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 |
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Download this section (compressed HTML)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.
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