Existing Annotations Review

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

Core Functions

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

regulation of apoptotic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:23431138
FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:31570756
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

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:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

mitochondrial outer membrane

Supporting Evidence:

file:human/FBXO10/FBXO10-deep-research-falcon.md
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.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:10531035

Identification of a family of human F-box proteins.

PMID:10531037

A family of mammalian F-box proteins.

PMID:23431138

Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma.

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.

PMID:31570756

Recent BCR stimulation induces a negative autoregulatory loop via FBXO10 mediated degradation of HGAL.

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.

PMID:34445249

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.

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.

file:human/FBXO10/FBXO10-deep-research-falcon.md

Falcon deep research report for human FBXO10

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.

"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)."
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.

"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."
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.

"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."
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.

"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."
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.

"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)."

Reactome:R-HSA-8952618

AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8952620

NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956040

COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956200

MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

Suggested Experiments

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.

Deep Research

Falcon

(FBXO10-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 29 citations 2 artifacts 2026-06-13T06:31:18.063200

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000040 The document provides evidence for FBXO10 geranylgeranylation-dependent mitochondrial outer membrane (OMM) localization and its rol (image/png)

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.

Research report: Human FBXO10 (UniProt Q9UK96) functional annotation

0) Target verification (gene/protein identity)

FBXO10 (F-box only protein 10) is the human gene/protein associated with UniProt accession Q9UK96 and is functionally characterized in the literature as an F-box substrate receptor within SCF (SKP1–CUL1–F-box) E3 ubiquitin ligase complexes (“SCF(FBXO10)” or “SCF^FBXO10”). Primary studies show FBXO10 binds core SCF components SKP1 and CUL1 and controls substrate ubiquitination and degradation, confirming the identity matches the requested target rather than other similarly named F-box proteins (e.g., FBXO11/FBXL10). (chiorazzi2013relatedfboxproteins pages 4-5, chiorazzi2013relatedfboxproteins pages 3-4, bhat2024geranylgeranylatedscffbxo10regulates pages 5-6)

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF E3 ligases

F-box proteins are substrate-recognition subunits of SCF (SKP1–CUL1–F-box) E3 ubiquitin ligase complexes. SCF complexes include invariant components (CUL1 scaffold, SKP1 adaptor, RBX1/2 RING subunit) and a variable F-box protein that confers substrate specificity by binding degron motifs on targets—often regulated by post-translational modifications such as phosphorylation. (wang2014rolesoffbox pages 1-3, tekcham2020fboxproteinsand pages 1-3)

In cancer biology, dysregulated SCF/F-box-mediated proteolysis can promote or suppress tumorigenesis depending on the substrates affected, and F-box proteins are thus discussed as mechanistically important and potentially druggable nodes in ubiquitin-mediated regulation. (wang2014rolesoffbox pages 1-3, wang2014rolesoffbox pages 14-16)

1.2 What FBXO10 does (high-level definition)

FBXO10 is an FBXO-class F-box protein that acts primarily as a substrate receptor: it recruits specific proteins to an SCF-type E3 ubiquitin ligase for ubiquitination, thereby controlling their stability and downstream pathway activity. In the best-established lymphoma context, a major substrate is the anti-apoptotic protein BCL2, with FBXO10 acting as a tumor-suppressive regulator by promoting BCL2 ubiquitination and degradation. (yang2015proteinubiquitinationin pages 11-13, chiorazzi2013relatedfboxproteins pages 4-5)

2) Molecular function, substrates, localization, and pathways

2.1 Canonical lymphoma axis: FBXO10 → BCL2 turnover → apoptosis

Mechanism and evidence. In human lymphoma models, FBXO10 physically associates with BCL2 and SCF components and promotes BCL2 ubiquitination and destabilization. Loss-of-function or hypomorphic lymphoma-derived FBXO10 mutations (e.g., R44H in the F-box) impair SKP1 binding/SCF assembly and diminish BCL2 destabilization and pro-apoptotic effects. (chiorazzi2013relatedfboxproteins pages 4-5, chiorazzi2013relatedfboxproteins pages 3-4)

Functional consequences. Forced expression of FBXO10 induces apoptosis in multiple lymphoma cell lines, as measured by apoptotic markers (e.g., activated caspase-3, cleaved PARP), and ectopic BCL2 partially rescues cells from FBXO10-induced death—supporting BCL2 as a key functional substrate in this context. (chiorazzi2013relatedfboxproteins pages 5-6)

Pathway context. This axis places FBXO10 as a post-translational brake on the mitochondrial apoptosis checkpoint regulated by BCL2. (yang2015proteinubiquitinationin pages 11-13, choi2019e3ubiquitinligases pages 8-9)

2.2 Mantle cell lymphoma (MCL): FBXO10 deficiency and BTK/NF-κB-driven BCL2 elevation

In mantle cell lymphoma models, BCL2 elevation is attributed to both transcriptional upregulation (via BTK-mediated canonical NF-κB activation) and impaired proteasomal degradation due to absent/very low FBXO10 expression. FBXO10 silencing stabilizes BCL2 in cycloheximide-chase experiments. Pharmacologically, combining BCL2 inhibition (ABT-199/venetoclax) with BTK inhibition (ibrutinib) shows synergistic activity in vitro and in vivo in this mechanistic framework. (li2016fbxo10deficiencyand pages 1-2, li2016fbxo10deficiencyand pages 8-9)

2.3 Inflammatory receptor proteostasis: FBXO10 targets RAGE

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. (evankovich2017receptorforadvanced pages 5-7, evankovich2017receptorforadvanced pages 1-2)

2.4 Subcellular targeting by lipidation: new 2024 mitochondrial mechanism

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. (bhat2024geranylgeranylatedscffbxo10regulates pages 1-3, bhat2024geranylgeranylatedscffbxo10regulates pages 8-9)

Substrate and function at mitochondria. 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. (bhat2024geranylgeranylatedscffbxo10regulates pages 9-11, bhat2024geranylgeranylatedscffbxo10regulates pages 11-13)

Visual evidence from the 2024 study. The paper contains microscopy and biochemical panels showing WT FBXO10 mitochondrial localization versus cytosolic distribution of the C953S mutant, and TUBE-based evidence of PGAM5 polyubiquitination dependent on WT FBXO10. (bhat2024geranylgeranylatedscffbxo10regulates media 66ac8191, bhat2024geranylgeranylatedscffbxo10regulates media 6d0eb518)

2.5 Ferroptosis and immunotherapy resistance (2023): FBXO10 and ACSL4

A 2023 Cell Death & Disease study links FBXO10 to ferroptosis regulation and anti-PD-1 response in colorectal cancer via a CYP1B1 → 20-HETE → PKC → FBXO10 axis. 20-HETE induces FBXO10 (blocked by PKC inhibition), and the pathway promotes ACSL4 polyubiquitination and decreases ACSL4 half-life/protein abundance. Because ACSL4 promotes PUFA lipid remodeling and ferroptosis sensitivity, its loss reduces ferroptosis and is associated with reduced anti-PD-1 efficacy in vivo; CYP1B1 knockdown improved response to anti-mPD-1 and increased 4-HNE (lipid peroxidation marker). (chen2023cyp1b1inhibitsferroptosis pages 2-6, chen2023cyp1b1inhibitsferroptosis pages 6-8)

2.6 BCR signaling and HGAL turnover (review-supported mechanistic model; 2023–2024)

A 2023 review of HGAL biology describes a spatially regulated mechanism in which B-cell receptor engagement induces rapid, reversible palmitoylation of SCF(FBXO10), relocalizing FBXO10 to the plasma membrane where it binds HGAL and triggers HGAL ubiquitination and proteasomal degradation. The reported interaction depends on a conserved HGAL residue (H91) and is described as phosphorylation-independent. (jiang2023roleofan pages 3-5, jiang2023roleofan pages 5-7)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: FBXO10 as a prenylation-controlled mitochondrial E3 (Cell Reports)

The 2024 Cell Reports study reframes FBXO10 biology by adding a mitochondrial OMM-localized pool that is controlled by geranylgeranylation and acts on OMM proteostasis (not just cytosolic/membrane receptors or BCL2). This introduces new mechanistic concepts for FBXO10: lipidation-dependent trafficking, OMM-delivered SCF activity, and control of mitochondrial network state, respiratory capacity, and differentiation outcomes via substrates such as PGAM5. (bhat2024geranylgeranylatedscffbxo10regulates pages 1-3, bhat2024geranylgeranylatedscffbxo10regulates pages 9-11, bhat2024geranylgeranylatedscffbxo10regulates pages 11-13)

3.2 2023: FBXO10 in ferroptosis and immunotherapy response (Cell Death & Disease)

The 2023 CRC study connects FBXO10-mediated ubiquitination to ferroptosis sensitivity and immune checkpoint blockade efficacy. It also provides human-tissue correlative observations (IHC negative correlation between CYP1B1 and ACSL4; high CYP1B1 associated with worse survival), positioning the FBXO10–ACSL4 arm as part of a clinically relevant resistance axis. (chen2023cyp1b1inhibitsferroptosis pages 6-8, chen2023cyp1b1inhibitsferroptosis pages 1-2)

3.3 2023: BCR/HGAL axis synthesis (review)

A 2023 review consolidates mechanistic evidence that HGAL protein levels are controlled post-translationally by FBXO10 in response to BCR activation via palmitoylation-driven FBXO10 membrane translocation, emphasizing temporally and spatially gated substrate access. (jiang2023roleofan pages 3-5, jiang2023roleofan pages 5-7)

4) Current applications and real-world implementations

4.1 Lymphoma therapeutic implications (indirect targeting through BCL2)

Although FBXO10 itself is not currently a standard drug target, its best-established substrate (BCL2) is directly druggable. Mechanistic evidence in mantle cell lymphoma supports that defects in FBXO10-mediated degradation contribute to BCL2 protein persistence and apoptosis resistance, and that BCL2 inhibition (ABT-199/venetoclax) can be required to enhance BTK inhibitor activity (e.g., ibrutinib), including in resistant settings. (li2016fbxo10deficiencyand pages 1-2, li2016fbxo10deficiencyand pages 8-9)

4.2 Immuno-oncology/ferroptosis axis (CRC)

The 2023 CRC work suggests that upstream blockade of the CYP1B1/20-HETE/PKC pathway could downregulate FBXO10 and restore ACSL4, increasing ferroptosis and improving anti-PD-1 response. This is an example of a real-world implementation path: rather than targeting FBXO10 directly, intervening upstream or at ferroptosis nodes may modulate an FBXO10-dependent phenotype. (chen2023cyp1b1inhibitsferroptosis pages 6-8, chen2023cyp1b1inhibitsferroptosis pages 1-2)

4.3 Mitochondrial disease and differentiation contexts (emerging)

The 2024 mitochondrial study points to potential future applications in muscle biology and mitochondrial quality-control disorders, as FBXO10 loss or prenylation blockade impaired bioenergetics and differentiation in myogenic models. This is currently preclinical mechanistic work but suggests new application areas beyond hematologic malignancies. (bhat2024geranylgeranylatedscffbxo10regulates pages 9-11, bhat2024geranylgeranylatedscffbxo10regulates pages 11-13)

4.4 Clinical trial landscape

A ClinicalTrials.gov-style query for “FBXO10” did not yield clearly FBXO10-targeted interventional trials in the retrieved results, consistent with FBXO10 being an emerging mechanistic node rather than a mature clinical target at present. (wang2014rolesoffbox pages 14-16)

5) Expert opinions and authoritative analysis

5.1 FBXO10 as a tumor suppressor in lymphoma via BCL2 control

Lymphoma-focused reviews and primary work interpret FBXO10 as a tumor-suppressive SCF substrate receptor in germinal-center–type DLBCL, where reduced FBXO10 expression and/or coding mutations impair BCL2 degradation and thereby enhance survival signaling. (yang2015proteinubiquitinationin pages 11-13)

5.2 Context dependence and redundancy (species and pathway context)

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). This highlights that FBXO10 biology can be context- and species-dependent, and functional redundancy may mask phenotypes in some systems. (maslefarquhar2021lossoffunctionoffbxo10 pages 1-2)

5.3 FBXO10 as a multi-compartment E3 substrate receptor

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). (evankovich2017receptorforadvanced pages 1-2, bhat2024geranylgeranylatedscffbxo10regulates pages 11-13, jiang2023roleofan pages 5-7)

6) Relevant statistics and data points from studies

DLBCL mutation frequency (FBXO10): In a lymphoma review summarizing sequencing cohorts, coding-region mutations in FBXO10 were found in approximately ~5% of GCB DLBCL and ~1% of ABC DLBCL, and these mutations include frameshift and missense variants (e.g., R44H) that impair SCF association and/or BCL2 destabilization. (yang2015proteinubiquitinationin pages 11-13)
Cell-line sensitivity to FBXO10-induced apoptosis: In the foundational PNAS study, FBXO10 expression was toxic to multiple lymphoma lines, affecting 5/6 ABC DLBCL, 4/8 GCB DLBCL, 4/6 MCL, and 1/3 PMBL cell lines tested; ectopic BCL2 partially rescued viability in an example experiment. (chiorazzi2013relatedfboxproteins pages 4-5)
MCL tissue microarray size: The MCL mechanistic study reports analyzing a 62-sample mantle cell lymphoma tissue microarray when examining BCL2/BTK relationships (specific quantitative correlation values are not available in the excerpted evidence). (li2016fbxo10deficiencyand pages 1-2)
OpenTargets evidence volume: OpenTargets lists FBXO10 associations with several diseases (e.g., hepatocellular carcinoma; kidney disease) with small evidence counts (e.g., 5 items per association in the retrieved output), indicating emerging/limited curated genetic/functional evidence rather than a mature clinical association profile. (OpenTargets Search: -FBXO10)

Summary of experimentally supported functions (at a glance)

Substrate/Process	Evidence type (binding/ubiquitination/degradation/phenotype)	Cell/tissue context	Subcellular localization of FBXO10 action	Key mechanistic notes (e.g., SCF complex, PTM required)	Primary citation (author-year, DOI URL, pub date)
BCL2	Binding to BCL2; promotion of BCL2 ubiquitination; accelerated degradation/shortened half-life; apoptosis induction in lymphoma cells; hypomorphic cancer mutations reduce activity	Human DLBCL and mantle cell lymphoma cell lines; lymphoma tumor context	Predominantly cytoplasmic, acting on mitochondrial outer membrane-associated/anti-apoptotic BCL2 pool	FBXO10 is the substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ligase; intact F-box needed for SKP1 binding/SCF assembly; tumor mutations include R44H (F-box), V762L and R825W (CASH/PbH1 region), impairing BCL2 destabilization; reduced FBXO10 expression/mutation linked to elevated BCL2 and survival signaling (chiorazzi2013relatedfboxproteins pages 5-6, yang2015proteinubiquitinationin pages 11-13, chiorazzi2013relatedfboxproteins pages 4-5, chiorazzi2013relatedfboxproteins pages 3-4, li2016fbxo10deficiencyand pages 1-2)	Chiorazzi et al. 2013, https://doi.org/10.1073/pnas.1217271110, Feb 2013; Li et al. 2016, https://doi.org/10.1038/onc.2016.155, Dec 2016
RAGE	FBXO10 identified in F-box screen; binding/association with RAGE; increased ubiquitination; enhanced degradation rate in cycloheximide chase; stabilization after FBXO10 knockdown	Human cell culture models studying inflammatory receptor turnover	Endomembrane/lysosomal pathway after receptor internalization	FBXO10 associates with SKP1/CUL1 consistent with SCF complex; RAGE recognition depends on cytoplasmic K374 and phosphorylation-sensitive S391; ODN2006 and PKCζ signaling promote degradation; reported endpoint is lysosomal degradation rather than classic solely proteasomal turnover (evankovich2017receptorforadvanced pages 5-7, evankovich2017receptorforadvanced pages 1-2)	Evankovich et al. 2017, https://doi.org/10.1096/fj.201700031r, Sep 2017
PGAM5	OMM-dependent binding; polyubiquitylation detected by TUBE pulldown; timed degradation during differentiation; loss of FBXO10 impairs mitochondrial ATP production, membrane potential, morphology, mitophagy resolution, and myotube formation	Human iPSC-derived myogenic cells, HeLa localization systems, murine C2C12 myoblast differentiation models	Outer mitochondrial membrane (OMM)	Major 2024 advance: FBXO10 is geranylgeranylated at C953 in a C-terminal CaaX motif; this PTM is required for OMM targeting via PDE6δ/HSP90/TOM70-linked delivery; WT but not C953S mutant localizes to mitochondria and assembles mitochondrial SCF(FBXO10); cullin neddylation/proteasome activity required for PGAM5 turnover (bhat2024geranylgeranylatedscffbxo10regulates pages 5-6, bhat2024geranylgeranylatedscffbxo10regulates pages 1-3, bhat2024geranylgeranylatedscffbxo10regulates pages 36-38, bhat2024geranylgeranylatedscffbxo10regulates pages 3-5, bhat2024geranylgeranylatedscffbxo10regulates pages 9-11, bhat2024geranylgeranylatedscffbxo10regulates pages 11-13, bhat2024geranylgeranylatedscffbxo10regulates pages 8-9, bhat2024geranylgeranylatedscffbxo10regulates media 66ac8191)	Bhat et al. 2024, https://doi.org/10.1016/j.celrep.2024.114783, Oct 2024
ACSL4	Increased FBXO10 expression downstream of CYP1B1/20-HETE/PKC; ACSL4 polyubiquitination and reduced half-life/protein abundance; ferroptosis suppression; reduced anti-PD-1 response in vivo when pathway is active	Colorectal cancer cell lines and mouse tumor models	Not definitively localized in the cited study; function inferred in cytoplasmic/endomembrane protein quality-control context affecting lipid metabolism	Study places FBXO10 in a CYP1B1 → 20-HETE → PKC → FBXO10 axis; elevated FBXO10 promotes ACSL4 degradation, lowering ferroptosis sensitivity and contributing to immunotherapy resistance; evidence for FBXO10 as ACSL4 E3 is strong but upstream signaling focus is on CYP1B1 (chen2023cyp1b1inhibitsferroptosis pages 2-6, chen2023cyp1b1inhibitsferroptosis pages 6-8, chen2023cyp1b1inhibitsferroptosis pages 1-2, chen2023cyp1b1inhibitsferroptosis pages 8-8)	Chen et al. 2023, https://doi.org/10.1038/s41419-023-05803-2, Apr 2023
HGAL	Review-based summary of prior experimental work: BCR-triggered FBXO10 relocalization enables HGAL binding, ubiquitination, and proteasomal degradation	Germinal-center B cells / DLBCL and Burkitt lymphoma signaling context after BCR engagement	Plasma membrane/cell membrane-associated compartment after BCR stimulation, followed by cytoplasmic proteasomal turnover	FBXO10 undergoes rapid, reversible palmitoylation after BCR engagement; palmitoylation drives relocation to the plasma membrane where FBXO10 binds HGAL; interaction reported as phosphorylation-independent and dependent on HGAL H91; included here as review-supported rather than directly re-read primary data in current context (jiang2023roleofan pages 3-5, jiang2023roleofan pages 5-7)	Jiang & Lossos 2023, https://doi.org/10.37349/ei.2023.00097, Jun 2023
Mitochondrial proteostasis / myogenic differentiation (process-level)	Comparative mitochondrial proteomics; localization assays; respiration, membrane potential, mitophagy, morphology, and differentiation phenotypes	Human and murine myogenic models	Outer mitochondrial membrane	FBXO10 acts as a prenylated mitochondrial SCF E3 controlling selective OMM proteostasis; ~18 candidate OMM/OMM-associated proteins changed reciprocally with WT versus C953S FBXO10, indicating broader substrate scope beyond PGAM5; WT promotes hyperfused/perinuclear mitochondrial networks, whereas prenylation-deficient or ΔF-box forms act dominantly negative (bhat2024geranylgeranylatedscffbxo10regulates pages 5-6, bhat2024geranylgeranylatedscffbxo10regulates pages 1-3, bhat2024geranylgeranylatedscffbxo10regulates pages 3-5, bhat2024geranylgeranylatedscffbxo10regulates pages 9-11, bhat2024geranylgeranylatedscffbxo10regulates pages 22-26)	Bhat et al. 2024, https://doi.org/10.1016/j.celrep.2024.114783, Oct 2024

Table: This table summarizes experimentally supported or review-supported FBXO10 substrates/processes, the kinds of evidence behind each assignment, and the cellular compartment where FBXO10 acts. It is useful for distinguishing well-established lymphoma-related roles from newer 2023-2024 findings in mitochondrial proteostasis and ferroptosis-related pathways.

References (URLs and publication dates)

The citations embedded above include DOI URLs and month/year publication metadata as captured in the retrieved sources, including: Chiorazzi et al., PNAS (Feb 2013) https://doi.org/10.1073/pnas.1217271110; Yang & Staudt, Immunological Reviews (Jan 2015) https://doi.org/10.1111/imr.12247; Li et al., Oncogene (Dec 2016) https://doi.org/10.1038/onc.2016.155; Evankovich et al., FASEB J (Sep 2017) https://doi.org/10.1096/fj.201700031r; Jiang & Lossos (Jun 2023) https://doi.org/10.37349/ei.2023.00097; Chen et al., Cell Death & Disease (Apr 2023) https://doi.org/10.1038/s41419-023-05803-2; Bhat et al., Cell Reports (Oct 2024) https://doi.org/10.1016/j.celrep.2024.114783. (chiorazzi2013relatedfboxproteins pages 5-6, li2016fbxo10deficiencyand pages 1-2, evankovich2017receptorforadvanced pages 5-7, jiang2023roleofan pages 3-5, chen2023cyp1b1inhibitsferroptosis pages 2-6, bhat2024geranylgeranylatedscffbxo10regulates pages 1-3)

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(bhat2024geranylgeranylatedscffbxo10regulates media 6d0eb518): Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, and Shafi Kuchay. Geranylgeranylated scffbxo10 regulates selective outer mitochondrial membrane proteostasis and function. Oct 2024. URL: https://doi.org/10.1016/j.celrep.2024.114783, doi:10.1016/j.celrep.2024.114783. This article has 11 citations and is from a highest quality peer-reviewed journal.
(chen2023cyp1b1inhibitsferroptosis pages 2-6): Congcong Chen, Yabing Yang, Yanguan Guo, Jiashuai He, Zuyang Chen, Shenghui Qiu, Yiran Zhang, Hui Ding, Jinghua Pan, and Yunlong Pan. Cyp1b1 inhibits ferroptosis and induces anti-pd-1 resistance by degrading acsl4 in colorectal cancer. Cell Death & Disease, Apr 2023. URL: https://doi.org/10.1038/s41419-023-05803-2, doi:10.1038/s41419-023-05803-2. This article has 123 citations and is from a peer-reviewed journal.
(chen2023cyp1b1inhibitsferroptosis pages 6-8): Congcong Chen, Yabing Yang, Yanguan Guo, Jiashuai He, Zuyang Chen, Shenghui Qiu, Yiran Zhang, Hui Ding, Jinghua Pan, and Yunlong Pan. Cyp1b1 inhibits ferroptosis and induces anti-pd-1 resistance by degrading acsl4 in colorectal cancer. Cell Death & Disease, Apr 2023. URL: https://doi.org/10.1038/s41419-023-05803-2, doi:10.1038/s41419-023-05803-2. This article has 123 citations and is from a peer-reviewed journal.
(jiang2023roleofan pages 3-5): Xiaoyu Jiang and Izidore S. Lossos. Role of an adaptor protein human germinal center-associated lymphoma (hgal) in cell signaling and lymphomagenesis. Exploration of Immunology, pages 186-206, Jun 2023. URL: https://doi.org/10.37349/ei.2023.00097, doi:10.37349/ei.2023.00097. This article has 1 citations.
(jiang2023roleofan pages 5-7): Xiaoyu Jiang and Izidore S. Lossos. Role of an adaptor protein human germinal center-associated lymphoma (hgal) in cell signaling and lymphomagenesis. Exploration of Immunology, pages 186-206, Jun 2023. URL: https://doi.org/10.37349/ei.2023.00097, doi:10.37349/ei.2023.00097. This article has 1 citations.
(chen2023cyp1b1inhibitsferroptosis pages 1-2): Congcong Chen, Yabing Yang, Yanguan Guo, Jiashuai He, Zuyang Chen, Shenghui Qiu, Yiran Zhang, Hui Ding, Jinghua Pan, and Yunlong Pan. Cyp1b1 inhibits ferroptosis and induces anti-pd-1 resistance by degrading acsl4 in colorectal cancer. Cell Death & Disease, Apr 2023. URL: https://doi.org/10.1038/s41419-023-05803-2, doi:10.1038/s41419-023-05803-2. This article has 123 citations and is from a peer-reviewed journal.
(maslefarquhar2021lossoffunctionoffbxo10 pages 1-2): Etienne Masle-Farquhar, Amanda Russell, Yangguang Li, Fen Zhu, Lixin Rui, Robert Brink, and Christopher C. Goodnow. Loss-of-function of fbxo10, encoding a post-translational regulator of bcl2 in lymphomas, has no discernible effect on bcl2 or b lymphocyte accumulation in mice. PLOS ONE, 16:e0237830, Apr 2021. URL: https://doi.org/10.1371/journal.pone.0237830, doi:10.1371/journal.pone.0237830. This article has 5 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXO10): Open Targets Query (-FBXO10, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(bhat2024geranylgeranylatedscffbxo10regulates pages 36-38): Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, and Shafi Kuchay. Geranylgeranylated scffbxo10 regulates selective outer mitochondrial membrane proteostasis and function. Oct 2024. URL: https://doi.org/10.1016/j.celrep.2024.114783, doi:10.1016/j.celrep.2024.114783. This article has 11 citations and is from a highest quality peer-reviewed journal.
(bhat2024geranylgeranylatedscffbxo10regulates pages 3-5): Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, and Shafi Kuchay. Geranylgeranylated scffbxo10 regulates selective outer mitochondrial membrane proteostasis and function. Oct 2024. URL: https://doi.org/10.1016/j.celrep.2024.114783, doi:10.1016/j.celrep.2024.114783. This article has 11 citations and is from a highest quality peer-reviewed journal.
(chen2023cyp1b1inhibitsferroptosis pages 8-8): Congcong Chen, Yabing Yang, Yanguan Guo, Jiashuai He, Zuyang Chen, Shenghui Qiu, Yiran Zhang, Hui Ding, Jinghua Pan, and Yunlong Pan. Cyp1b1 inhibits ferroptosis and induces anti-pd-1 resistance by degrading acsl4 in colorectal cancer. Cell Death & Disease, Apr 2023. URL: https://doi.org/10.1038/s41419-023-05803-2, doi:10.1038/s41419-023-05803-2. This article has 123 citations and is from a peer-reviewed journal.
(bhat2024geranylgeranylatedscffbxo10regulates pages 22-26): Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, and Shafi Kuchay. Geranylgeranylated scffbxo10 regulates selective outer mitochondrial membrane proteostasis and function. Oct 2024. URL: https://doi.org/10.1016/j.celrep.2024.114783, doi:10.1016/j.celrep.2024.114783. This article has 11 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

chiorazzi2013relatedfboxproteins pages 5-6
wang2014rolesoffbox pages 14-16
yang2015proteinubiquitinationin pages 11-13
chiorazzi2013relatedfboxproteins pages 4-5
chiorazzi2013relatedfboxproteins pages 3-4
wang2014rolesoffbox pages 1-3
tekcham2020fboxproteinsand pages 1-3
evankovich2017receptorforadvanced pages 5-7
evankovich2017receptorforadvanced pages 1-2
jiang2023roleofan pages 3-5
jiang2023roleofan pages 5-7
https://doi.org/10.1073/pnas.1217271110,
https://doi.org/10.1038/onc.2016.155,
https://doi.org/10.1096/fj.201700031r,
https://doi.org/10.1016/j.celrep.2024.114783,
https://doi.org/10.1038/s41419-023-05803-2,
https://doi.org/10.37349/ei.2023.00097,
https://doi.org/10.1073/pnas.1217271110;
https://doi.org/10.1111/imr.12247;
https://doi.org/10.1038/onc.2016.155;
https://doi.org/10.1096/fj.201700031r;
https://doi.org/10.37349/ei.2023.00097;
https://doi.org/10.1038/s41419-023-05803-2;
https://doi.org/10.1016/j.celrep.2024.114783.
https://doi.org/10.1038/nrc3700,
https://doi.org/10.7150/thno.42735,
https://doi.org/10.1111/imr.12247,
https://doi.org/10.1016/j.cellimm.2019.02.004,
https://doi.org/10.1371/journal.pone.0237830,

📚 Additional Documentation

Pn Notes

(FBXO10-pn-notes.md)

FBXO10 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UK96
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO10/FBXO10-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO10/FBXO10-ai-review.html
Gene notes: missing - genes/human/FBXO10/FBXO10-notes.md
GOA TSV: present - genes/human/FBXO10/FBXO10-goa.tsv
UniProt record: present - genes/human/FBXO10/FBXO10-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO10.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO10.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXO10/FBXO10-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 9; KEEP_AS_NON_CORE: 16; MODIFY: 2

PN Consistency Summary

Consistency: Consistent and well-aligned. Review explicitly executes the canonical F-box pattern: two NAS GO:0004842 ubiquitin-protein transferase annotations MODIFY → GO:1990756 (verified real), exactly matching the PN projection. DR ↔ YAML agree on BCL2/HGAL/PGAM5/RAGE substrates and SCF(FBXO10) membership.
PN story / NEW pressure: PN asserts the adaptor MF; review supplies it via MODIFY of the wrong catalytic-transferase terms — already captured/improved, not over-reach. Beyond the PN family story, the review carries substantial extra biology (apoptosis via BCL2 IMP PMID:23431138; mitochondrial OMM PGAM5 degradation; species caveat from Fbxo10 KO mice) that PN does not assert. No additional NEW GO pressure beyond GO:1990756. Validated substrates present (not a substrate-less F-box).
Evidence alignment: PN cites only 15340381. Review uses PMID:23431138 (BCL2), 31570756 (HGAL), 34445249 (SCF), 10531035/10531037 (family cloning, source of the transferase NAS terms), plus Falcon PGAM5/RAGE leads. Expansion, no conflict.
Verdict: Consistent; review already implements the PN adaptor-MF mapping via MODIFY GO:0004842→GO:1990756.

Full Consistency Review

UniProt: Q9UK96 · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|CASH (aux domain IPR006633) ; PN-node mapping: subtype/type no_mapping; group Cul1 substrate receptor=mapped / ok_for_propagation_to_go → GO:1990756 (new_to_goa); class context_only/too_broad (GO:0061630).
Consistency: Consistent and well-aligned. Review explicitly executes the canonical F-box pattern: two NAS GO:0004842 ubiquitin-protein transferase annotations MODIFY → GO:1990756 (verified real), exactly matching the PN projection. DR ↔ YAML agree on BCL2/HGAL/PGAM5/RAGE substrates and SCF(FBXO10) membership.
PN story / NEW pressure: PN asserts the adaptor MF; review supplies it via MODIFY of the wrong catalytic-transferase terms — already captured/improved, not over-reach. Beyond the PN family story, the review carries substantial extra biology (apoptosis via BCL2 IMP PMID:23431138; mitochondrial OMM PGAM5 degradation; species caveat from Fbxo10 KO mice) that PN does not assert. No additional NEW GO pressure beyond GO:1990756. Validated substrates present (not a substrate-less F-box).
Mapping strategy: Gene does not change the node; status/scope correct. PN-projected GO:1990756 is at correct altitude (matches the review's MODIFY replacement target). Class GO:0061630 correctly too_broad.
Evidence alignment: PN cites only 15340381. Review uses PMID:23431138 (BCL2), 31570756 (HGAL), 34445249 (SCF), 10531035/10531037 (family cloning, source of the transferase NAS terms), plus Falcon PGAM5/RAGE leads. Expansion, no conflict.
Verdict: Consistent; review already implements the PN adaptor-MF mapping via MODIFY GO:0004842→GO:1990756.
Recommended edits: none to FBXO10-ai-review.yaml. [MAP] none — node mapping and review concur.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO10/FBXO10-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | CASH

UniProt: Q9UK96
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: IPR006633
PN references (titles):
- 15340381 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|CASH
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

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.

📄 View Raw YAML

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.

FBXO10

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXO10 (UniProt Q9UK96) functional annotation

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 F-box proteins and SCF E3 ligases

1.2 What FBXO10 does (high-level definition)

2) Molecular function, substrates, localization, and pathways

2.1 Canonical lymphoma axis: FBXO10 → BCL2 turnover → apoptosis

2.2 Mantle cell lymphoma (MCL): FBXO10 deficiency and BTK/NF-κB-driven BCL2 elevation

2.3 Inflammatory receptor proteostasis: FBXO10 targets RAGE

2.4 Subcellular targeting by lipidation: new 2024 mitochondrial mechanism

2.5 Ferroptosis and immunotherapy resistance (2023): FBXO10 and ACSL4

2.6 BCR signaling and HGAL turnover (review-supported mechanistic model; 2023–2024)

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 2024: FBXO10 as a prenylation-controlled mitochondrial E3 (Cell Reports)

3.2 2023: FBXO10 in ferroptosis and immunotherapy response (Cell Death & Disease)

3.3 2023: BCR/HGAL axis synthesis (review)

4) Current applications and real-world implementations

4.1 Lymphoma therapeutic implications (indirect targeting through BCL2)

4.2 Immuno-oncology/ferroptosis axis (CRC)

4.3 Mitochondrial disease and differentiation contexts (emerging)

4.4 Clinical trial landscape

5) Expert opinions and authoritative analysis

5.1 FBXO10 as a tumor suppressor in lymphoma via BCL2 control

5.2 Context dependence and redundancy (species and pathway context)

5.3 FBXO10 as a multi-compartment E3 substrate receptor

6) Relevant statistics and data points from studies

Summary of experimentally supported functions (at a glance)

References (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXO10 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | CASH

Projected GO annotations (1)

Note

📄 View Raw YAML