2023ararefbxo25–sept14 pages 5-6, liao2023ararefbxo25–sept14 pages 2-5). | Primary study, single-case report | Liao 2023 | 2023-09 | https://doi.org/10.1515/oncologie-2023-0217 |
| Key quantitative data | Quantitative highlights across studies: 132 potential interactors and β-actin with 63 yeast-two-hybrid hits; 75 putative ubiquitination substrates; cardiac phenotypes of ~37% larger cardiomyocyte area, ~41% higher protein synthesis, and ~4.5-fold TAC-induced protein increase; ADHD GWAS meta-analysis n=55,374 with FBXO25 p=0.010756; Drosophila overexpression ~450% or ~650% expression versus control with behavioral sample sizes n=64, n=56, n=63 and significant night-activity/sleep effects; one reported FBXO25–SEPT14 CML case (teixeira2010identificationoffbxo25‐interacting pages 21-23, fischer2023identificationofhypertrophymodulating pages 1-2, harich2020frommanto pages 6-8, OpenTargets Search: -FBXO25, harich2020frommanto pages 4-6, liao2023ararefbxo25–sept14 pages 2-5). | Primary study, database summary | Teixeira 2010; Fischer 2023; Harich 2020; OpenTargets; Liao 2023 | 2010-08; 2023-03; 2020-12; OpenTargets accessed in current query; 2023-09 | https://doi.org/10.1002/pmic.200900419; https://doi.org/10.3389/fphys.2023.1134339; https://doi.org/10.1111/jcpp.13161; https://platform.opentargets.org/target/ENSG00000147364; https://doi.org/10.1515/oncologie-2023-0217 |
Table: This table summarizes the best-supported validated and proposed functions of human FBXO25, emphasizing molecular function, localization, substrates, regulatory interactions, and disease links. It also flags where evidence comes from model systems, candidate screens, or a single-case clinical report.
References
(teixeira2013thefboxprotein pages 1-2): Felipe R. Teixeira, Adriana O. Manfiolli, Cláudia S. Soares, Munira M.A. Baqui, Tie Koide, and Marcelo D. Gomes. The f-box protein fbxo25 promotes the proteasome-dependent degradation of elk-1 protein. Journal of Biological Chemistry, 288:28152-28162, Sep 2013. URL: https://doi.org/10.1074/jbc.m113.504308, doi:10.1074/jbc.m113.504308. This article has 24 citations and is from a domain leading peer-reviewed journal.
(teixeira2013thefboxprotein pages 3-4): Felipe R. Teixeira, Adriana O. Manfiolli, Cláudia S. Soares, Munira M.A. Baqui, Tie Koide, and Marcelo D. Gomes. The f-box protein fbxo25 promotes the proteasome-dependent degradation of elk-1 protein. Journal of Biological Chemistry, 288:28152-28162, Sep 2013. URL: https://doi.org/10.1074/jbc.m113.504308, doi:10.1074/jbc.m113.504308. This article has 24 citations and is from a domain leading peer-reviewed journal.
(teixeira2013thefboxprotein pages 5-6): Felipe R. Teixeira, Adriana O. Manfiolli, Cláudia S. Soares, Munira M.A. Baqui, Tie Koide, and Marcelo D. Gomes. The f-box protein fbxo25 promotes the proteasome-dependent degradation of elk-1 protein. Journal of Biological Chemistry, 288:28152-28162, Sep 2013. URL: https://doi.org/10.1074/jbc.m113.504308, doi:10.1074/jbc.m113.504308. This article has 24 citations and is from a domain leading peer-reviewed journal.
(teixeira2013thefboxprotein pages 7-8): Felipe R. Teixeira, Adriana O. Manfiolli, Cláudia S. Soares, Munira M.A. Baqui, Tie Koide, and Marcelo D. Gomes. The f-box protein fbxo25 promotes the proteasome-dependent degradation of elk-1 protein. Journal of Biological Chemistry, 288:28152-28162, Sep 2013. URL: https://doi.org/10.1074/jbc.m113.504308, doi:10.1074/jbc.m113.504308. This article has 24 citations and is from a domain leading peer-reviewed journal.
(teixeira2010identificationoffbxo25‐interacting pages 1-2): Felipe R. Teixeira, Sami Yokoo, Carlos A. Gartner, Adriana O. Manfiolli, Munira M. A. Baqui, Eliana M. Assmann, Ana Leticia G. C. Maragno, Huijun Yu, Primal de Lanerolle, Jörg Kobarg, Steven P. Gygi, and Marcelo Damário Gomes. Identification of fbxo25‐interacting proteins using an integrated proteomics approach. PROTEOMICS, 10:2746-2757, Aug 2010. URL: https://doi.org/10.1002/pmic.200900419, doi:10.1002/pmic.200900419. This article has 11 citations and is from a peer-reviewed journal.
(teixeira2010identificationoffbxo25‐interacting pages 4-6): Felipe R. Teixeira, Sami Yokoo, Carlos A. Gartner, Adriana O. Manfiolli, Munira M. A. Baqui, Eliana M. Assmann, Ana Leticia G. C. Maragno, Huijun Yu, Primal de Lanerolle, Jörg Kobarg, Steven P. Gygi, and Marcelo Damário Gomes. Identification of fbxo25‐interacting proteins using an integrated proteomics approach. PROTEOMICS, 10:2746-2757, Aug 2010. URL: https://doi.org/10.1002/pmic.200900419, doi:10.1002/pmic.200900419. This article has 11 citations and is from a peer-reviewed journal.
(teixeira2013thefboxprotein pages 9-10): Felipe R. Teixeira, Adriana O. Manfiolli, Cláudia S. Soares, Munira M.A. Baqui, Tie Koide, and Marcelo D. Gomes. The f-box protein fbxo25 promotes the proteasome-dependent degradation of elk-1 protein. Journal of Biological Chemistry, 288:28152-28162, Sep 2013. URL: https://doi.org/10.1074/jbc.m113.504308, doi:10.1074/jbc.m113.504308. This article has 24 citations and is from a domain leading peer-reviewed journal.
(teixeira2010identificationoffbxo25‐interacting pages 21-23): Felipe R. Teixeira, Sami Yokoo, Carlos A. Gartner, Adriana O. Manfiolli, Munira M. A. Baqui, Eliana M. Assmann, Ana Leticia G. C. Maragno, Huijun Yu, Primal de Lanerolle, Jörg Kobarg, Steven P. Gygi, and Marcelo Damário Gomes. Identification of fbxo25‐interacting proteins using an integrated proteomics approach. PROTEOMICS, 10:2746-2757, Aug 2010. URL: https://doi.org/10.1002/pmic.200900419, doi:10.1002/pmic.200900419. This article has 11 citations and is from a peer-reviewed journal.
(he2019lncrnaodir1inhibits pages 8-11): Shiwei He, Sheng Yang, Yanru Zhang, Xiaoling Li, Dan Gao, Yancheng Zhong, Lihua Cao, Haotian Ma, Ying Liu, Guiyuan Li, Shuping Peng, and Cijun Shuai. Lncrna odir1 inhibits osteogenic differentiation of huc-mscs through the fbxo25/h2bk120ub/h3k4me3/osx axis. Cell Death & Disease, Dec 2019. URL: https://doi.org/10.1038/s41419-019-2148-2, doi:10.1038/s41419-019-2148-2. This article has 117 citations and is from a peer-reviewed journal.
(he2019lncrnaodir1inhibits pages 15-16): Shiwei He, Sheng Yang, Yanru Zhang, Xiaoling Li, Dan Gao, Yancheng Zhong, Lihua Cao, Haotian Ma, Ying Liu, Guiyuan Li, Shuping Peng, and Cijun Shuai. Lncrna odir1 inhibits osteogenic differentiation of huc-mscs through the fbxo25/h2bk120ub/h3k4me3/osx axis. Cell Death & Disease, Dec 2019. URL: https://doi.org/10.1038/s41419-019-2148-2, doi:10.1038/s41419-019-2148-2. This article has 117 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.
(liao2023ararefbxo25–sept14 pages 1-2): Yun Liao, Jiayue Liu, Mengyu Wei, Rongrong Chen, Xiaomin Chen, Haoshu Zhong, Yang Liu, Hao Xiong, and Chunlan Huang. A rare fbxo25–sept14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report. Oncologie, 25:743-748, Sep 2023. URL: https://doi.org/10.1515/oncologie-2023-0217, doi:10.1515/oncologie-2023-0217. This article has 0 citations and is from a peer-reviewed journal.
(liao2023ararefbxo25–sept14 pages 2-5): Yun Liao, Jiayue Liu, Mengyu Wei, Rongrong Chen, Xiaomin Chen, Haoshu Zhong, Yang Liu, Hao Xiong, and Chunlan Huang. A rare fbxo25–sept14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report. Oncologie, 25:743-748, Sep 2023. URL: https://doi.org/10.1515/oncologie-2023-0217, doi:10.1515/oncologie-2023-0217. This article has 0 citations and is from a peer-reviewed journal.
(harich2020frommanto pages 6-8): Benjamin Harich, Marieke Klein, Charlotte W. Ockeloen, Monique van der Voet, Marlies Schimmel‐Naber, Nicole de Leeuw, Annette Schenck, and Barbara Franke. From man to fly – convergent evidence links fbxo25 to adhd and comorbid psychiatric phenotypes. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 61:545-555, Dec 2020. URL: https://doi.org/10.1111/jcpp.13161, doi:10.1111/jcpp.13161. This article has 15 citations.
(harich2020frommanto pages 4-6): Benjamin Harich, Marieke Klein, Charlotte W. Ockeloen, Monique van der Voet, Marlies Schimmel‐Naber, Nicole de Leeuw, Annette Schenck, and Barbara Franke. From man to fly – convergent evidence links fbxo25 to adhd and comorbid psychiatric phenotypes. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 61:545-555, Dec 2020. URL: https://doi.org/10.1111/jcpp.13161, doi:10.1111/jcpp.13161. This article has 15 citations.
(harich2020frommanto pages 3-4): Benjamin Harich, Marieke Klein, Charlotte W. Ockeloen, Monique van der Voet, Marlies Schimmel‐Naber, Nicole de Leeuw, Annette Schenck, and Barbara Franke. From man to fly – convergent evidence links fbxo25 to adhd and comorbid psychiatric phenotypes. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 61:545-555, Dec 2020. URL: https://doi.org/10.1111/jcpp.13161, doi:10.1111/jcpp.13161. This article has 15 citations.
(OpenTargets Search: -FBXO25): Open Targets Query (-FBXO25, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(harich2020frommanto pages 1-2): Benjamin Harich, Marieke Klein, Charlotte W. Ockeloen, Monique van der Voet, Marlies Schimmel‐Naber, Nicole de Leeuw, Annette Schenck, and Barbara Franke. From man to fly – convergent evidence links fbxo25 to adhd and comorbid psychiatric phenotypes. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 61:545-555, Dec 2020. URL: https://doi.org/10.1111/jcpp.13161, doi:10.1111/jcpp.13161. This article has 15 citations.
(liao2023ararefbxo25–sept14 pages 5-6): Yun Liao, Jiayue Liu, Mengyu Wei, Rongrong Chen, Xiaomin Chen, Haoshu Zhong, Yang Liu, Hao Xiong, and Chunlan Huang. A rare fbxo25–sept14 fusion in a patient with chronic myeloid leukemia treatment to tyrosine kinase inhibitors: a case report. Oncologie, 25:743-748, Sep 2023. URL: https://doi.org/10.1515/oncologie-2023-0217, doi:10.1515/oncologie-2023-0217. This article has 0 citations and is from a peer-reviewed journal.
UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|other ; PN-node mapping: group=mapped GO:1990756; subtype/type/branch=no_mapping; class=context_only (GO:0061630).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.
id: Q8TCJ0
gene_symbol: FBXO25
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
FBXO25 (F-box only protein 25, FBX25) is a member of the FBXO ("F-box only")
class of F-box proteins. It serves as a substrate-recognition (adaptor)
subunit of a SKP1-CUL1-F-box (SCF)-type E3 ubiquitin-protein ligase complex,
in which it assembles with SKP1, CUL1 and the catalytic RING subunit RBX1.
The C-terminal F-box motif mediates binding to SKP1 (an atypical serine in
the F-box, Ser244, is required for this interaction), thereby linking
specific substrates to the cullin-RING catalytic core for ubiquitination and
proteasomal degradation; FBXO25 itself does not possess the catalytic
ubiquitin-transfer activity, which resides in the RING/E2 module. FBXO25 is
broadly expressed with notable expression in brain and testis, and a region
in its N-terminus binds beta-actin. The protein localizes to the nucleus
where it concentrates in discrete SKP1-colocalized subnuclear (dot-like)
domains termed FBXO25-associated nuclear domains (FANDs) that co-localize with
the proteasome and ubiquitinated proteins (their integrity depends on actin
polymerization and RNA polymerase I activity), and is excluded from the
nucleolus. Its best-validated endogenous substrate is the ETS transcription
factor ELK-1: SCF(FBXO25) binds ELK-1 and promotes its ubiquitination and
proteasome-dependent degradation, dampening mitogen-induced ELK-1 target genes
such as c-fos and egr-1. FBXO25 has also been reported to promote histone H2B
K120 monoubiquitination (with downstream H3K4me3 and activation of the
osteogenic factor OSX/SP7) during osteogenic differentiation, and other
reported substrate/process associations (HAX1, NRF1/NFE2L1, and handling of
expanded-polyglutamine huntingtin) point to roles in SCF-dependent protein
turnover, but most of these remain thinly characterized. A chromosomal
translocation disrupting FBXO25 has been linked to X-linked intellectual
disability, and the gene has been associated with ADHD-related phenotypes and
cardiomyocyte hypertrophy in model systems.
alternative_products:
- name: '1'
id: Q8TCJ0-1
- name: '2'
id: Q8TCJ0-2
sequence_note: VSP_007374
- name: '3'
id: Q8TCJ0-3
sequence_note: VSP_013060, VSP_013061, VSP_007374
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: Phylogenetic assignment of nuclear localization, consistent with the experimentally demonstrated nuclear localization of FBXO25.
action: ACCEPT
reason: Nuclear localization is directly supported by experimental (IDA) evidence and by the UniProt subcellular location; FBXO25 concentrates in SKP1-colocalized subnuclear domains.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}. Note=In the nucleus, associates with a subnuclear dot-like structure. Colocalized with SKP1.'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: Phylogenetic assignment of cytoplasmic localization based on the F-box protein family tree. The experimentally documented localization of human FBXO25 is nuclear, so cytoplasmic localization is plausible (SCF complexes act in both compartments) but not the demonstrated primary site.
action: KEEP_AS_NON_CORE
reason: Inferred from orthologs by phylogeny; the experimental evidence for human FBXO25 emphasizes nuclear (subnuclear dot-like) localization. A cytoplasmic pool is plausible but not the core, experimentally established compartment.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.'
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Phylogenetic assignment of involvement in protein ubiquitination, the general process to which an SCF substrate-recognition subunit contributes.
action: KEEP_AS_NON_CORE
reason: Correct but generic; FBXO25 participates in ubiquitination by providing substrate specificity to the SCF complex. The more specific SCF-dependent catabolic process and substrate-adaptor function better capture the core role.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'FUNCTION: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
- term:
id: GO:0019005
label: SCF ubiquitin ligase complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: Phylogenetic assignment of SCF ubiquitin ligase complex membership, the core cellular-component context for FBXO25 as an F-box protein.
action: ACCEPT
reason: Core localization/context; FBXO25 was experimentally shown to be part of an SCF complex (FBXO25-SKP1-CUL1-RBX1) and to interact directly with SKP1 and CUL1.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1.'
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Electronic transfer of nuclear localization from the UniProt subcellular location vocabulary, redundant with the experimental (IDA) nuclear annotation.
action: ACCEPT
reason: Correct core localization; matches the experimentally established nuclear localization of FBXO25.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.'
- 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 protein ubiquitination, redundant with the IBA/ISS/NAS protein ubiquitination annotations.
action: KEEP_AS_NON_CORE
reason: Correct but generic process; captured more specifically by the SCF-dependent proteasomal catabolic process and substrate-adaptor function.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-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/author-statement assignment of SCF ubiquitin ligase complex membership; FBXO25 is the variable substrate-recognition subunit of one of the ~69 human SCF complexes.
action: ACCEPT
reason: Core context; consistent with both the experimental SCF identification for FBXO25 and the review describing F-box proteins as the variable, substrate-specifying subunit of SCF complexes.
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: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 assignment of involvement in SCF-dependent proteasomal degradation, the canonical biological role of an SCF F-box substrate-recognition subunit.
action: ACCEPT
reason: Represents the core biological process for FBXO25 - directing substrates for SCF-mediated poly-ubiquitination and proteasomal degradation - although the specific endogenous substrate repertoire of FBXO25 remains incompletely defined.
supported_by:
- reference_id: PMID:34445249
supporting_text: 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:0005730
label: nucleolus
evidence_type: IDA
original_reference_id: PMID:16278047
qualifier: located_in
negated: true
review:
summary: Direct-assay negative annotation indicating FBXO25 is NOT located in the nucleolus, refining its nuclear localization to non-nucleolar (subnuclear dot-like) domains.
action: ACCEPT
reason: Correct NOT annotation; consistent with the UniProt description of nuclear, SKP1-colocalized subnuclear domains rather than nucleolar localization. The cached abstract is abstract-only, so the exact figure is not quotable, but the negation is supported by the documented subnuclear-domain localization.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: Note=In the nucleus, associates with a subnuclear dot-like structure. Colocalized with SKP1.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:16278047
qualifier: located_in
review:
summary: Direct-assay evidence for nuclear localization of FBXO25 from the characterization study, the core experimentally established compartment.
action: ACCEPT
reason: Core localization with direct experimental support; FBXO25 localizes to the nucleus where it concentrates in SKP1-colocalized subnuclear domains.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.'
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: involved_in
review:
summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of involvement in protein ubiquitination.
action: KEEP_AS_NON_CORE
reason: Correct but generic; the substrate-recognition role within the SCF complex is captured more specifically by the SCF-dependent catabolic process and adaptor-activity annotations.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'FUNCTION: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: located_in
review:
summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of nuclear localization, consistent with the experimental human data.
action: ACCEPT
reason: Correct core localization; redundant with the IDA/IEA nuclear annotations.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16278047, ECO:0000269|PubMed:18287534}.'
- term:
id: GO:0019005
label: SCF ubiquitin ligase complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
qualifier: part_of
review:
summary: Sequence-similarity transfer (from mouse ortholog Q9D2Y6) of SCF ubiquitin ligase complex membership, the core cellular-component context.
action: ACCEPT
reason: Core context; redundant with the experimentally supported and IBA/NAS SCF complex annotations.
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1.'
- term:
id: GO:0000151
label: ubiquitin ligase complex
evidence_type: NAS
original_reference_id: PMID:10531035
qualifier: part_of
review:
summary: Author-statement assignment of ubiquitin ligase complex membership from the founding F-box family paper, which identified FBXO25/FBX25 as one of a family of human F-box proteins that are subunits of SCF ubiquitin ligases.
action: KEEP_AS_NON_CORE
reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) is the parent-refined, accurate cellular-component context for FBXO25.
supported_by:
- reference_id: PMID:10531035
supporting_text: 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: NAS
original_reference_id: PMID:10531035
qualifier: enables
review:
summary: Author-statement assignment of ubiquitin-protein transferase activity. As an F-box protein, FBXO25 is the substrate-recognition subunit that recruits substrates to the SCF; the catalytic ubiquitin-transfer activity resides in the RING subunit (RBX1) acting with the E2, not in the F-box protein itself.
action: MODIFY
reason: The F-box protein is the substrate receptor, not the catalytic transferase. The ligase-substrate adaptor activity term more accurately captures FBXO25's molecular role of bridging substrates to the catalytic SCF core.
proposed_replacement_terms:
- id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
supported_by:
- reference_id: PMID:10531035
supporting_text: SCF ligases bring ubiquitin conjugating enzymes (either Ubc3 or Ubc4) to substrates that are specifically recruited by the different F-box proteins.
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: NAS
original_reference_id: PMID:10531035
qualifier: involved_in
review:
summary: Author-statement assignment of involvement in protein ubiquitination, reflecting FBXO25's role as a substrate-recruiting subunit of an SCF ubiquitin ligase.
action: KEEP_AS_NON_CORE
reason: Correct but generic; the substrate-recognition contribution to SCF-dependent ubiquitination/degradation is captured more specifically by other annotations.
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:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity
findings: []
- 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: PMID:10531035
title: Identification of a family of human F-box proteins.
findings:
- statement: FBXO25/FBX25 was identified as one of a family of 26 human F-box proteins; F-box proteins are the substrate-recruiting subunit of SCF (SKP1-CUL1-F-box-RBX1) ubiquitin ligases.
reference_section_type: ABSTRACT
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Abstract-only in cache. Founding F-box family paper that first described FBXO25 (FBX25) and the general SCF architecture in which F-box proteins specify substrates. Supports the SCF-complex and substrate-adaptor framing; the catalytic activity it attributes generically to SCFs resides in the RING/E2 module, motivating the MODIFY of GO:0004842 to a substrate-adaptor term.
- id: PMID:16278047
title: Characterization of FBX25, encoding a novel brain-expressed F-box protein.
findings:
- statement: hFBX25 was established as an F-box protein by verifying its interaction with SKP1 and CUL1; an atypical F-box serine (Ser244) is crucial for SKP1 binding; subcellular localization was determined (nuclear, non-nucleolar, SKP1-colocalized subnuclear domains) and strong brain expression was observed.
reference_section_type: ABSTRACT
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Abstract-only in cache. Primary experimental characterization of human FBXO25 - source of the SKP1/CUL1 interaction, Ser244 F-box mutagenesis, nuclear localization (IDA) and the NOT-nucleolus annotation.
- id: PMID:34445249
title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
findings:
- statement: The SCF complex comprises ~69 E3 ubiquitin ligase complexes distinguished by variable F-box proteins that determine substrate specificity and target substrates with poly-ubiquitin chains for proteasomal degradation; functions of most individual SCF complexes remain largely unknown.
reference_section_type: ABSTRACT
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Abstract-only review (ComplexPortal NAS source). Supports the general SCF complex membership and SCF-dependent proteasomal degradation role; explicitly notes that most individual SCF (including FBXO25) functions are uncharacterized, supporting cautious non-core framing of substrate/process claims.
- id: file:human/FBXO25/FBXO25-deep-research-falcon.md
title: Falcon deep research report for human FBXO25
findings:
- statement: FBXO25 assembles an active SCF1(FBXO25) complex with SKP1, CUL1, and Roc1/RBX1, and its best-validated endogenous substrate is the transcription factor ELK-1, which it ubiquitinates for proteasome-dependent degradation.
supporting_text: >-
Validated substrate: The transcription factor **ELK-1** is the clearest
experimentally validated endogenous substrate. FBXO25 physically
associates with ELK-1 and promotes ELK-1 ubiquitination and
proteasome-dependent degradation in human cells.
- statement: By degrading ELK-1, FBXO25 suppresses mitogen-induced ELK-1 target genes c-fos and egr-1, linking it to regulation of mitogen-responsive transcription.
supporting_text: >-
FBXO25 overexpression suppresses induction of ELK-1 target genes **c-fos**
and **egr-1** following mitogen stimulation (PMA), consistent with reduced
ELK-1 activity due to decreased ELK-1 protein levels.
- statement: FBXO25 localizes to discrete nuclear puncta (FBXO25-associated nuclear domains, FANDs) that co-localize with the proteasome and ubiquitinated proteins, and whose integrity depends on actin polymerization and RNA polymerase I activity, suggesting a nuclear proteostasis compartment.
supporting_text: >-
FBXO25 is not merely diffuse in the nucleus; it localizes to discrete
nuclear puncta termed **FBXO25-associated nuclear domains (FANDs)**. These
FANDs are reported to co-localize with the **proteasome** and
**ubiquitinated proteins**, suggesting FBXO25 participates in a nuclear
proteostasis/ubiquitin signaling compartment.
- statement: In human umbilical-cord MSCs, FBXO25 promotes histone H2B K120 monoubiquitination (with downstream H3K4me3 and OSX/SP7 activation) during osteogenic differentiation, indicating a chromatin-linked role beyond classical substrate degradation.
supporting_text: >-
In human umbilical cord-derived MSCs (hUC-MSCs), He et al. report that
FBXO25 promotes **H2B K120 monoubiquitination (H2BK120ub)**, which is
associated with increased **H3K4 trimethylation (H3K4me3)** and
transcriptional activation of the osteogenic transcription factor **OSX
(osterix/SP7)**.
reference_review:
relevance: HIGH
correctness: UNVERIFIED
review_notes: >-
Falcon (Edison Scientific) deep-research synthesis. Cross-checked against
the UniProt FUNCTION block and the primary FBXO25 characterization paper
(PMID:16278047) already in this review; used as leads for the ELK-1
substrate and FAND nuclear compartment (Teixeira 2010 Proteomics, Teixeira
2013 JBC) and the H2BK120ub/osteogenesis axis (He 2019). Notably the
Falcon corpus foregrounds ELK-1 as the best-validated substrate and does
not corroborate the HAX1/NRF1 associations carried in older summaries.
Cites author-year/DOIs rather than PMIDs, so individual primary claims
remain UNVERIFIED here.
core_functions:
- description: Substrate-recognition (adaptor) subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex; via its C-terminal F-box it binds SKP1 (requiring Ser244) and CUL1, bridging specific substrates to the catalytic CUL1-RBX1-E2 core for poly-ubiquitination, rather than itself catalyzing ubiquitin transfer.
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'FUNCTION: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex.'
- reference_id: file:human/FBXO25/FBXO25-uniprot.txt
supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex consisting of FBXO25, SKP1, CUL1 and RBX1. Interacts directly with SKP1 and CUL1.'
directly_involved_in:
- id: GO:0031146
label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: As the SCF(FBXO25) substrate receptor, recognizes the ETS transcription factor ELK-1 and promotes its ubiquitination and proteasome-dependent degradation in the nucleus, thereby dampening mitogen-induced ELK-1 target-gene expression (e.g. c-fos, egr-1); FBXO25 concentrates in nuclear FBXO25-associated domains (FANDs) enriched for the proteasome and ubiquitinated proteins.
molecular_function:
id: GO:1990756
label: ubiquitin-like ligase-substrate adaptor activity
locations:
- id: GO:0005634
label: nucleus
supported_by:
- reference_id: file:human/FBXO25/FBXO25-deep-research-falcon.md
supporting_text: >-
Validated substrate: The transcription factor **ELK-1** is the clearest
experimentally validated endogenous substrate. FBXO25 physically
associates with ELK-1 and promotes ELK-1 ubiquitination and
proteasome-dependent degradation in human cells.
directly_involved_in:
- id: GO:0031146
label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: Which endogenous substrates does FBXO25 recognize in vivo, and what degron/post-translational features (e.g. phosphodegrons) determine its substrate selectivity?
- question: What is the functional significance of FBXO25 localization to discrete SKP1-colocalized subnuclear domains (FANDs) that co-localize with the proteasome and ubiquitinated proteins, and how does the N-terminal beta-actin interaction (and actin-polymerization/RNA Pol I dependence of FAND integrity) relate to its SCF substrate-targeting function?
- question: Is the reported FBXO25-dependent increase in histone H2B K120 monoubiquitination a direct activity of an FBXO25-containing ligase or an indirect effect on the H2B ubiquitination machinery, and how is it reconciled with FBXO25's canonical role as a degradative SCF substrate adaptor?
suggested_experiments:
- description: Perform quantitative ubiquitinome/proteome profiling (e.g. diGly enrichment and TMT proteomics) in FBXO25-knockout versus wild-type cells to define the endogenous substrate repertoire and confirm reported substrates (HAX1, NRF1/NFE2L1, ELK1, polyQ-HTT).
- description: Reconstitute the FBXO25-SKP1-CUL1-RBX1 SCF complex in vitro with an E1, E2 and ubiquitin to test substrate-dependent ubiquitination of candidate substrates, including the Ser244Leu F-box mutant to confirm dependence on SKP1 binding for substrate turnover.