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.