FBXO2

UniProt ID: Q9UK22
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXO2 (FBG1/FBX2/NFB42) is a 296-residue cytoplasmic F-box protein that serves as the substrate-recognition subunit of a Skp1-Cul1-F-box (SCF) E3 ubiquitin-protein ligase complex. It contains an N-terminal F-box domain (residues 44-91) that binds SKP1, bridging the receptor to the CUL1-RBX1 catalytic core, and a C-terminal F-box-associated (FBA) sugar-binding domain (residues 113-296) that folds as a galactose-binding-domain-like lectin and binds N-linked high-mannose oligosaccharides. The FBA domain recognizes the innermost N-glycan core (Man3GlcNAc2 / the chitobiose-proximal GlcNAc2 moiety) through a small hydrophobic pocket, a "sugar degron" that becomes exposed when a glycoprotein is misfolded, denatured, or aberrantly retrotranslocated to the cytosol. Through this lectin activity FBXO2 recognizes N-glycans on misfolded/denatured glycoproteins that have been retrotranslocated from the endoplasmic reticulum into the cytosol, recruiting them to the SCF complex for polyubiquitination and proteasomal degradation as part of the ER-associated degradation (ERAD) pathway, thereby preventing the accumulation of cytosolic aggregates of unfolded glycoproteins. Reported glycoprotein clients in the Fbs1/Fbs2 quality-control orbit include pre-integrin beta-1, the T-cell receptor alpha chain, the asialoglycoprotein receptor subunit, and the disease variant CFTR-deltaF508; in neurons FBXO2 additionally turns over APP and BACE1 to limit amyloidogenic processing. FBXO2 is most highly expressed in the nervous system, where it has additional roles in synaptic protein turnover and in clearance of damaged glycan-bearing membranes (lysophagy) and intracellular bacteria (xenophagy), recognizing GlcNAc/high- mannose glycans on these targets. The protein is a peripheral cytoplasmic-side membrane protein and is itself a glycoprotein-specific lectin, not a glycosidase.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0036503 ERAD pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of involvement in ER-associated degradation, a core biological process for the FBA/lectin F-box family.
Reason: Core biological process; FBXO2 recognizes N-glycans on retrotranslocated misfolded glycoproteins and targets them for ERAD, supported by UniProt and the founding literature. The Falcon deep-research synthesis reinforces the mechanism (recognition of the innermost N-glycan core after ER retrotranslocation) and adds named ERAD clients.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
file:human/FBXO2/FBXO2-deep-research-falcon.md
lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of cytoplasmic site of action, consistent with FBXO2 acting on retrotranslocated cytosolic glycoproteins.
Reason: FBXO2 is a cytoplasmic protein that acts on the cytosolic side; supported by UniProt and IDA evidence.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006516 glycoprotein catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of involvement in glycoprotein catabolism, the substrate-class-defining process for this lectin F-box subfamily.
Reason: Core process; FBXO2 directs ubiquitin-dependent degradation of N-glycosylated substrates recognized via its FBA lectin domain.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
GO:0019005 SCF ubiquitin ligase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of FBXO2 as part of the SCF complex, its core complex context as a substrate receptor.
Reason: Core; FBXO2 is the substrate-recognition subunit of SCF(FBXO2) (CUL1, RBX1, SKP1, FBXO2).
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO2).
Reason: Core biological process; SCF(FBXO2) mediates ubiquitination and proteasomal degradation of its glycoprotein substrates.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
GO:0061630 ubiquitin protein ligase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assignment of ubiquitin ligase activity with the contributes_to qualifier, reflecting FBXO2's role as a non-catalytic receptor subunit within the SCF ligase whose catalytic activity resides in RBX1.
Reason: Appropriate with contributes_to; FBXO2 is the substrate-recognition subunit and does not itself carry the catalytic RING activity (RBX1), but contributes to the complex's ligase function.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally and curator-supported cytoplasmic location.
Reason: Correct core localization; redundant with IDA and UniProt.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: High-throughput interactome interaction. Bare protein binding is uninformative per curation guidelines.
Reason: Records a real screen-derived interaction but bare protein binding is uninformative and not a core function.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Q9UK22; P63208: SKP1
GO:0005515 protein binding
IPI
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complex... 		KEEP AS NON CORE
Summary: Interaction captured in a Polycomb complexome map. Bare protein binding is uninformative.
Reason: High-throughput interaction; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Q9UK22; O15212: PFDN6
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: Binary interactome reference map interaction. Bare protein binding is uninformative.
Reason: High-throughput interaction; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Q9UK22; P63208: SKP1
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: Cell-specific interactome interaction. Bare protein binding is uninformative.
Reason: High-throughput interactome; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Q9UK22; P63208: SKP1
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-map interaction. Bare protein binding is uninformative.
Reason: High-throughput cell-map interaction; bare protein binding is uninformative.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Q9UK22; P63208: SKP1
GO:0001540 amyloid-beta binding
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-based electronic transfer of amyloid-beta binding. FBXO2 has been reported to bind/regulate APP-derived species, but this is a context-specific neuronal activity rather than the core lectin/ERAD function.
Reason: Plausible secondary neuronal activity (FBXO2 regulates APP/amyloid-related substrates) but not the core carbohydrate-binding/ERAD function; retained as non-core.
GO:0005829 cytosol
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment of cytosolic localization, consistent with the cytoplasmic/cytosolic site of action.
Reason: Correct localization; FBXO2 acts on the cytosolic side; redundant with UniProt ISS and IDA.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0016567 protein ubiquitination
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic assignment of protein ubiquitination, a parent process of the specific SCF-dependent catabolism FBXO2 mediates.
Reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture the role.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0019005 SCF ubiquitin ligase complex
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment of SCF complex membership, the core complex context.
Reason: Core; redundant with IBA/ISS/NAS SCF annotations.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
GO:0030246 carbohydrate binding
IEA
GO_REF:0000107 		ACCEPT
Summary: Electronic assignment (UniProt keyword Lectin) of carbohydrate binding, the defining molecular function of the FBA domain.
Reason: Core molecular function; the FBA domain is a lectin that binds N-linked high-mannose glycans (carbohydrate-binding sites at residues 210-212 and 278-279). The Falcon deep-research synthesis specifies that the bound determinant is the innermost N-glycan core (Man3GlcNAc2) engaged by a hydrophobic pocket, with preference for high-mannose glycans on denatured glycoproteins.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type
file:human/FBXO2/FBXO2-deep-research-falcon.md
it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible)
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000107 		ACCEPT
Summary: Ortholog-based electronic assignment of SCF-dependent proteasomal catabolism, the core process.
Reason: Core biological process; redundant with IBA/ISS/NAS evidence.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
GO:0043197 dendritic spine
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-based electronic transfer of dendritic spine localization, reflecting FBXO2's neuronal/synaptic expression and role in synaptic protein turnover.
Reason: Plausible neuronal localization tied to a secondary synaptic role; not the core ERAD compartment.
GO:0098978 glutamatergic synapse
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-based electronic transfer of glutamatergic synapse localization/activity, reflecting a neuronal synaptic role.
Reason: Secondary neuronal/synaptic context; not the core ERAD/lectin function.
GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ortholog-based electronic transfer of a postsynaptic protein-catabolism regulatory role, reflecting FBXO2's neuronal function in synaptic protein turnover.
Reason: Secondary, neuronal-context process; not the core ERAD/glycoprotein catabolism function.
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: Author-stated SCF complex membership. Core complex context.
Reason: Core; consistent with the SCF(FBXO2) complex composition.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromoso... 		ACCEPT
Summary: Author-stated involvement in SCF-dependent proteasomal degradation. Core process.
Reason: Core biological process; consistent with FBXO2's SCF substrate-receptor function.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
GO:1904415 regulation of xenophagy
NAS
PMID:34515398
FBXO2/SCF ubiquitin ligase complex directs xenophagy through... 		KEEP AS NON CORE
Summary: FBXO2/SCF directs xenophagy against group A Streptococcus by recognizing GlcNAc side chains of the bacterial surface carbohydrate; FBXO2 knockout reduces ubiquitin accumulation and xenophagic degradation. A documented secondary (immune/autophagy) role of the lectin activity.
Reason: Experimentally supported secondary role extending the lectin/glycan-recognition function to bacterial glycans; distinct from the core ERAD function.
Supporting Evidence:
PMID:34515398
FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS
GO:0005737 cytoplasm
IDA
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 ... 		ACCEPT
Summary: Direct assay placing FBXO2 in the cytoplasm in the study of Skp1/CRM1-controlled F-box protein localization. Core localization.
Reason: IDA-supported cytoplasmic localization consistent with the documented site of action.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		ACCEPT
Summary: Reactome neddylation-pathway annotation of cytosolic localization for the CRL1/SCF context. Correct compartment.
Reason: Correct cytosolic localization; redundant with IDA/ISS evidence.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		ACCEPT
Summary: Reactome CRL1/neddylation cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant with other evidence.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		ACCEPT
Summary: Reactome (CAND1 binds cytosolic CRL) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		ACCEPT
Summary: Reactome (COMMD/CAND1) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		ACCEPT
Summary: Reactome (COP9 signalosome deneddylation) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		ACCEPT
Summary: Reactome (DCUN1D3 binds CRL1) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		ACCEPT
Summary: Reactome (Transfer of Ub from E2 to substrate) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		ACCEPT
Summary: Reactome (Release of E3 from polyubiquitinated substrate) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		ACCEPT
Summary: Reactome (Polyubiquitination of substrate) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		ACCEPT
Summary: Reactome (Interaction of E3 with substrate and E2-Ub) cytosolic localization annotation. Correct compartment.
Reason: Correct cytosolic localization; redundant.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
ISS
GO_REF:0000024 		ACCEPT
Summary: Curator sequence-similarity transfer of cytosolic localization. Correct compartment.
Reason: Correct cytosolic localization; redundant with IDA.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006516 glycoprotein catabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: Curator sequence-similarity transfer of glycoprotein catabolic process, the substrate-class-defining core process.
Reason: Core process; redundant with IBA.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
GO:0016567 protein ubiquitination
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Curator sequence-similarity transfer of protein ubiquitination, a parent of the specific SCF-dependent catabolism.
Reason: Correct but generic; specific SCF-dependent catabolism/ERAD annotations are preferred.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0019005 SCF ubiquitin ligase complex
ISS
GO_REF:0000024 		ACCEPT
Summary: Curator sequence-similarity transfer of SCF complex membership. Core complex context.
Reason: Core; redundant with IBA/IEA/NAS.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
ISS
GO_REF:0000024 		ACCEPT
Summary: Curator sequence-similarity transfer of SCF-dependent proteasomal catabolism. Core process.
Reason: Core biological process; redundant with IBA/IEA/NAS.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
GO:0004842 ubiquitin-protein transferase activity
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		KEEP AS NON CORE
Summary: Author statement from the F-box family identification paper attributing ubiquitin-protein transferase activity to the SCF complex containing this F-box protein. FBXO2 itself is the substrate receptor, not the catalytic subunit.
Reason: The catalytic transferase activity resides in the RBX1/CUL1 core, not the F-box receptor; this term over-attributes catalysis to FBXO2. Retained as non-core (contributes_to ligase activity is the more accurate framing).
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
GO:0006508 proteolysis
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		KEEP AS NON CORE
Summary: Author statement of involvement in proteolysis, a very general parent of the specific proteasomal/ERAD catabolism.
Reason: Correct but overly generic; specific SCF-dependent catabolism and ERAD annotations better capture the role.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
GO:0036211 protein modification process
TAS
PMID:10531035
Identification of a family of human F-box proteins. 		KEEP AS NON CORE
Summary: Author statement of involvement in protein modification, a very general parent of protein ubiquitination.
Reason: Correct but overly generic; the specific ubiquitination/SCF-catabolism annotations are preferred.
Supporting Evidence:
file:human/FBXO2/FBXO2-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.

Core Functions

Substrate-recognition subunit of the SCF(FBXO2) E3 ubiquitin ligase that uses its FBA lectin domain to bind N-linked high-mannose oligosaccharides on misfolded/denatured glycoproteins retrotranslocated from the ER, targeting them for ubiquitination and proteasomal degradation via ERAD.

Molecular Function:
carbohydrate binding
Directly Involved In:
ERAD pathway
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/FBXO2/FBXO2-uniprot.txt
    recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation

As the substrate receptor within SCF(FBXO2) (SKP1-CUL1-RBX1-FBXO2), contributes to SCF-dependent proteasomal ubiquitin-dependent catabolism of glycoprotein substrates, bridging glycan-bearing clients to the CUL1-RBX1 catalytic core via SKP1.

Molecular Function:
carbohydrate binding
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/FBXO2/FBXO2-uniprot.txt
    Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10531035
Identification of a family of human F-box proteins.
PMID:21378169
A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls the localization of a subset of F-box proteins.
  • Skp1 and CRM1/exportin-1 compete for binding to a subset of F-box proteins, controlling their subcellular localization; FBXO2 was assayed and localized to the cytoplasm.
PMID:25416956
A proteome-scale map of the human interactome network.
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complexome.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:34445249
The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
PMID:34515398
FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan.
  • FBXO2, a glycoprotein-specific SCF substrate receptor, recognizes GlcNAc side chains of the group A Streptococcus surface carbohydrate and promotes ubiquitin-mediated xenophagy; FBXO2 knockout decreases ubiquitin accumulation and xenophagic degradation of bacteria. FBXO2/FBXO6/FBXO27 are FBA-family lectins that bind high-mannose N-glycoproteins and act as ERAD ubiquitin-ligase subunits.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
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
file:human/FBXO2/FBXO2-deep-research-falcon.md
Falcon deep research report for human FBXO2
  • FBXO2/Fbs1 is the substrate-recognition adaptor of an SCF (SKP1-CUL1-RBX1-FBXO2) E3 ligase, not itself an enzyme; the F-box binds SKP1 and the C-terminal domain binds substrate while RBX1-associated E2 executes ubiquitin transfer.
    "FBXO2 is best understood as a **substrate-recognition adaptor** that confers specificity to an SCF E3 ligase complex (SKP1–CUL1–RBX1–FBXO2). In this architecture, the **F-box** binds **SKP1**, which bridges to **CUL1/RBX1**, while FBXO2's C-terminal region binds the substrate; ubiquitin transfer is executed by the RBX1-associated E2 enzyme."
  • FBXO2 recognizes a glycan-based degron, binding the innermost N-glycan core (Man3GlcNAc2) through a small hydrophobic pocket, preferring high-mannose N-glycans on denatured/misfolded glycoproteins.
    "it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible)."
  • Lectin-type F-box proteins such as FBXO2 act in the nucleocytoplasmic compartment on retrotranslocated ER glycoproteins as part of ERAD.
    "lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms."
  • Glycoprotein quality-control substrates cited for the Fbs1/Fbs2 pathway include integrin beta-1, TCRalpha, asialoglycoprotein receptor H2a, and CFTR-deltaF508.
    "Examples of glycoprotein targets/processes cited in the mechanistic literature include **integrin Ξ²1, TCRΞ±, asialoglycoprotein receptor H2a**, and **CFTRΞ”F508** as glycoproteins in the orbit of Fbs1/Fbs2-mediated quality control."
  • FBXO2 mediates clearance of damaged lysosomes (lysophagy) in CNS contexts; loss delays clearance and exacerbates neurodegeneration in a Niemann-Pick C model.
    "Fbxo2 functions as part of an SCF complex and **mediates clearance of damaged lysosomes** in CNS contexts. Loss of Fbxo2 **delayed clearance of damaged lysosomes** and reduced viability after lysosomal damage in mouse primary cortical cultures; in an NPC disease model, Fbxo2 deficiency **exacerbated neurodegeneration and reduced survival**."

Suggested Questions for Experts

Q: What is the endogenous high-mannose glycoprotein substrate repertoire of SCF(FBXO2) in different tissues, and how is substrate selection partitioned among the FBA paralogs FBXO2, FBXO6, and FBXO27?

Q: How are FBXO2's neuronal/synaptic roles (dendritic spine, synaptic protein catabolism) and its lysophagy/xenophagy functions mechanistically related to its core ERAD lectin activity, and do they use distinct substrate pools?

Suggested Experiments

Experiment: Glycan-array and ITC/SPR binding assays with purified FBXO2 FBA domain (wild type vs carbohydrate-binding-site mutants at residues 173, 210-212, 278-279) to quantify high-mannose vs GlcNAc specificity and map the binding determinants.

Experiment: Quantitative ubiquitinome/proteome profiling in FBXO2-knockout versus wild-type cells (neuronal and epithelial) under ER-stress and ERAD-substrate challenge to define the endogenous glycoprotein substrate set and assess redundancy with FBXO6/FBXO27.

Deep Research

Falcon

(FBXO2-deep-research-falcon.md)
Research report: Human **FBXO2** (UniProt **Q9UK22**) β€” functional annotation Falcon Edison Scientific Literature 26 citations 2 artifacts 2026-06-13T06:19:07.317266
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000017 The requested information can be found in Figures 1 and 2. Figure 1 provides detailed structural information for Fbs1: - Panel A il (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 FBXO2 (UniProt Q9UK22) β€” functional annotation

0) Mandatory identity verification (correct gene/protein)

Target identity: The body of evidence retrieved is consistent with human FBXO2 (also called Fbs1 in the lectin-type F-box literature) being a glycan-binding F-box protein that functions as the substrate-recognition subunit of an SCF (SKP1–CUL1–RBX1–F-box) E3 ubiquitin ligase. This matches the UniProt-provided description β€œF-box only protein 2” for Homo sapiens, and aligns with UniProt-listed domains (F-box plus a C-terminal sugar-binding/galactose-binding–like fold) because the literature describes an N-terminal F-box (SKP1-binding) and a C-terminal substrate-binding domain (SBD) that binds the innermost N-glycan core (Man3GlcNAc2). (suzuki2021foldingandquality pages 15-16, yoshida2019sugarrecognizingubiquitinligases pages 2-4)

1) Key concepts and definitions (current understanding)

1.1 FBXO2 as an SCF E3 ligase β€œadaptor” (not an enzyme)

FBXO2 is best understood as a substrate-recognition adaptor that confers specificity to an SCF E3 ligase complex (SKP1–CUL1–RBX1–FBXO2). In this architecture, the F-box binds SKP1, which bridges to CUL1/RBX1, while FBXO2’s C-terminal region binds the substrate; ubiquitin transfer is executed by the RBX1-associated E2 enzyme. (suzuki2021foldingandquality pages 15-16, yoshida2018cytosolicnglycanstriggers pages 5-6)

1.2 β€œSugar degron” recognition and glycan specificity

A central concept for FBXO2/Fbs1 is that it recognizes a glycan-based degradation signal (β€œsugar degron”): it binds the innermost N-glycan core (described as Man3GlcNAc2 / innermost GlcNAc2 moiety) using a small hydrophobic pocket in its SBD, with preference for high-mannose N-glycans and denatured/misfolded glycoproteins (where the core glycan becomes accessible). (yoshida2019sugarrecognizingubiquitinligases pages 2-4, yoshida2018cytosolicnglycanstriggers pages 5-6)

Visual evidence: Structural and schematic support for FBXO2/Fbs1 domain organization, SCF assembly, and Man3GlcNAc2 recognition pocket are shown in Yoshida et al. 2019 (Figures summarizing domain map/SCF model and glycan-binding pocket). (yoshida2019sugarrecognizingubiquitinligases media c9dd2277)

1.3 Relationship to ER protein quality control and ERAD

Although N-glycoproteins are produced in the ER/secretory pathway, lectin-type F-box proteins such as FBXO2 are described as operating in the nucleocytoplasmic compartment, where they can recognize retrotranslocated ER glycoproteins and promote their ubiquitination as part of ER-associated degradation (ERAD) and broader proteostasis mechanisms. (yoshida2019sugarrecognizingubiquitinligases pages 2-4, yoshida2019sugarrecognizingubiquitinligases pages 4-5)

2) Molecular function, pathways, and cellular localization

2.1 Mechanistic role in glycoprotein quality control (ERAD substrates)

Authoritative reviews describe SCF(Fbs1/FBXO2) and SCF(Fbs2) as binding the innermost N-glycan core and acting on ERAD substrates. Examples of glycoprotein targets/processes cited in the mechanistic literature include integrin Ξ²1, TCRΞ±, asialoglycoprotein receptor H2a, and CFTRΞ”F508 as glycoproteins in the orbit of Fbs1/Fbs2-mediated quality control. (yoshida2019sugarrecognizingubiquitinligases pages 4-5)

2.2 Neuronal proteostasis and the APP/BACE1 axis (Alzheimer’s-relevant)

Reviews summarizing primary work report that FBXO2/Fbs1 can modulate the amyloid pathway by promoting degradation of BACE1 (Ξ²-secretase) and by regulating APP levels/processing; FBXO2 is described as neuron/brain enriched in these accounts. (suzuki2021foldingandquality pages 15-16, yoshida2019sugarrecognizingubiquitinligases pages 5-6)

A 2024 preprint further leverages this biology to build a human iPSC-derived cortical neuron model in which early downregulation of FBXO2 is reported to lead to AΞ² aggregation, tau hyperphosphorylation, and neuronal network impairment, positioning FBXO2 reduction as a potential driver of sporadic AD-like phenotypes in vitro (note: preprint, not yet peer reviewed). URL and date: bioRxiv (Sep 2024) https://doi.org/10.1101/2024.09.01.610673. (xue2024skp2mediatedfbxo2proteasomal pages 1-5)

2.3 Lysosome quality control/lysophagy in CNS (Niemann–Pick C context)

A peer-reviewed primary study (JCI Insight, Oct 2020; https://doi.org/10.1172/jci.insight.136676) reports that Fbxo2 functions as part of an SCF complex and mediates clearance of damaged lysosomes in CNS contexts. Loss of Fbxo2 delayed clearance of damaged lysosomes and reduced viability after lysosomal damage in mouse primary cortical cultures; in an NPC disease model, Fbxo2 deficiency exacerbated neurodegeneration and reduced survival. (liu2020fbxo2mediatesclearance pages 1-2)

2.4 Subcellular localization

Direct localization evidence in human cancer cells is available from a 2024 study in papillary thyroid carcinoma (PTC), where immunofluorescence localized FBXO2 mainly to the cytoplasm of PTC cells. (Scientific Reports, Sep 2024; https://doi.org/10.1038/s41598-024-73455-z). (guo2024fbxo2promotesthe pages 3-5)

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

3.1 Glioblastoma recurrence and tumor–microenvironment interactions (2023)

A Neuro-Oncology study (Jul 2023; https://doi.org/10.1093/neuonc/noac169) used SWATH-MS proteomics across paired primary and recurrent glioblastomas and identified FBXO2 as consistently upregulated at recurrence, validated by immunohistochemistry. Functionally, FBXO2 knockout in human glioma cells conferred a survival benefit in orthotopic xenograft mouse models and reduced invasive growth in organotypic brain slice cultures, consistent with a protumorigenic role in this context. FBXO2 expression was reported enriched in the tumor infiltration zone, and FBXO2-positive cancer cells associated with synaptic signaling programs. (buehler2023quantitativeproteomiclandscapes pages 1-2)

3.2 Papillary thyroid carcinoma: FBXO2 targets p53 for degradation (2024, peer reviewed)

A Scientific Reports paper (Sep 2024; https://doi.org/10.1038/s41598-024-73455-z) reports that FBXO2 is overexpressed in PTC and that FBXO2 binds p53 and promotes p53 ubiquitination and degradation. Experimentally, the study used co-immunoprecipitation/GST pulldown and ubiquitination assays (MG132-treated cells; p53 IP; ubiquitin detection) and showed that FBXO2 knockdown reduced proliferation and increased apoptosis, with xenograft tumor growth suppressed upon FBXO2 targeting. Clinically, FBXO2 expression correlated with tumor size and metastatic/invasive features (as reported by the authors). (guo2024fbxo2promotesthe pages 7-8, guo2024fbxo2promotesthe pages 2-3)

3.3 Hepatocellular carcinoma: SKP2–FBXO2–Hsp47 axis (2024, preprint)

A bioRxiv preprint (Mar 2024; https://doi.org/10.1101/2024.03.28.586926) proposes FBXO2 acts as a tumor suppressor in HCC by binding and promoting ubiquitination/proteasomal degradation of Hsp47/SERPINH1. A key quantitative datapoint reported is that FBXO2 protein was frequently downregulated in HCC tissues by IHC: 149/258 tumors classified as low FBXO2 (P<0.001). The authors also describe a regulatory mechanism in which DNA-PKcs-mediated phosphorylation at S17 enables SKP2-mediated ubiquitination (at K79) and proteasomal degradation of FBXO2. (xue2024skp2mediatedfbxo2proteasomal pages 5-8, xue2024skp2mediatedfbxo2proteasomal pages 11-14)

3.4 High-grade serous ovarian cancer (HGSOC): chemoresistance biomarker and functional support (2024)

A Heliyon study (Apr 2024; https://doi.org/10.1016/j.heliyon.2024.e28490) integrated scRNA-seq and bulk RNA-seq and identified FBXO2 as a candidate biomarker associated with chemoresistance. The authors describe FBXO2 as an ER-associated F-box component implicated in protein processing in the ER, report higher FBXO2 expression in malignant epithelial cells, and present functional evidence that silencing FBXO2 lowered cisplatin IC50 in A2780 and SKOV3 ovarian cancer cell lines. The study further reports that high FBXO2 associates with worse overall and disease-free survival in their computational analyses. (lai2024integratedanalysisof pages 10-11)

4) Current applications and real-world implementations

4.1 Biomarker and prognostic use cases

Recent studies position FBXO2 as a potential biomarker or stratification variable in multiple cancers:
- Glioblastoma: FBXO2 abundance increases at recurrence and correlates with infiltrative-zone programs; FBXO2 genetic loss reduces tumor aggressiveness in models, making it a candidate dependency/biomarker for recurrence biology. (buehler2023quantitativeproteomiclandscapes pages 1-2)
- HGSOC: FBXO2 is proposed as a biomarker for chemoresistance and prognosis, with supporting in vitro cisplatin-sensitization upon knockdown. (lai2024integratedanalysisof pages 10-11)
- PTC: FBXO2 expression correlates with aggressive clinicopathologic features and mechanistically impacts p53 stability, suggesting diagnostic/prognostic relevance. (guo2024fbxo2promotesthe pages 7-8)

4.2 Therapeutic implications (expert analysis)

From an E3-ligase biology perspective, FBXO2 is not a catalytic enzyme but a specificity factor; thus, interventions could conceptually target (i) its substrate-binding interface (glycan pocket / substrate docking), (ii) its SCF assembly (F-box–SKP1 interaction), or (iii) upstream regulatory nodes that tune FBXO2 abundance (e.g., the SKP2 axis proposed in HCC). The 2019 mechanistic synthesis emphasizes that identifying physiological substrates and complex components is essential for understanding pathophysiological rolesβ€”an argument that remains salient given context-dependent oncogenic vs tumor-suppressive roles across cancers. (yoshida2019sugarrecognizingubiquitinligases pages 5-6, xue2024skp2mediatedfbxo2proteasomal pages 11-14)

5) Expert opinions and authoritative synthesis

Mechanistic reviews by Yoshida/Tanaka and colleagues provide a coherent expert framework: cytosolic exposure of N-glycans (from ER retrotranslocation or membrane damage) is interpreted as a signal of unwanted proteins/organelles, and lectin-type SCF complexes (including SCF(Fbs1/FBXO2)) translate this signal into ubiquitination and degradation (proteasome and, in related paralogs, autophagy). These reviews highlight structural determinants of glycan recognition and caution that detailed physiological substrate mapping is still needed to understand tissue- and disease-specific outcomes. (yoshida2019sugarrecognizingubiquitinligases pages 2-4, yoshida2018cytosolicnglycanstriggers pages 5-6)

6) Summary of substrates/processes and evidence strength

A concise cross-study summary is provided in the table below.

FBXO2/Fbs1 role Key substrate(s) / process Main evidence type Recent source(s) (2023–2024) Foundational source(s) Year(s) DOI / URL Citation
SCF-type F-box substrate receptor for glycoprotein quality control; binds innermost Man3GlcNAc2 N-glycan core via substrate-binding domain after SKP1 association through the F-box domain Recognition of misfolded/high-mannose glycoproteins in ERAD; broad lectin-like glycan sensing rather than classical enzyme catalysis Structural biology, SCF complex modeling, glycan-binding biochemistry, review synthesis β€” Yoshida et al., Front Physiol (2019); Suzuki & Fujihira, Comprehensive Glycoscience (2021) 2019, 2021 https://doi.org/10.3389/fphys.2019.00104 ; https://doi.org/10.1016/B978-0-12-409547-2.14947-9 (yoshida2019sugarrecognizingubiquitinligases pages 2-4, suzuki2021foldingandquality pages 15-16, yoshida2019sugarrecognizingubiquitinligases media c9dd2277)
Glycan-directed ER-associated degradation adaptor in the cytosol/nucleocytoplasm ERAD substrates cited for Fbs1/Fbs2 pathway include CFTRΞ”F508, TCRΞ±, integrin Ξ²1, asialoglycoprotein receptor H2a Review of primary ERAD studies; substrate lists from prior cell-based and biochemical work HGSOC biomarker study links FBXO2 to ER protein processing and chemoresistance-related ER pathways Yoshida et al., Front Physiol (2019); Yoshida & Tanaka, BioEssays (2018) 2018, 2019, 2024 https://doi.org/10.3389/fphys.2019.00104 ; https://doi.org/10.1002/bies.201700215 ; https://doi.org/10.1016/j.heliyon.2024.e28490 (yoshida2019sugarrecognizingubiquitinligases pages 4-5, yoshida2018cytosolicnglycanstriggers pages 5-6, lai2024integratedanalysisof pages 10-11)
Neuron-enriched SCF adaptor regulating APP pathway glycoproteins APP is a reported FBXO2 substrate; FBXO2 also reduces BACE1 levels, lowering amyloidogenic processing In vitro/in vivo substrate studies, knockout mouse/neuron experiments, disease-focused reviews 2024 preprint: FBXO2 downregulation in human iPSC-derived neurons induces AΞ² aggregation and tau hyperphosphorylation Atkin et al., J Biol Chem (2014); Suzuki & Fujihira (2021); Yoshida et al. (2019) 2014, 2019, 2021, 2024 https://doi.org/10.1074/jbc.M113.515056 ; https://doi.org/10.3389/fphys.2019.00104 ; https://doi.org/10.1016/B978-0-12-409547-2.14947-9 ; https://doi.org/10.1101/2024.09.01.610673 (suzuki2021foldingandquality pages 15-16, yoshida2019sugarrecognizingubiquitinligases pages 4-5, yoshida2019sugarrecognizingubiquitinligases pages 5-6)
Metabolic regulator when induced in liver; still acting through ubiquitin-ligase substrate recognition rather than catalysis Insulin receptor ubiquitination reported in obese liver context, disrupting glucose homeostasis Review synthesis of prior mechanistic studies β€” Yoshida & Tanaka, BioEssays (2018) 2018 https://doi.org/10.1002/bies.201700215 (yoshida2018cytosolicnglycanstriggers pages 5-6)
CNS lysosomal quality-control factor; glycan-binding F-box protein in an SCF complex Damaged lysosome clearance / lysophagy in CNS; loss delays damaged lysosome clearance and reduces viability after lysosomal injury Mouse primary cortical culture assays, NPC human fibroblast sensitivity assays, knockout disease model β€” Liu et al., JCI Insight (2020) 2020 https://doi.org/10.1172/jci.insight.136676 (liu2020fbxo2mediatesclearance pages 1-2)
Recurrent glioblastoma-associated FBXO2 program, likely via tumor–microenvironment interactions Increased FBXO2 abundance in recurrent glioblastoma; enriched in tumor infiltration zone; associated with synaptic signaling processes SWATH-MS proteomics, immunohistochemistry, CRISPR/KO, orthotopic xenografts, organotypic brain slices Buehler et al., Neuro-Oncology (2023) β€” 2023 https://doi.org/10.1093/neuonc/noac169 (buehler2023quantitativeproteomiclandscapes pages 1-2)
Oncogenic FBXO2 in papillary thyroid carcinoma acting through ubiquitin-mediated substrate turnover p53 direct binding, ubiquitination, and degradation; FBXO2 overexpression correlates with tumor size, lymph-node metastasis, and invasion; mainly cytoplasmic localization in PTC cells Co-IP, GST pulldown, in vivo ubiquitination assay, IF/IHC, xenografts, proliferation/apoptosis assays Guo et al., Scientific Reports (2024) β€” 2024 https://doi.org/10.1038/s41598-024-73455-z (guo2024fbxo2promotesthe pages 7-8, guo2024fbxo2promotesthe pages 2-3, guo2024fbxo2promotesthe pages 3-5)
Tumor-suppressive FBXO2 in hepatocellular carcinoma through degradation of a pro-fibrotic chaperone Hsp47/SERPINH1 ubiquitination and proteasomal degradation; FBXO2 protein low in 149/258 HCCs; low FBXO2 associated with advanced stage and worse median survival Human tumor IHC, ubiquitination and half-life studies, phospho-regulation analysis, hepatocyte-specific knockout mice, metastasis assays Xue et al., bioRxiv (2024) β€” 2024 https://doi.org/10.1101/2024.03.28.586926 (xue2024skp2mediatedfbxo2proteasomal pages 5-8, xue2024skp2mediatedfbxo2proteasomal pages 1-5, xue2024skp2mediatedfbxo2proteasomal pages 11-14)
Candidate biomarker/therapeutic target in ovarian chemoresistance with ER-processing links High FBXO2 associated with worse OS/DFS; FBXO2 knockdown lowers cisplatin IC50 in A2780 and SKOV3 cells scRNA-seq + bulk RNA-seq integration, survival analysis, cisplatin-response assays, knockdown Lai et al., Heliyon (2024) β€” 2024 https://doi.org/10.1016/j.heliyon.2024.e28490 (lai2024integratedanalysisof pages 10-11)

Table: This table summarizes the best-supported molecular roles, substrates/processes, and evidence types for human FBXO2/Fbs1, contrasting recent 2023–2024 disease studies with foundational mechanistic literature on SCF assembly and glycan recognition.

7) Disease/target association landscape (database evidence)

Open Targets lists disease associations for FBXO2 including hepatocellular carcinoma, papillary thyroid carcinoma, hearing loss/deafness, and neurodegenerative disease, with underlying evidence including recent literature links (via PubMed IDs) and functional genomics screens. This supports that FBXO2 is repeatedly implicated across cancer and neurological phenotypes, though the mechanistic directionality is context dependent. (OpenTargets Search: -FBXO2)

References (URLs and publication dates)

  • Yoshida Y, Mizushima T, Tanaka K. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Frontiers in Physiology. Feb 2019. https://doi.org/10.3389/fphys.2019.00104 (yoshida2019sugarrecognizingubiquitinligases pages 2-4)
  • Yoshida Y, Tanaka K. Cytosolic N-Glycans: Triggers for Ubiquitination… BioEssays. Feb 2018. https://doi.org/10.1002/bies.201700215 (yoshida2018cytosolicnglycanstriggers pages 5-6)
  • Liu EA et al. Fbxo2 mediates clearance of damaged lysosomes… JCI Insight. Oct 2020. https://doi.org/10.1172/jci.insight.136676 (liu2020fbxo2mediatesclearance pages 1-2)
  • Buehler M et al. Quantitative proteomic landscapes of primary and recurrent glioblastoma… Neuro-Oncology. Jul 2023. https://doi.org/10.1093/neuonc/noac169 (buehler2023quantitativeproteomiclandscapes pages 1-2)
  • Guo W et al. FBXO2 promotes the progression of papillary thyroid carcinoma through the p53 pathway. Scientific Reports. Sep 2024. https://doi.org/10.1038/s41598-024-73455-z (guo2024fbxo2promotesthe pages 7-8)
  • Lai W et al. Integrated analysis… identifies FBXO2 as a candidate biomarker associated with chemoresistance in HGSOC. Heliyon. Apr 2024. https://doi.org/10.1016/j.heliyon.2024.e28490 (lai2024integratedanalysisof pages 10-11)
  • Xue C et al. SKP2-mediated FBXO2 proteasomal degradation drives HCC progression via stabilizing Hsp47. bioRxiv. Mar 2024 (preprint). https://doi.org/10.1101/2024.03.28.586926 (xue2024skp2mediatedfbxo2proteasomal pages 5-8)

Note on evidence quality: Two key 2024 items are preprints (bioRxiv) and should be interpreted as provisional until peer-reviewed; core mechanistic aspects of FBXO2 glycan recognition and SCF adaptor function are supported by peer-reviewed reviews and established structural work summarized therein. (yoshida2019sugarrecognizingubiquitinligases pages 2-4, yoshida2018cytosolicnglycanstriggers pages 5-6)

References

  1. (suzuki2021foldingandquality pages 15-16): Tadashi Suzuki and Haruhiko Fujihira. Folding and quality control of glycoproteins. Comprehensive Glycoscience, pages 1-28, Dec 2021. URL: https://doi.org/10.1016/b978-0-12-409547-2.14947-9, doi:10.1016/b978-0-12-409547-2.14947-9. This article has 12 citations.

  2. (yoshida2019sugarrecognizingubiquitinligases pages 2-4): Yukiko Yoshida, Tsunehiro Mizushima, and Keiji Tanaka. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Frontiers in Physiology, Feb 2019. URL: https://doi.org/10.3389/fphys.2019.00104, doi:10.3389/fphys.2019.00104. This article has 31 citations.

  3. (yoshida2018cytosolicnglycanstriggers pages 5-6): Yukiko Yoshida and Keiji Tanaka. Cytosolic n-glycans: triggers for ubiquitination directing proteasomal and autophagic degradation: molecular systems for monitoring cytosolic n-glycans as signals for unwanted proteins and organelles. BioEssays : news and reviews in molecular, cellular and developmental biology, Feb 2018. URL: https://doi.org/10.1002/bies.201700215, doi:10.1002/bies.201700215. This article has 19 citations.

  4. (yoshida2019sugarrecognizingubiquitinligases media c9dd2277): Yukiko Yoshida, Tsunehiro Mizushima, and Keiji Tanaka. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Frontiers in Physiology, Feb 2019. URL: https://doi.org/10.3389/fphys.2019.00104, doi:10.3389/fphys.2019.00104. This article has 31 citations.

  5. (yoshida2019sugarrecognizingubiquitinligases pages 4-5): Yukiko Yoshida, Tsunehiro Mizushima, and Keiji Tanaka. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Frontiers in Physiology, Feb 2019. URL: https://doi.org/10.3389/fphys.2019.00104, doi:10.3389/fphys.2019.00104. This article has 31 citations.

  6. (yoshida2019sugarrecognizingubiquitinligases pages 5-6): Yukiko Yoshida, Tsunehiro Mizushima, and Keiji Tanaka. Sugar-recognizing ubiquitin ligases: action mechanisms and physiology. Frontiers in Physiology, Feb 2019. URL: https://doi.org/10.3389/fphys.2019.00104, doi:10.3389/fphys.2019.00104. This article has 31 citations.

  7. (xue2024skp2mediatedfbxo2proteasomal pages 1-5): Cailin Xue, Fei Yang, Guojian Bao, Jiawu Yan, Rao Fu, Minglu Zhang, Jialu Ding, Jiale Feng, Jianbo Han, Xihu Qin, Hua Su, and Beicheng Sun. Skp2-mediated fbxo2 proteasomal degradation drives hepatocellular carcinoma progression via stabilizing hsp47. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.28.586926, doi:10.1101/2024.03.28.586926. This article has 0 citations.

  8. (liu2020fbxo2mediatesclearance pages 1-2): Elaine A. Liu, Mark L. Schultz, Chisaki Mochida, Chan Chung, Henry L. Paulson, and Andrew P. Lieberman. Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the niemann-pick c brain. JCI Insight, Oct 2020. URL: https://doi.org/10.1172/jci.insight.136676, doi:10.1172/jci.insight.136676. This article has 53 citations and is from a domain leading peer-reviewed journal.

  9. (guo2024fbxo2promotesthe pages 3-5): Wenke Guo, Yaoqiang Ren, and Xinguang Qiu. Fbxo2 promotes the progression of papillary thyroid carcinoma through the p53 pathway. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-73455-z, doi:10.1038/s41598-024-73455-z. This article has 9 citations and is from a peer-reviewed journal.

  10. (buehler2023quantitativeproteomiclandscapes pages 1-2): Marcel Buehler, Xiao Yi, Weigang Ge, Peter Blattmann, Elisabeth Rushing, Guido Reifenberger, Joerg Felsberg, Charles Yeh, Jacob E Corn, Luca Regli, Junyi Zhang, Ann Cloos, Vidhya M Ravi, Benedikt Wiestler, Dieter Henrik Heiland, Ruedi Aebersold, Michael Weller, Tiannan Guo, and Tobias Weiss. Quantitative proteomic landscapes of primary and recurrent glioblastoma reveal a protumorigeneic role for fbxo2-dependent glioma-microenvironment interactions. Neuro-oncology, 25:290-302, Jul 2023. URL: https://doi.org/10.1093/neuonc/noac169, doi:10.1093/neuonc/noac169. This article has 32 citations and is from a domain leading peer-reviewed journal.

  11. (guo2024fbxo2promotesthe pages 7-8): Wenke Guo, Yaoqiang Ren, and Xinguang Qiu. Fbxo2 promotes the progression of papillary thyroid carcinoma through the p53 pathway. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-73455-z, doi:10.1038/s41598-024-73455-z. This article has 9 citations and is from a peer-reviewed journal.

  12. (guo2024fbxo2promotesthe pages 2-3): Wenke Guo, Yaoqiang Ren, and Xinguang Qiu. Fbxo2 promotes the progression of papillary thyroid carcinoma through the p53 pathway. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-73455-z, doi:10.1038/s41598-024-73455-z. This article has 9 citations and is from a peer-reviewed journal.

  13. (xue2024skp2mediatedfbxo2proteasomal pages 5-8): Cailin Xue, Fei Yang, Guojian Bao, Jiawu Yan, Rao Fu, Minglu Zhang, Jialu Ding, Jiale Feng, Jianbo Han, Xihu Qin, Hua Su, and Beicheng Sun. Skp2-mediated fbxo2 proteasomal degradation drives hepatocellular carcinoma progression via stabilizing hsp47. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.28.586926, doi:10.1101/2024.03.28.586926. This article has 0 citations.

  14. (xue2024skp2mediatedfbxo2proteasomal pages 11-14): Cailin Xue, Fei Yang, Guojian Bao, Jiawu Yan, Rao Fu, Minglu Zhang, Jialu Ding, Jiale Feng, Jianbo Han, Xihu Qin, Hua Su, and Beicheng Sun. Skp2-mediated fbxo2 proteasomal degradation drives hepatocellular carcinoma progression via stabilizing hsp47. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.28.586926, doi:10.1101/2024.03.28.586926. This article has 0 citations.

  15. (lai2024integratedanalysisof pages 10-11): Wenwen Lai, Ruixiang Xie, Chen Chen, Weiming Lou, Haiyan Yang, Libin Deng, Quqin Lu, and Xiaoli Tang. Integrated analysis of scrna-seq and bulk rna-seq identifies fbxo2 as a candidate biomarker associated with chemoresistance in hgsoc. Apr 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e28490, doi:10.1016/j.heliyon.2024.e28490. This article has 8 citations.

  16. (OpenTargets Search: -FBXO2): Open Targets Query (-FBXO2, 35 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Citations

  1. yoshida2019sugarrecognizingubiquitinligases pages 4-5
  2. buehler2023quantitativeproteomiclandscapes pages 1-2
  3. lai2024integratedanalysisof pages 10-11
  4. yoshida2018cytosolicnglycanstriggers pages 5-6
  5. yoshida2019sugarrecognizingubiquitinligases pages 2-4
  6. suzuki2021foldingandquality pages 15-16
  7. yoshida2019sugarrecognizingubiquitinligases pages 5-6
  8. https://doi.org/10.1101/2024.09.01.610673.
  9. https://doi.org/10.1172/jci.insight.136676
  10. https://doi.org/10.1038/s41598-024-73455-z
  11. https://doi.org/10.1093/neuonc/noac169
  12. https://doi.org/10.1101/2024.03.28.586926
  13. https://doi.org/10.1016/j.heliyon.2024.e28490
  14. https://doi.org/10.3389/fphys.2019.00104
  15. https://doi.org/10.1016/B978-0-12-409547-2.14947-9
  16. https://doi.org/10.1002/bies.201700215
  17. https://doi.org/10.1074/jbc.M113.515056
  18. https://doi.org/10.1101/2024.09.01.610673
  19. https://doi.org/10.1016/b978-0-12-409547-2.14947-9,
  20. https://doi.org/10.3389/fphys.2019.00104,
  21. https://doi.org/10.1002/bies.201700215,
  22. https://doi.org/10.1101/2024.03.28.586926,
  23. https://doi.org/10.1172/jci.insight.136676,
  24. https://doi.org/10.1038/s41598-024-73455-z,
  25. https://doi.org/10.1093/neuonc/noac169,
  26. https://doi.org/10.1016/j.heliyon.2024.e28490,

πŸ“š Additional Documentation

Pn Notes

(FBXO2-pn-notes.md)

FBXO2 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UK22
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: FBXO2 (FBG1/FBX2/NFB42) is a 296-residue cytoplasmic F-box protein that serves as the substrate-recognition subunit of a Skp1-Cul1-F-box (SCF) E3 ubiquitin-protein ligase complex. It contains an N-terminal F-box domain (residues 44-91) that binds SKP1, bridging the receptor to the CUL1-RBX1 catalytic core, and a C-terminal F-box-associated (FBA) sugar-binding domain (residues 113-296) that folds as a galactose-binding-domain-like lectin and binds N-linked high-mannose oligosaccharides. The FBA domain recognizes the innermost N-glycan core (Man3GlcNAc2 / the chitobiose-proximal GlcNAc2 moiety) through a small hydrophobic pocket, a "sugar degron" that becomes exposed when a glycoprotein is misfolded, denatured, or aberrantly retrotranslocated to the cytosol. Through this lectin activity FBXO2 recognizes N-glycans on misfolded/denatured glycoproteins that have been retrotranslocated from the endoplasmic reticulum into the cytosol, recruiting them to the SCF complex for polyubiquitination and proteasomal degradation as part of the ER-associated degradation (ERAD) pathway, thereby preventing the accumulation of cytosolic aggregates of unfolded glycoproteins. Reported glycoprotein clients in the Fbs1/Fbs2 quality-control orbit include pre-integrin beta-1, the T-cell receptor alpha chain, the asialoglycoprotein receptor subunit, and the disease variant CFTR-deltaF508; in neurons FBXO2 additionally turns over APP and BACE1 to limit amyloidogenic processing. FBXO2 is most highly expressed in the nervous system, where it has additional roles in synaptic protein turnover and in clearance of damaged glycan-bearing membranes (lysophagy) and intracellular bacteria (xenophagy), recognizing GlcNAc/high- mannose glycans on these targets. The protein is a peripheral cytoplasmic-side membrane protein and is itself a glycoprotein-specific lectin, not a glycosidase.
  • Existing/core annotation action counts: ACCEPT: 28; KEEP_AS_NON_CORE: 15

PN Consistency Summary

  • Consistency: Consistent on substance; one nuance. Falcon DR, review YAML, and the PN FBA F-box receptor placement converge on FBXO2 as a lectin-type SCF substrate receptor for glycoprotein-ERAD. SPECIAL CASE confirmed: FBA = real carbohydrate-binding MF (GO:0030246, verified real), recognizing the innermost Man3GlcNAc2 N-glycan core on misfolded glycoproteins.
  • PN story / NEW pressure: PN projects the generic GO:1990756 adaptor term (new_to_goa). The review's chosen core MF is the more informative, substrate-class-specific GO:0030246 carbohydrate binding (ACCEPT, already in GOA via IEA/keyword Lectin) β€” a genuine lectin activity beyond bare adaptor binding. Review also correctly demotes catalytic TAS GO:0004842/GO:0061630 to non-core/contributes_to. Conclude: PN adaptor term is captured at family level but the gene's distinctive MF (carbohydrate binding) is already in GOA and is the better core β€” no new term needed; FBXO2 lectin function over-rides the generic adaptor projection.
  • Evidence alignment: PN reference only "15340381 / rev"; review draws on PMID:10531035 (family), PMID:18203720-equivalent FBA-lectin work (cited heavily for FBXO6), PMID:34515398 (xenophagy/glycan, HIGH/VERIFIED), PMID:34445249, plus Falcon DR (Yoshida/Suzuki reviews, lysophagy). Strong gene-specific evidence; PN family review is a subset.
  • Verdict: Consistent; core MF correctly GO:0030246 (lectin, in GOA) rather than the generic PN adaptor term. No over-reach; secondary xenophagy/lysophagy/synaptic roles kept non-core.

Full Consistency Review

  • UniProt: Q9UK22 (FBXO2/FBG1/Fbs1) Β· batch: proteostasis-batch-2026-06-13 (Falcon DR) Β· review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|FBA ; PN-node mapping: group Cul1 substrate receptor=mapped/ok_for_propagationβ†’GO:1990756; F-box/FBA subtype+type=no_mapping; class=context_only/too_broadβ†’GO:0061630.
  • Consistency: Consistent on substance; one nuance. Falcon DR, review YAML, and the PN FBA F-box receptor placement converge on FBXO2 as a lectin-type SCF substrate receptor for glycoprotein-ERAD. SPECIAL CASE confirmed: FBA = real carbohydrate-binding MF (GO:0030246, verified real), recognizing the innermost Man3GlcNAc2 N-glycan core on misfolded glycoproteins.
  • PN story / NEW pressure: PN projects the generic GO:1990756 adaptor term (new_to_goa). The review's chosen core MF is the more informative, substrate-class-specific GO:0030246 carbohydrate binding (ACCEPT, already in GOA via IEA/keyword Lectin) β€” a genuine lectin activity beyond bare adaptor binding. Review also correctly demotes catalytic TAS GO:0004842/GO:0061630 to non-core/contributes_to. Conclude: PN adaptor term is captured at family level but the gene's distinctive MF (carbohydrate binding) is already in GOA and is the better core β€” no new term needed; FBXO2 lectin function over-rides the generic adaptor projection.
  • Mapping strategy: Gene refines, does not change, the node. The GO:1990756 group projection is the lowest-common-denominator F-box MF; for the FBA lectin subfamily the more specific GO:0030246 is preferable and already present, so the projection is not wrong but is broader than the gene's best MF. Consider noting FBA-lectin subfamilies carry carbohydrate binding as the distinguishing MF.
  • Evidence alignment: PN reference only "15340381 / rev"; review draws on PMID:10531035 (family), PMID:18203720-equivalent FBA-lectin work (cited heavily for FBXO6), PMID:34515398 (xenophagy/glycan, HIGH/VERIFIED), PMID:34445249, plus Falcon DR (Yoshida/Suzuki reviews, lysophagy). Strong gene-specific evidence; PN family review is a subset.
  • Verdict: Consistent; core MF correctly GO:0030246 (lectin, in GOA) rather than the generic PN adaptor term. No over-reach; secondary xenophagy/lysophagy/synaptic roles kept non-core.
  • Recommended edits: none to FBXO2-ai-review.yaml. [MAP] Optionally annotate FBA-lectin F-box subfamily nodes so carbohydrate binding (GO:0030246) is recognized as their distinguishing MF alongside the generic GO:1990756.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXO2/FBXO2-ai-review.yaml
  • PN workbook rows: 1

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

  • UniProt: Q9UK22
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR007397
  • 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|FBA
      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.

πŸ“„ View Raw YAML

 
id: Q9UK22
gene_symbol: FBXO2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO2 (FBG1/FBX2/NFB42) is a 296-residue cytoplasmic F-box protein that serves
  as the substrate-recognition subunit of a Skp1-Cul1-F-box (SCF) E3
  ubiquitin-protein ligase complex. It contains an N-terminal F-box domain
  (residues 44-91) that binds SKP1, bridging the receptor to the CUL1-RBX1
  catalytic core, and a C-terminal F-box-associated (FBA) sugar-binding domain
  (residues 113-296) that folds as a galactose-binding-domain-like lectin and
  binds N-linked high-mannose oligosaccharides. The FBA domain recognizes the
  innermost N-glycan core (Man3GlcNAc2 / the chitobiose-proximal GlcNAc2 moiety)
  through a small hydrophobic pocket, a "sugar degron" that becomes exposed when
  a glycoprotein is misfolded, denatured, or aberrantly retrotranslocated to the
  cytosol. Through this lectin activity FBXO2 recognizes N-glycans on
  misfolded/denatured glycoproteins that have been retrotranslocated from the
  endoplasmic reticulum into the cytosol, recruiting them to the SCF complex for
  polyubiquitination and proteasomal degradation as part of the ER-associated
  degradation (ERAD) pathway, thereby preventing the accumulation of cytosolic
  aggregates of unfolded glycoproteins. Reported glycoprotein clients in the
  Fbs1/Fbs2 quality-control orbit include pre-integrin beta-1, the T-cell
  receptor alpha chain, the asialoglycoprotein receptor subunit, and the disease
  variant CFTR-deltaF508; in neurons FBXO2 additionally turns over APP and BACE1
  to limit amyloidogenic processing. FBXO2 is most
  highly expressed in the nervous system, where it has additional roles in
  synaptic protein turnover and in clearance of damaged glycan-bearing membranes
  (lysophagy) and intracellular bacteria (xenophagy), recognizing GlcNAc/high-
  mannose glycans on these targets. The protein is a peripheral cytoplasmic-side
  membrane protein and is itself a glycoprotein-specific lectin, not a
  glycosidase.
existing_annotations:
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in ER-associated degradation, a core biological process for the FBA/lectin F-box family.
    action: ACCEPT
    reason: Core biological process; FBXO2 recognizes N-glycans on retrotranslocated misfolded glycoproteins and targets them for ERAD, supported by UniProt and the founding literature. The Falcon deep-research synthesis reinforces the mechanism (recognition of the innermost N-glycan core after ER retrotranslocation) and adds named ERAD clients.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
    - reference_id: file:human/FBXO2/FBXO2-deep-research-falcon.md
      supporting_text: lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of cytoplasmic site of action, consistent with FBXO2 acting on retrotranslocated cytosolic glycoproteins.
    action: ACCEPT
    reason: FBXO2 is a cytoplasmic protein that acts on the cytosolic side; supported by UniProt and IDA evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006516
    label: glycoprotein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in glycoprotein catabolism, the substrate-class-defining process for this lectin F-box subfamily.
    action: ACCEPT
    reason: Core process; FBXO2 directs ubiquitin-dependent degradation of N-glycosylated substrates recognized via its FBA lectin domain.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of FBXO2 as part of the SCF complex, its core complex context as a substrate receptor.
    action: ACCEPT
    reason: Core; FBXO2 is the substrate-recognition subunit of SCF(FBXO2) (CUL1, RBX1, SKP1, FBXO2).
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO2).
    action: ACCEPT
    reason: Core biological process; SCF(FBXO2) mediates ubiquitination and proteasomal degradation of its glycoprotein substrates.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic assignment of ubiquitin ligase activity with the contributes_to qualifier, reflecting FBXO2's role as a non-catalytic receptor subunit within the SCF ligase whose catalytic activity resides in RBX1.
    action: ACCEPT
    reason: Appropriate with contributes_to; FBXO2 is the substrate-recognition subunit and does not itself carry the catalytic RING activity (RBX1), but contributes to the complex's ligase function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally and curator-supported cytoplasmic location.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA and UniProt.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: High-throughput interactome interaction. Bare protein binding is uninformative per curation guidelines.
    action: KEEP_AS_NON_CORE
    reason: Records a real screen-derived interaction but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: Interaction captured in a Polycomb complexome map. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; O15212: PFDN6'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput cell-map interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'Q9UK22; P63208: SKP1'
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Ortholog-based electronic transfer of amyloid-beta binding. FBXO2 has been reported to bind/regulate APP-derived species, but this is a context-specific neuronal activity rather than the core lectin/ERAD function.
    action: KEEP_AS_NON_CORE
    reason: Plausible secondary neuronal activity (FBXO2 regulates APP/amyloid-related substrates) but not the core carbohydrate-binding/ERAD function; retained as non-core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment of cytosolic localization, consistent with the cytoplasmic/cytosolic site of action.
    action: ACCEPT
    reason: Correct localization; FBXO2 acts on the cytosolic side; redundant with UniProt ISS and IDA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of protein ubiquitination, a parent process of the specific SCF-dependent catabolism FBXO2 mediates.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: Ortholog-based electronic assignment of SCF complex membership, the core complex context.
    action: ACCEPT
    reason: Core; redundant with IBA/ISS/NAS SCF annotations.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Electronic assignment (UniProt keyword Lectin) of carbohydrate binding, the defining molecular function of the FBA domain.
    action: ACCEPT
    reason: Core molecular function; the FBA domain is a lectin that binds N-linked high-mannose glycans (carbohydrate-binding sites at residues 210-212 and 278-279). The Falcon deep-research synthesis specifies that the bound determinant is the innermost N-glycan core (Man3GlcNAc2) engaged by a hydrophobic pocket, with preference for high-mannose glycans on denatured glycoproteins.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type
    - reference_id: file:human/FBXO2/FBXO2-deep-research-falcon.md
      supporting_text: it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible)
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of SCF-dependent proteasomal catabolism, the core process.
    action: ACCEPT
    reason: Core biological process; redundant with IBA/ISS/NAS evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0043197
    label: dendritic spine
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic transfer of dendritic spine localization, reflecting FBXO2's neuronal/synaptic expression and role in synaptic protein turnover.
    action: KEEP_AS_NON_CORE
    reason: Plausible neuronal localization tied to a secondary synaptic role; not the core ERAD compartment.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Ortholog-based electronic transfer of glutamatergic synapse localization/activity, reflecting a neuronal synaptic role.
    action: KEEP_AS_NON_CORE
    reason: Secondary neuronal/synaptic context; not the core ERAD/lectin function.
- term:
    id: GO:0099576
    label: regulation of protein catabolic process at postsynapse, modulating synaptic transmission
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic transfer of a postsynaptic protein-catabolism regulatory role, reflecting FBXO2's neuronal function in synaptic protein turnover.
    action: KEEP_AS_NON_CORE
    reason: Secondary, neuronal-context process; not the core ERAD/glycoprotein catabolism function.
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: Author-stated SCF complex membership. Core complex context.
    action: ACCEPT
    reason: Core; consistent with the SCF(FBXO2) complex composition.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: involved_in
  review:
    summary: Author-stated involvement in SCF-dependent proteasomal degradation. Core process.
    action: ACCEPT
    reason: Core biological process; consistent with FBXO2's SCF substrate-receptor function.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:1904415
    label: regulation of xenophagy
  evidence_type: NAS
  original_reference_id: PMID:34515398
  qualifier: involved_in
  review:
    summary: FBXO2/SCF directs xenophagy against group A Streptococcus by recognizing GlcNAc side chains of the bacterial surface carbohydrate; FBXO2 knockout reduces ubiquitin accumulation and xenophagic degradation. A documented secondary (immune/autophagy) role of the lectin activity.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported secondary role extending the lectin/glycan-recognition function to bacterial glycans; distinct from the core ERAD function.
    supported_by:
    - reference_id: PMID:34515398
      supporting_text: FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21378169
  qualifier: located_in
  review:
    summary: Direct assay placing FBXO2 in the cytoplasm in the study of Skp1/CRM1-controlled F-box protein localization. Core localization.
    action: ACCEPT
    reason: IDA-supported cytoplasmic localization consistent with the documented site of action.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome neddylation-pathway annotation of cytosolic localization for the CRL1/SCF context. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with IDA/ISS evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 CRL1/neddylation cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with other evidence.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (CAND1 binds cytosolic CRL) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (COMMD/CAND1) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (COP9 signalosome deneddylation) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (DCUN1D3 binds CRL1) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (Transfer of Ub from E2 to substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (Release of E3 from polyubiquitinated substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (Polyubiquitination of substrate) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-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 (Interaction of E3 with substrate and E2-Ub) cytosolic localization annotation. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Curator sequence-similarity transfer of cytosolic localization. Correct compartment.
    action: ACCEPT
    reason: Correct cytosolic localization; redundant with IDA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006516
    label: glycoprotein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of glycoprotein catabolic process, the substrate-class-defining core process.
    action: ACCEPT
    reason: Core process; redundant with IBA.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of protein ubiquitination, a parent of the specific SCF-dependent catabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; specific SCF-dependent catabolism/ERAD annotations are preferred.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Curator sequence-similarity transfer of SCF complex membership. Core complex context.
    action: ACCEPT
    reason: Core; redundant with IBA/IEA/NAS.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Curator sequence-similarity transfer of SCF-dependent proteasomal catabolism. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with IBA/IEA/NAS.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Author statement from the F-box family identification paper attributing ubiquitin-protein transferase activity to the SCF complex containing this F-box protein. FBXO2 itself is the substrate receptor, not the catalytic subunit.
    action: KEEP_AS_NON_CORE
    reason: The catalytic transferase activity resides in the RBX1/CUL1 core, not the F-box receptor; this term over-attributes catalysis to FBXO2. Retained as non-core (contributes_to ligase activity is the more accurate framing).
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex
- term:
    id: GO:0006508
    label: proteolysis
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author statement of involvement in proteolysis, a very general parent of the specific proteasomal/ERAD catabolism.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; specific SCF-dependent catabolism and ERAD annotations better capture the role.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: TAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author statement of involvement in protein modification, a very general parent of protein ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; the specific ubiquitination/SCF-catabolism annotations are preferred.
    supported_by:
    - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Founding identification of human F-box proteins (including FBXO2); abstract-only in cache. Source of the TAS transferase/proteolysis/modification annotations, which over-attribute catalysis to the receptor subunit.
- id: PMID:21378169
  title: A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls the localization of a subset of F-box proteins.
  findings:
  - statement: Skp1 and CRM1/exportin-1 compete for binding to a subset of F-box proteins, controlling their subcellular localization; FBXO2 was assayed and localized to the cytoplasm.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; primarily about Fbxo7 but FBXO2 cytoplasmic localization (IDA) derives from this study.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a bare protein binding annotation.
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Polycomb complexome map; source of a bare protein binding annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of a bare protein binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of a bare protein binding annotation.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only in cache; basis for NAS SCF complex membership and SCF-dependent catabolism annotations.
- id: PMID:34515398
  title: FBXO2/SCF ubiquitin ligase complex directs xenophagy through recognizing bacterial surface glycan.
  findings:
  - statement: FBXO2, a glycoprotein-specific SCF substrate receptor, recognizes GlcNAc side chains of the group A Streptococcus surface carbohydrate and promotes ubiquitin-mediated xenophagy; FBXO2 knockout decreases ubiquitin accumulation and xenophagic degradation of bacteria. FBXO2/FBXO6/FBXO27 are FBA-family lectins that bind high-mannose N-glycoproteins and act as ERAD ubiquitin-ligase subunits.
    reference_section_type: DISCUSSION
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; experimentally establishes FBXO2 glycan-recognition-dependent xenophagy and recapitulates the FBA-family lectin/ERAD role.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map study; source of a bare protein binding annotation.
- 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: []
- id: file:human/FBXO2/FBXO2-deep-research-falcon.md
  title: Falcon deep research report for human FBXO2
  findings:
  - statement: FBXO2/Fbs1 is the substrate-recognition adaptor of an SCF (SKP1-CUL1-RBX1-FBXO2) E3 ligase, not itself an enzyme; the F-box binds SKP1 and the C-terminal domain binds substrate while RBX1-associated E2 executes ubiquitin transfer.
    supporting_text: FBXO2 is best understood as a **substrate-recognition adaptor** that confers specificity to an SCF E3 ligase complex (SKP1–CUL1–RBX1–FBXO2). In this architecture, the **F-box** binds **SKP1**, which bridges to **CUL1/RBX1**, while FBXO2's C-terminal region binds the substrate; ubiquitin transfer is executed by the RBX1-associated E2 enzyme.
  - statement: FBXO2 recognizes a glycan-based degron, binding the innermost N-glycan core (Man3GlcNAc2) through a small hydrophobic pocket, preferring high-mannose N-glycans on denatured/misfolded glycoproteins.
    supporting_text: it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible).
  - statement: Lectin-type F-box proteins such as FBXO2 act in the nucleocytoplasmic compartment on retrotranslocated ER glycoproteins as part of ERAD.
    supporting_text: lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms.
  - statement: Glycoprotein quality-control substrates cited for the Fbs1/Fbs2 pathway include integrin beta-1, TCRalpha, asialoglycoprotein receptor H2a, and CFTR-deltaF508.
    supporting_text: Examples of glycoprotein targets/processes cited in the mechanistic literature include **integrin Ξ²1, TCRΞ±, asialoglycoprotein receptor H2a**, and **CFTRΞ”F508** as glycoproteins in the orbit of Fbs1/Fbs2-mediated quality control.
  - statement: FBXO2 mediates clearance of damaged lysosomes (lysophagy) in CNS contexts; loss delays clearance and exacerbates neurodegeneration in a Niemann-Pick C model.
    supporting_text: Fbxo2 functions as part of an SCF complex and **mediates clearance of damaged lysosomes** in CNS contexts. Loss of Fbxo2 **delayed clearance of damaged lysosomes** and reduced viability after lysosomal damage in mouse primary cortical cultures; in an NPC disease model, Fbxo2 deficiency **exacerbated neurodegeneration and reduced survival**.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis of peer-reviewed reviews (Yoshida 2019, Yoshida & Tanaka 2018, Suzuki & Fujihira 2021) and primary work (Liu 2020 JCI Insight) corroborates the FBA-lectin/ERAD mechanism, the Man3GlcNAc2 sugar-degron, and named substrates; cross-checked against UniProt. Recent cancer studies (p53, Hsp47) are context-dependent and partly preprints, treated as leads only.
core_functions:
- description: Substrate-recognition subunit of the SCF(FBXO2) E3 ubiquitin ligase that uses its FBA lectin domain to bind N-linked high-mannose oligosaccharides on misfolded/denatured glycoproteins retrotranslocated from the ER, targeting them for ubiquitination and proteasomal degradation via ERAD.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
    supporting_text: recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
- description: As the substrate receptor within SCF(FBXO2) (SKP1-CUL1-RBX1-FBXO2), contributes to SCF-dependent proteasomal ubiquitin-dependent catabolism of glycoprotein substrates, bridging glycan-bearing clients to the CUL1-RBX1 catalytic core via SKP1.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXO2/FBXO2-uniprot.txt
    supporting_text: Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What is the endogenous high-mannose glycoprotein substrate repertoire of SCF(FBXO2) in different tissues, and how is substrate selection partitioned among the FBA paralogs FBXO2, FBXO6, and FBXO27?
- question: How are FBXO2's neuronal/synaptic roles (dendritic spine, synaptic protein catabolism) and its lysophagy/xenophagy functions mechanistically related to its core ERAD lectin activity, and do they use distinct substrate pools?
suggested_experiments:
- description: Glycan-array and ITC/SPR binding assays with purified FBXO2 FBA domain (wild type vs carbohydrate-binding-site mutants at residues 173, 210-212, 278-279) to quantify high-mannose vs GlcNAc specificity and map the binding determinants.
- description: Quantitative ubiquitinome/proteome profiling in FBXO2-knockout versus wild-type cells (neuronal and epithelial) under ER-stress and ERAD-substrate challenge to define the endogenous glycoprotein substrate set and assess redundancy with FBXO6/FBXO27.