id: Q9UK96 gene_symbol: FBXO10 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- 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. alternative_products: - name: '1' id: Q9UK96-1 - name: '2' id: Q9UK96-2 sequence_note: VSP_056318 existing_annotations: - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT 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. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Mediates the ubiquitination and degradation of BCL2, an antiapoptotic protein - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:23431138 supporting_text: FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location, the documented predominant compartment for FBXO10. action: ACCEPT 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). supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived general protein ubiquitination process, consistent with FBXO10's role in the SCF ubiquitination pathway. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/FBXO10/FBXO10-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: Membership in the SCF E3 ubiquitin ligase complex; FBXO10 is the F-box substrate-recognition subunit of SCF(FBXO10) (CUL1-SKP1-FBXO10). action: ACCEPT 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). supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 - 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: Involvement in SCF-dependent proteasomal protein catabolism, the specific catabolic pathway in which the SCF(FBXO10) complex degrades its substrates. action: ACCEPT reason: Core biological process; precisely captures the SCF-dependent degradation route FBXO10 directs substrates into, consistent with the BCL2-degradation work (PMID:23431138). supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:31570756 qualifier: located_in review: summary: Experimental evidence for cytoplasmic localization of FBXO10; the protein relocates from cytoplasm to the cell membrane upon BCR stimulation/palmitoylation. action: ACCEPT reason: Experimentally supported localization in the predominant resting compartment, consistent with the UniProt-curated cytoplasmic location. supported_by: - reference_id: PMID:31570756 supporting_text: relies on a single evolutionarily conserved HGAL amino acid residue (H91) and FBXO10 relocalization to the cytoplasmic membrane - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome pathway annotation placing FBXO10/the CRL1 complex in the cytosol, a generic localization derived from neddylation/CRL-cycle reactions. action: KEEP_AS_NON_CORE reason: Correct but generic compartment derived from Reactome CRL-cycle pathway curation; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome pathway annotation placing FBXO10/the CRL1 complex in the cytosol (NEDD8 conjugation reaction). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (CAND1 binding reaction). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (COMMD/CAND1 reaction). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome pathway annotation placing the cytosolic CRL E3 ligase (with FBXO10) in the cytosol (COP9 signalosome deneddylation). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome pathway annotation placing the CRL1 complex (with FBXO10) in the cytosol (DCUN1D3 binding). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (transfer of Ub to substrate). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (release of E3 from polyubiquitinated substrate). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (polyubiquitination of substrate). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome pathway annotation placing the E3-substrate complex (with FBXO10) in the cytosol (interaction of E3 with substrate and E2-Ub). action: KEEP_AS_NON_CORE reason: Correct but generic, pathway-derived cytosol localization; redundant with the experimentally supported cytoplasm annotations. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:23431138 qualifier: involved_in review: summary: Mutant-phenotype evidence that FBXO10 drives ubiquitin-dependent degradation of BCL2; lymphoma-associated FBXO10 mutations impair its control of BCL2 stability. action: ACCEPT reason: Core biological process with direct experimental (IMP) support; FBXO10 promotes BCL2 ubiquitination/degradation, and loss-of-function variants cause BCL2 accumulation. supported_by: - reference_id: PMID:23431138 supporting_text: FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23431138 qualifier: enables review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Interacts with BCL2 (PubMed:23431138) - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:23431138 qualifier: located_in review: summary: Direct assay evidence for cytoplasmic localization of FBXO10, consistent with the UniProt-curated predominant compartment. action: ACCEPT reason: Experimentally supported (IDA) localization in the documented predominant compartment for FBXO10. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: 'Cytoplasm {ECO:0000269|PubMed:23431138, ECO:0000269|PubMed:31570756}' - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: IMP original_reference_id: PMID:23431138 qualifier: involved_in review: 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. action: ACCEPT reason: Core biological process with direct experimental (IMP) support; this is the best-characterized physiological role of FBXO10. supported_by: - reference_id: PMID:23431138 supporting_text: FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death - term: id: GO:0016567 label: protein ubiquitination evidence_type: NAS original_reference_id: PMID:10531035 qualifier: involved_in review: summary: Author-statement (family-level) assignment of involvement in protein ubiquitination from the original human F-box protein family paper. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0016567 label: protein ubiquitination evidence_type: NAS original_reference_id: PMID:10531037 qualifier: involved_in review: summary: Author-statement (family-level) assignment of involvement in protein ubiquitination from the parallel mammalian F-box protein family paper. action: KEEP_AS_NON_CORE reason: Correct but generic family-level inference; redundant with the other GO:0016567 annotation and subsumed by the specific SCF-dependent catabolism terms. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:10531035 qualifier: part_of review: summary: Author-statement assignment that FBXO10 is part of a ubiquitin ligase complex, the (generic) parent of the specific SCF complex it belongs to. action: KEEP_AS_NON_CORE reason: Correct but generic relative to the specific GO:0019005 (SCF ubiquitin ligase complex) annotation, which precisely captures FBXO10's complex membership. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:10531037 qualifier: part_of review: summary: Author-statement assignment that FBXO10 is part of a ubiquitin ligase complex (parallel F-box family paper). action: KEEP_AS_NON_CORE reason: Correct but generic; redundant with the other GO:0000151 annotation and subsumed by the specific SCF complex (GO:0019005) annotation. supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Component of the SCF(FBXO10) complex consisting of CUL1, SKP1 and FBXO10 - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: NAS original_reference_id: PMID:10531035 qualifier: enables review: 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. action: MODIFY 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_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: NAS original_reference_id: PMID:10531037 qualifier: enables review: 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. action: MODIFY 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_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO10/FBXO10-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex references: - 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: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: One of the two 1999 papers that identified FBXO10 (FBX10) as a member of the human F-box protein family; source of the family-level NAS molecular-function and complex annotations. F-box proteins were characterized as SCF substrate-recognition subunits, supporting the MODIFY of the transferase-activity annotation to an adaptor function. - id: PMID:10531037 title: A family of mammalian F-box proteins. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Parallel 1999 paper identifying the mammalian F-box protein family including FBXO10; source of duplicate family-level NAS annotations. - id: PMID:23431138 title: Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma. findings: - statement: FBXO10 binds BCL2 and promotes its degradation, thereby initiating cell death; some diffuse large B-cell lymphomas have inactivating FBXO10 mutations or low FBXO10 expression. DRE-1/FBXO10 is a conserved regulator of apoptosis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (PNAS 2013, PMC3593917); the key substrate paper establishing FBXO10 as the SCF substrate receptor for BCL2 and its apoptosis-regulatory and lymphoma-relevant roles. Source of the IMP catabolic-process/apoptosis annotations, the IPI BCL2 interaction, and the IDA cytoplasm localization. Abstract-only in cache; full text (read by curators) characterizes the SCF(FBXO10) complex and lymphoma variants. - id: PMID:31570756 title: Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL. findings: - statement: BCR stimulation induces palmitoylation of SCF-FBXO10 and its relocation to the cell membrane, where it targets HGAL/GCSAM for ubiquitylation and degradation, reducing BCR-induced calcium influx and proximal effector phosphorylation; recognition relies on HGAL residue H91. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Leukemia 2020); establishes the HGAL/GCSAM substrate and the BCR-stimulated, palmitoylation-driven cytoplasm-to-membrane relocalization of SCF-FBXO10. Source of the EXP cytoplasm localization annotation. Abstract-only in cache. - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: The SCF (SKP1-CUL1-F-box protein) complex comprises a group of E3 ubiquitin ligase complexes that modify substrates with poly-ubiquitin chains to target them for proteasomal degradation; the variable F-box protein determines substrate specificity. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Int J Mol Sci 2021, PMC8395177) review of SCF biology; ComplexPortal-cited source of the SCF complex (GO:0019005) and SCF-dependent catabolism (GO:0031146) NAS annotations. General SCF review rather than FBXO10-specific. - id: file:human/FBXO10/FBXO10-deep-research-falcon.md title: Falcon deep research report for human FBXO10 findings: - statement: FBXO10 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ligase whose effective substrate spectrum depends on regulated localization across the plasma membrane, cytoplasm/mitochondria, endomembrane/lysosomal pathway, and outer mitochondrial membrane. supporting_text: >- Across the evidence base, FBXO10 is increasingly understood not as a single-compartment factor but as a substrate receptor whose effective substrate spectrum depends on regulated localization—e.g., plasma membrane (palmitoylation; HGAL pathway per review), cytoplasmic/mitochondria-associated pools (BCL2), endomembrane/lysosomal trafficking (RAGE), and OMM targeting controlled by geranylgeranylation (PGAM5). - statement: FBXO10 is geranylgeranylated at a C-terminal CaaX motif (C953), which is required for stable targeting to the outer mitochondrial membrane, where it forms a mitochondrial SCF(FBXO10) with SKP1 and CUL1. supporting_text: >- A major 2024 advance is that FBXO10 can be **post-translationally geranylgeranylated** at a C-terminal CaaX motif (C953), which is required for its stable targeting to the **outer mitochondrial membrane (OMM)**. This lipidation enables mitochondrial delivery via a PDE6δ/HSP90-dependent pathway linked to TOM70 docking, forming a mitochondrial SCF(FBXO10) complex with SKP1 and CUL1 at the OMM. - statement: At the outer mitochondrial membrane, FBXO10 promotes polyubiquitylation and degradation of the mitochondrial phosphatase PGAM5; loss of FBXO10 or a prenylation-deficient C953S mutant prevents PGAM5 degradation and disrupts mitochondrial morphology, bioenergetics, and myogenic differentiation. supporting_text: >- Proteomics and biochemical assays support **PGAM5** (a mitochondrial phosphatase) as an FBXO10-regulated OMM substrate: FBXO10 promotes PGAM5 polyubiquitylation and degradation in a manner sensitive to proteasome inhibition and cullin neddylation blockade. Loss of FBXO10 or expression of prenylation-deficient FBXO10(C953S) prevents PGAM5 degradation, disrupts mitochondrial morphology and bioenergetics, and impairs myogenic differentiation in human and murine myogenic models. - statement: FBXO10 was identified in an F-box screen as a factor that promotes ubiquitination and lysosomal degradation of the inflammatory receptor RAGE, recognized via cytoplasmic K374 and the phosphorylation-sensitive S391. supporting_text: >- FBXO10 was identified in an F-box screen as a factor that decreases RAGE protein levels and accelerates RAGE degradation. FBXO10 depletion stabilizes RAGE, supporting endogenous control. RAGE recognition involves specific cytoplasmic residues (e.g., K374 and S391), consistent with the general paradigm that degrons and post-translational modification states influence SCF substrate engagement. In this study, RAGE undergoes monoubiquitination and is routed to lysosomal degradation. - statement: Engineered Fbxo10 loss-of-function mice show no discernible increase in BCL2 protein or B-cell accumulation, indicating that FBXO10 either does not regulate BCL2 in mice or functions redundantly with other ligases. supporting_text: >- A mouse genetics study engineered Fbxo10 loss-of-function alleles and observed no discernible increase in BCL2 protein or B-cell accumulation in mice, concluding that FBXO10 either does not regulate BCL2 in mice or functions redundantly with other ligases (suggesting candidates such as FBXO11 or ARTS-XIAP). reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: >- Falcon (Edison Scientific) deep-research synthesis. Cross-checked against the UniProt FUNCTION block and the BCL2/HGAL primary papers (PMID:23431138, PMID:31570756) already in this review; used as leads for substrates/mechanisms not yet in UniProt (PGAM5/OMM geranylgeranylation per Bhat 2024 Cell Reports, RAGE per Evankovich 2017 FASEB J, ACSL4/ferroptosis per Chen 2023, and the Fbxo10 mouse-knockout caveat per Masle-Farquhar 2021). Cites author-year/DOIs rather than PMIDs, so individual primary claims remain UNVERIFIED here. - id: Reactome:R-HSA-8952618 title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952620 title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956040 title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956200 title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-983140 title: Transfer of Ub from E2 to substrate and release of E2 findings: [] - id: Reactome:R-HSA-983147 title: Release of E3 from polyubiquitinated substrate findings: [] - id: Reactome:R-HSA-983156 title: Polyubiquitination of substrate findings: [] - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] core_functions: - description: Substrate-recognition subunit (F-box adaptor) of the SCF(FBXO10) E3 ubiquitin ligase complex (CUL1-SKP1-FBXO10) that binds the antiapoptotic protein BCL2 and targets it for ubiquitination and proteasomal degradation, thereby promoting apoptosis; loss of this function permits BCL2 accumulation in diffuse large B-cell lymphoma. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:23431138 supporting_text: FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death directly_involved_in: - id: GO:0042981 label: regulation of apoptotic process - description: SCF(FBXO10) substrate adaptor that, upon B-cell receptor stimulation and palmitoylation-driven relocation to the cell membrane, targets the germinal-center protein HGAL/GCSAM for ubiquitination and degradation, forming a negative-feedback loop that dampens BCR signaling. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:31570756 supporting_text: it targets the human germinal center-associated lymphoma (HGAL) protein for ubiquitylation and degradation, leading to decreases in both BCR-induced calcium influx and phosphorylation of proximal BCR effectors directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: A geranylgeranylation-targeted (CaaX/Cys953) pool of FBXO10 assembles a mitochondrial SCF(FBXO10) at the outer mitochondrial membrane that polyubiquitinates the mitochondrial phosphatase PGAM5 for proteasomal degradation, controlling selective outer-mitochondrial-membrane proteostasis, mitochondrial morphology and bioenergetics, and myogenic differentiation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005741 label: mitochondrial outer membrane supported_by: - reference_id: file:human/FBXO10/FBXO10-deep-research-falcon.md supporting_text: >- A major 2024 advance is that FBXO10 can be **post-translationally geranylgeranylated** at a C-terminal CaaX motif (C953), which is required for its stable targeting to the **outer mitochondrial membrane (OMM)**. This lipidation enables mitochondrial delivery via a PDE6δ/HSP90-dependent pathway linked to TOM70 docking, forming a mitochondrial SCF(FBXO10) complex with SKP1 and CUL1 at the OMM. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: 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? - question: 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? - question: 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? - question: 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? - question: Why do Fbxo10 loss-of-function mice fail to accumulate BCL2 despite the human lymphoma phenotype—does another E3 (e.g. FBXO11 or ARTS/XIAP) provide redundant BCL2 turnover, and is this redundancy species-specific? suggested_experiments: - description: 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. - description: 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. - description: 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.