FBXO10 (F-box only protein 10) is a large (956 aa) F-box protein that serves as the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box)-type E3 ubiquitin ligase complex. Through an N-terminal F-box motif it binds SKP1, docking onto the CUL1-RBX1 catalytic core (the SCF(FBXO10) complex consists of CUL1, SKP1 and FBXO10), while its extensive C-terminal beta-helix/PbH1 repeat region provides the substrate-binding surface. As the adaptor it does not itself catalyze ubiquitin transfer; rather it selects substrates that the CUL1-RBX1-E2 machinery polyubiquitinates for degradation. Its best-characterized substrate is the antiapoptotic protein BCL2: FBXO10 binds BCL2 and promotes its ubiquitination and degradation, thereby promoting apoptosis, a role conserved with the C. elegans F-box protein DRE-1, which inactivates the BCL2 ortholog CED-9. Loss-of-function mutations or reduced FBXO10 expression occur in diffuse large B-cell lymphoma, where they permit BCL2 accumulation. FBXO10 also targets the germinal-center protein HGAL/GCSAM for ubiquitination and degradation; upon B-cell receptor stimulation FBXO10 is palmitoylated and relocates to the plasma membrane, where HGAL degradation forms a negative-feedback loop that dampens BCR signaling. An additional reported substrate is the receptor for advanced glycation end products (RAGE/ AGER), which FBXO10 targets for ubiquitination and lysosomal degradation (recognized via cytoplasmic residues K374 and the phosphorylation-sensitive S391). A distinct, lipidation-controlled pool of FBXO10 is geranylgeranylated at a C-terminal CaaX motif (Cys953) and delivered to the outer mitochondrial membrane via a PDE6delta/HSP90/TOM70 route, where it assembles a mitochondrial SCF(FBXO10) that polyubiquitinates and degrades the mitochondrial phosphatase PGAM5 to control outer-mitochondrial-membrane proteostasis, mitochondrial morphology/bioenergetics, and myogenic differentiation. In colorectal cancer, an upstream CYP1B1/20-HETE/PKC axis induces FBXO10, which polyubiquitinates ACSL4 to suppress ferroptosis. FBXO10 is widely expressed and predominantly cytoplasmic, with regulated pools at the plasma membrane and outer mitochondrial membrane. Notably, engineered Fbxo10 loss-of-function mice show no increase in BCL2 or B-cell accumulation, suggesting species-dependent regulation or functional redundancy with other ligases.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006511 ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that FBXO10 is involved in ubiquitin-dependent protein catabolism, consistent with its role as an SCF substrate adaptor that directs substrates (e.g. BCL2) to proteasomal degradation. Reason: Core biological process; the SCF(FBXO10) complex targets BCL2/HGAL for ubiquitin-dependent degradation, supported experimentally (IMP, PMID:23431138) and conserved across the family. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Mediates the ubiquitination and degradation of BCL2, an antiapoptotic protein |
| GO:0042981 regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of a role in regulating apoptosis, the core biological role of FBXO10 via control of BCL2 stability; conserved with C. elegans DRE-1 acting on CED-9. Reason: Core biological process; directly supported by IMP evidence (PMID:23431138) showing FBXO10 promotes BCL2 degradation to initiate cell death, and conserved across the DRE-1/FBXO10 family. Supporting Evidence: PMID:23431138 FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location, the documented predominant compartment for FBXO10. Reason: Correct localization; the cytoplasm is the documented predominant compartment for FBXO10, redundant with and concordant with the experimentally supported cytoplasm annotations (EXP PMID:31570756, IDA PMID:23431138). Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, consistent with FBXO10's role in the SCF ubiquitination pathway. Reason: Correct but generic; the substrate-adaptor role within ubiquitin-dependent catabolism is better captured by GO:0006511 and GO:0031146. FBXO10 contributes to ubiquitination as the substrate receptor, not as the catalytic enzyme. Supporting Evidence: file:human/FBXO10/FBXO10-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: Membership in the SCF E3 ubiquitin ligase complex; FBXO10 is the F-box substrate-recognition subunit of SCF(FBXO10) (CUL1-SKP1-FBXO10). Reason: Core cellular-component assignment; FBXO10 is documented as a component of the SCF(FBXO10) complex (CUL1, SKP1, FBXO10), with a dedicated ComplexPortal entry (CPX-7923). Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 |
| 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: Involvement in SCF-dependent proteasomal protein catabolism, the specific catabolic pathway in which the SCF(FBXO10) complex degrades its substrates. Reason: Core biological process; precisely captures the SCF-dependent degradation route FBXO10 directs substrates into, consistent with the BCL2-degradation work (PMID:23431138). Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0005737 cytoplasm | EXP PMID:31570756 Recent BCR stimulation induces a negative autoregulatory loo... | ACCEPT | Summary: Experimental evidence for cytoplasmic localization of FBXO10; the protein relocates from cytoplasm to the cell membrane upon BCR stimulation/palmitoylation. Reason: Experimentally supported localization in the predominant resting compartment, consistent with the UniProt-curated cytoplasmic location. Supporting Evidence: PMID:31570756 relies on a single evolutionarily conserved HGAL amino acid residue (H91) and FBXO10 relocalization to the cytoplasmic membrane |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FBXO10/the CRL1 complex in the cytosol, a generic localization derived from neddylation/CRL-cycle reactions. Reason: Correct but generic compartment derived from Reactome CRL-cycle pathway curation; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing FBXO10/the CRL1 complex in the cytosol (NEDD8 conjugation reaction). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (CAND1 binding reaction). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (COMMD/CAND1 reaction). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (COP9 signalosome deneddylation). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the CRL1 complex (with FBXO10) in the cytosol (DCUN1D3 binding). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (transfer of Ub to substrate). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (release of E3 from polyubiquitinated substrate). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (polyubiquitination of substrate). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (interaction of E3 with substrate and E2-Ub). Reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006511 ubiquitin-dependent protein catabolic process | IMP PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: Mutant-phenotype evidence that FBXO10 drives ubiquitin-dependent degradation of BCL2; lymphoma-associated FBXO10 mutations impair its control of BCL2 stability. Reason: Core biological process with direct experimental (IMP) support; FBXO10 promotes BCL2 ubiquitination/degradation, and loss-of-function variants cause BCL2 accumulation. Supporting Evidence: PMID:23431138 FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death |
| GO:0005515 protein binding | IPI PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | KEEP AS NON CORE | Summary: IPI interaction with BCL2 (UniProtKB:P10415), the principal FBXO10 substrate, captured during the lymphoma cell-death study. The bare protein binding term is uninformative. Reason: Records the functionally important FBXO10-BCL2 substrate interaction, but bare protein binding is uninformative per curation guidelines; the substrate relationship is captured by the catabolic-process and apoptosis annotations. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Interacts with BCL2 (PubMed:23431138) |
| GO:0005737 cytoplasm | IDA PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: Direct assay evidence for cytoplasmic localization of FBXO10, consistent with the UniProt-curated predominant compartment. Reason: Experimentally supported (IDA) localization in the documented predominant compartment for FBXO10. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Cytoplasm {ECO:0000269|PubMed:23431138, ECO:0000269|PubMed:31570756} |
| GO:0042981 regulation of apoptotic process | IMP PMID:23431138 Related F-box proteins control cell death in Caenorhabditis ... | ACCEPT | Summary: Mutant-phenotype evidence that FBXO10 regulates apoptosis by controlling BCL2 stability; degradation of antiapoptotic BCL2 initiates cell death, and FBXO10 inactivation in lymphoma blocks this. Reason: Core biological process with direct experimental (IMP) support; this is the best-characterized physiological role of FBXO10. Supporting Evidence: PMID:23431138 FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death |
| GO:0016567 protein ubiquitination | NAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author-statement (family-level) assignment of involvement in protein ubiquitination from the original human F-box protein family paper. Reason: Correct but generic family-level inference; FBXO10's specific role is captured by the SCF-dependent catabolism and ubiquitin-dependent catabolic process annotations. FBXO10 is the substrate adaptor, contributing to ubiquitination indirectly. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0016567 protein ubiquitination | NAS PMID:10531037 A family of mammalian F-box proteins. | KEEP AS NON CORE | Summary: Author-statement (family-level) assignment of involvement in protein ubiquitination from the parallel mammalian F-box protein family paper. Reason: Correct but generic family-level inference; redundant with the other GO:0016567 annotation and subsumed by the specific SCF-dependent catabolism terms. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| 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 that FBXO10 is part of a ubiquitin ligase complex, the (generic) parent of the specific SCF complex it belongs to. Reason: Correct but generic relative to the specific GO:0019005 (SCF ubiquitin ligase complex) annotation, which precisely captures FBXO10's complex membership. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 |
| GO:0000151 ubiquitin ligase complex | NAS PMID:10531037 A family of mammalian F-box proteins. | KEEP AS NON CORE | Summary: Author-statement assignment that FBXO10 is part of a ubiquitin ligase complex (parallel F-box family paper). Reason: Correct but generic; redundant with the other GO:0000151 annotation and subsumed by the specific SCF complex (GO:0019005) annotation. Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 |
| GO:0004842 ubiquitin-protein transferase activity | NAS PMID:10531035 Identification of a family of human F-box proteins. | MODIFY | Summary: Author-statement (family-level) attribution of ubiquitin-protein transferase activity to FBXO10 from the original human F-box family paper. F-box proteins are the substrate-recognition adaptors of SCF, not the catalytic transferase; ubiquitin transfer is mediated by the RBX1 RING subunit and the charged E2. Reason: Over-attributes catalytic transferase activity to the adaptor subunit. The correct molecular function for the F-box substrate receptor is ubiquitin-like ligase-substrate adaptor activity (GO:1990756); catalytic ubiquitin transfer is performed by RBX1/E2, not by FBXO10. This is a 1999 family-level NAS inference predating mechanistic understanding of SCF architecture. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
| GO:0004842 ubiquitin-protein transferase activity | NAS PMID:10531037 A family of mammalian F-box proteins. | MODIFY | Summary: Author-statement (family-level) attribution of ubiquitin-protein transferase activity from the parallel mammalian F-box family paper. As above, the F-box protein is the substrate-recognition adaptor, not the catalytic ubiquitin transferase. Reason: Over-attributes catalytic transferase activity to the adaptor subunit; the appropriate molecular function is ubiquitin-like ligase-substrate adaptor activity (GO:1990756). Catalytic transfer is mediated by RBX1/E2 within the SCF complex. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO10/FBXO10-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex |
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Download this section (compressed HTML)Q: What sequence/structural features of the FBXO10 C-terminal beta-helix (PbH1 repeat) region determine recognition of structurally diverse substrates (BCL2, HGAL/GCSAM, RAGE), and are these substrates degron-dependent?
Q: How is FBXO10 substrate choice and subcellular targeting regulated by post-translational modification (e.g. BCR-induced palmitoylation and membrane relocalization), and does this redirect the SCF(FBXO10) substrate repertoire?
Q: Does FBXO10 contribute to lymphomagenesis primarily through BCL2 stabilization, deregulated BCR signaling via HGAL, or both, and how do the recurrent DLBCL variants (e.g. R44H, V762C, R825W) mechanistically impair these activities?
Q: How is the FBXO10 substrate repertoire partitioned between its cytoplasmic, plasma-membrane (palmitoylation-driven), and outer-mitochondrial-membrane (geranylgeranylation/Cys953-driven) pools, and is the OMM PGAM5-degrading activity functionally separable from the cytoplasmic BCL2/apoptosis activity?
Q: Why do Fbxo10 loss-of-function mice fail to accumulate BCL2 despite the human lymphoma phenotypeβdoes another E3 (e.g. FBXO11 or ARTS/XIAP) provide redundant BCL2 turnover, and is this redundancy species-specific?
Experiment: Reconstitute SCF(FBXO10) ubiquitination of BCL2 in vitro with purified CUL1, SKP1, RBX1, an E2, and FBXO10 (wild-type vs lymphoma variants R44H, V762C, R825W) to confirm adaptor function, map BCL2 ubiquitination sites, and quantify the catalytic contribution of each component.
Experiment: Perform global ubiquitinome/proteome profiling in FBXO10-knockout versus wild-type B cells, with and without BCR stimulation, to define the endogenous SCF(FBXO10) substrate repertoire and test the BCR-induced membrane-relocalization model.
Experiment: Use co-immunoprecipitation and proximity-labeling (BioID/TurboID) of FBXO10 to verify assembly with SKP1/CUL1 via the F-box motif and identify additional substrates beyond BCL2, HGAL/GCSAM and RAGE.
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