Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0036503 ERAD pathway	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic (PAN-GO/PANTHER) transfer of an ERAD role from the FBA lectin-ligase family. Reason: ERAD/GERAD is the role of the high-mannose-binding members of this family (FBXO2, FBXO6), which recognize the high-mannose signal on retrotranslocated misfolded ER glycoproteins. The experimental characterization of FBXO17 shows it does NOT bind high-mannose glycans and instead binds complex-type and sulfated glycans, so the authors explicitly conclude only FBXO2 and FBXO6 are likely to function in GERAD. The more general glycoprotein catabolic process / SCF-dependent catabolism terms better capture FBXO17's role; the specific ERAD assignment is a family-level over-propagation. Supporting Evidence: PMID:18203720 Our results lead us to conclude that only some members of the FBA family (FBXO2 and FBXO6) could function in GERAD by recognizing the signature high mannose glycan moiety present on retrotranslocated ER proteins. file:human/FBXO17/FBXO17-uniprot.txt Does not bind high-mannose glycoproteins.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of cytoplasmic localization, consistent with FBXO17 being a cytoplasmic SCF substrate-recognition subunit. Reason: FBA proteins are described as cytoplasmic F-box proteins; the localization is consistent with cytosolic SCF assembly. Correct but generic relative to the SCF complex annotation. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0006516 glycoprotein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic transfer of a glycoprotein-catabolism role; FBXO17 recognizes glycans on glycoprotein substrates and feeds them to the SCF/proteasome system. Reason: Captures the core biological role of the FBA family in glycoprotein quality control. FBXO17 binds complex and sulfated glycoproteins via its FBA/G domain and is a substrate receptor that targets glycoproteins for degradation, consistent with this term. Supporting Evidence: PMID:18203720 These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control.
GO:0019005 SCF ubiquitin ligase complex	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of SCF complex membership, the defining cellular context for FBXO17 as an F-box protein. Reason: Core localization/context. Directly demonstrated experimentally for FBXO17 (co-precipitates SKP1, CUL1 and RBX1) and supported by ComplexPortal (CPX-7927, SCF E3 ubiquitin ligase complex, FBXO17 variant). Supporting Evidence: PMID:18203720 All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1) file:human/FBXO17/FBXO17-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
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 complexes containing FBXO17. Reason: Core biological process. As an F-box substrate receptor, FBXO17 directs target glycoproteins into SCF-dependent, proteasome-mediated degradation. Supporting Evidence: PMID:18203720 When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein.
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment of ubiquitin ligase activity with the contributes_to qualifier, reflecting that the F-box subunit contributes substrate specificity to the catalytically active SCF complex. Reason: F-box proteins have no intrinsic catalytic activity; ubiquitin transfer is performed by the E2 enzyme recruited through the RBX1 RING subunit. The contributes_to qualifier correctly attributes the holo-complex activity to FBXO17 as a substrate receptor, but FBXO17 itself is not the catalytic entity, so this is retained as non-core rather than as a core molecular function (the lectin/carbohydrate-binding activity is the core MF). Supporting Evidence: PMID:18203720 As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own.
GO:0005737 cytoplasm	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning electronic assignment of cytoplasmic localization, redundant with the IBA cytoplasm annotation. Reason: Consistent with FBXO17 being a cytoplasmic F-box/SCF substrate receptor; redundant with the IBA cytoplasm annotation. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005515 protein binding	IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by...	KEEP AS NON CORE	Summary: IntAct interaction with CUL1 (Q13616) from a quantitative proteomics survey of cullin-RING ligase networks; CUL1 is the scaffold of the SCF complex. Reason: Records the functionally meaningful FBXO17-CUL1 interaction (SCF scaffold), but bare protein binding is uninformative per curation guidelines; the SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: IntAct interaction with SKP1 (P63208) from a proteome-scale interactome map; SKP1 is the F-box adaptor that links FBXO17 into the SCF complex. Reason: Records the core SKP1 interaction, but bare protein binding is uninformative; the SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;
GO:0005515 protein binding	IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex...	KEEP AS NON CORE	Summary: IntAct interaction with SKP1 (P63208) captured in a Polycomb complexome AP-MS map. Bare protein binding is uninformative. Reason: Records the SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from a large-scale interactome (BioPlex). Bare protein binding is uninformative. Reason: Records the SKP1/CUL1 SCF interactions but bare protein binding is uninformative; captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;
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 capturing numerous FBXO17 partners (SKP1 plus many candidate substrates/Y2H hits such as ADAMTSL4, KRT75, RUNX1). Bare protein binding is uninformative. Reason: High-throughput binary interactome; many partners may be candidate glycoprotein substrates but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Cell-specific interactome capturing FBXO17 partners SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. Reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;
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 study capturing FBXO17 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. Reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;
GO:0019005 SCF ubiquitin ligase complex	NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso...	ACCEPT	Summary: ComplexPortal (NAS) assignment of SCF complex membership, consistent with the FBXO17-variant SCF complex (CPX-7927). Reason: Core context; FBXO17 is the F-box substrate-recognition subunit of an SCF complex, supported experimentally and by ComplexPortal CPX-7927. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt ComplexPortal; CPX-7927; SCF E3 ubiquitin ligase complex, FBXO17 variant.
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: ComplexPortal (NAS) assignment of SCF-dependent proteasomal degradation, the generic process executed by SCF complexes. Reason: Core biological process for an F-box substrate receptor; SCF complexes poly-ubiquitinate substrates to target them for proteasomal degradation. Supporting Evidence: PMID:34445249 The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952618	ACCEPT	Summary: Reactome curation of cytosolic localization within the CRL1/SCF neddylation pathway. Consistent with cytoplasmic SCF assembly. Reason: Correct localization; cytosol is the compartment of SCF assembly/neddylation. Redundant with the cytoplasm annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-8952620	ACCEPT	Summary: Reactome curation of cytosolic localization (CRL1 neddylation reaction). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	ACCEPT	Summary: Reactome curation of cytosolic localization (CAND1 binding to cytosolic CRL ligases). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	ACCEPT	Summary: Reactome curation of cytosolic localization (COMMD displacement of CAND1 from cytosolic CRL ligases). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	ACCEPT	Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation of cytosolic CRL ligases). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-8956200	ACCEPT	Summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	ACCEPT	Summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate, antigen processing/proteasome pathway). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	ACCEPT	Summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	ACCEPT	Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	ACCEPT	Summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub complex). Redundant cytosol annotation. Reason: Correct localization; redundant with other cytoplasm/cytosol annotations. Supporting Evidence: PMID:18203720 how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
GO:0005515 protein binding	IDA PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c...	KEEP AS NON CORE	Summary: Direct experimental demonstration that FBXO17 binds SCF components (SKP1, CUL1) by co-immunoprecipitation. Bare protein binding is uninformative. Reason: Records the experimentally demonstrated FBXO17-SCF interaction, but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: PMID:18203720 All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)
GO:0005515 protein binding	IPI PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c...	KEEP AS NON CORE	Summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from the FBXO17 characterization study. Bare protein binding is uninformative. Reason: Records the core SKP1/CUL1 SCF interactions, but bare protein binding is uninformative; captured by GO:0019005. Supporting Evidence: file:human/FBXO17/FBXO17-uniprot.txt Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;
GO:0019005 SCF ubiquitin ligase complex	IDA PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c...	ACCEPT	Summary: Direct experimental evidence that FBXO17 assembles into an SCF complex (co-precipitation of SKP1, CUL1 and RBX1; mutagenesis of the glycan-binding pocket). Core cellular context. Reason: Core, experimentally demonstrated localization/context. FBXO17 binds SKP1 directly via its F-box domain and incorporates into a full SCF complex. Supporting Evidence: PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex file:human/FBXO17/FBXO17-uniprot.txt Interacts with SKP1 and CUL1. {ECO:0000269\|PubMed:18203720}.
GO:0030246 carbohydrate binding	IDA PMID:18203720 Diversity in tissue expression, substrate binding, and SCF c...	NEW	Summary: Proposed annotation for FBXO17's core lectin molecular function, which is not currently in GOA. The FBA/G domain directly binds glycans (complex-type glycoproteins and sulfated glycans such as heparin) via a conserved hydrophobic pocket; FBXO17 does not bind high-mannose glycans. Reason: The defining molecular function of FBXO17 as a sugar-recognizing F-box protein is carbohydrate binding, demonstrated experimentally by glycan arrays and glycoprotein pulldowns (heparin, chondroitin sulfate, lactoferrin), yet there is no corresponding molecular-function annotation in the existing GOA set. Adding GO:0030246 captures this lectin activity. Supporting Evidence: PMID:18203720 FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans. file:human/FBXO17/FBXO17-uniprot.txt Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans.

Core Functions

Carbohydrate-binding (lectin) substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex. The C-terminal FBA/G domain binds glycans on glycoprotein substrates (complex-type N-glycans and sulfated glycans such as heparin, but not high-mannose glycans) via a conserved hydrophobic pocket, selecting glycosylated targets for the SCF machinery.

Molecular Function:

carbohydrate binding

Directly Involved In:

glycoprotein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

PMID:18203720
FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans.
file:human/FBXO17/FBXO17-uniprot.txt
Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans.

F-box substrate receptor that links selected glycoprotein substrates into a SKP1-CUL1-RBX1 SCF complex (binding SKP1 via its F-box domain), contributing substrate specificity to SCF-dependent, proteasome-mediated protein degradation. FBXO17 has no intrinsic catalytic activity; ubiquitin transfer is performed by the SCF-associated E2/RBX1 module.

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

PMID:18203720
All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)
file:human/FBXO17/FBXO17-deep-research-falcon.md
A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β.

Beyond glycoprotein recognition, SCF(FBXO17) targets at least one validated protein substrate, the kinase GSK3-beta (GSK3B): FBXO17 binds GSK3-beta and promotes its polyubiquitination and proteasomal degradation in lung epithelium, thereby restraining GSK3-beta-dependent pro-inflammatory cytokine production (IL-6, CXCL1). This indicates FBXO17's substrate scope is not limited to its lectin/glycan-recognition activity.

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytosol

Supporting Evidence:

file:human/FBXO17/FBXO17-deep-research-falcon.md
A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:18203720

Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.

FBXO17 is a member of the FBA lectin family of F-box proteins; it does NOT bind high-mannose glycans but binds complex-type glycoproteins (e.g. lactoferrin) and sulfated glycans (heparin strongly, chondroitin sulfate weakly) via a conserved hydrophobic pocket in the FBA/G domain, and it assembles into a canonical SCF complex with SKP1, CUL1 and RBX1.

PMID:21145461

Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:27705803

A High-Density Map for Navigating the Human Polycomb Complexome.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

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.

SCF (SKP1-CUL1-F-box) complexes are E3 ubiquitin ligases that modify substrates with poly-ubiquitin chains for proteasomal degradation, with the variable F-box protein conferring substrate specificity.

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/FBXO17/FBXO17-deep-research-falcon.md

Falcon deep research report for human FBXO17

FBXO17 (also known as FBG4) is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase (SCF^FBXO17), with the ~40-aa F-box domain binding SKP1 to link the substrate-recognition module to the CUL1-RBX1 catalytic core.

"SCF E3 ubiquitin ligases use F-box proteins as substrate adaptors**; the ~40-aa **F-box domain** binds **SKP1**, linking the variable substrate-recognition module to the CUL1-RBX1 catalytic core."
The best-validated FBXO17 substrate is the protein kinase GSK3-beta; SCF^FBXO17 associates with GSK3-beta, promotes its polyubiquitination, and drives proteasome-dependent turnover in lung epithelial cells.

"A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β."
By degrading GSK3-beta, FBXO17 dampens GSK3-beta-dependent pro-inflammatory cytokine production; FBXO17 overexpression reduces TNF-alpha/LPS-induced IL-6 and KC/CXCL1, partially rescued by GSK3-beta re-expression.

"FBXO17 overexpression reduces **TNFα- and LPS-induced IL-6 and KC/CXCL1**."
FBXO17 has a non-canonical, SCF-independent mode that does not require the F-box domain - it binds IRF3 and recruits PP2A to promote IRF3 dephosphorylation, negatively regulating type I interferon signaling.

"FBXO17 can regulate signaling **independently of its canonical SCF function** by recruiting **PP2A** to the transcription factor **IRF3** to promote IRF3 dephosphorylation and suppress type I interferon signaling. This is explicitly described as not requiring the F-box domain and using the "F-box associated region.""
FBXO17 and its demonstrated substrate GSK3-beta colocalize in the cytoplasm, consistent with a cytoplasmic site of action.

"Direct experimental localization in the mechanistic SCF substrate study indicates **cytoplasmic colocalization** of FBXO17 with its demonstrated substrate GSK3β."

Suggested Experiments

Experiment: Identify endogenous FBXO17 substrates by comparing the ubiquitinome/proteome of FBXO17-knockout versus wild-type cells, with parallel glycoproteomics to test enrichment for complex-type and sulfated glycoproteins, and to confirm GSK3-beta as an endogenous substrate.

Experiment: Reconstitute SCF(FBXO17) in vitro with SKP1, CUL1, RBX1 and an E2 to test ubiquitination of candidate complex/sulfated glycoproteins and of GSK3-beta, using the FBA/G-domain pocket mutant (S257A/W258A) and the 151-200 deletion as substrate-recognition-deficient controls to dissect glycan-dependent versus protein-dependent recognition.

Experiment: Dissect the non-canonical IRF3/PP2A scaffold mode by testing whether F-box-deletion and FBA-region mutants of FBXO17 still recruit PP2A to IRF3 and suppress type I interferon reporter activity, separating it from SCF-dependent ubiquitination.

Deep Research

Falcon

(FBXO17-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 25 citations 2 artifacts 2026-06-13T06:36:24.173064

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000013 The requested figure panels are as follows: 1. **FBXO17 interaction and colocalization with GSK3β**: This is shown in **Figure 5** (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 FBXO17 (UniProt Q96EF6) Functional Annotation

1) Target verification and identity (critical disambiguation)

Target: Homo sapiens FBXO17 (F-box only protein 17; UniProt Q96EF6). The mechanistic primary literature retrieved uses the gene/protein name FBXO17 and studies its function as an F-box protein in the SKP1–CUL1–F-box (SCF) ubiquitin ligase system, consistent with the UniProt description of an F-box protein with an F-box–associated region and predicted sugar-binding-like features (as expected for “FBA-family” FBXO proteins). (suber2017scffbxo17e3ligase pages 4-5, skaar2013mechanismsandfunction pages 1-2)

Synonymy seen in literature: In a core mechanistic paper, FBXO17 is explicitly stated to be “also known as FBG4,” confirming at least one UniProt synonym in the experimental literature base. (suber2017scffbxo17e3ligase pages 4-5)

Canonical SCF role (definition): Authoritative reviews summarize that SCF E3 ubiquitin ligases use F-box proteins as substrate adaptors; the ~40-aa F-box domain binds SKP1, linking the variable substrate-recognition module to the CUL1-RBX1 catalytic core. (skaar2013mechanismsandfunction pages 1-2)

2) Key concepts and current understanding

2.1 What FBXO17 is (conceptual definition)

FBXO17 is best understood as a substrate-recognition adaptor for an SCF-type E3 ubiquitin ligase (SCF^FBXO17), where FBXO17 contributes substrate specificity by binding target proteins and positioning them for ubiquitin transfer and subsequent proteasomal degradation. (suber2017scffbxo17e3ligase pages 1-2, skaar2013mechanismsandfunction pages 1-2)

2.2 Two mechanistic “modes” of FBXO17 function

Available evidence supports two separable functional modes:

1) Canonical SCF ubiquitin-ligase adaptor mode: FBXO17 binds targets (experimentally demonstrated for GSK3β) and promotes their ubiquitination and proteasomal degradation. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 2-3)

2) Non-canonical signaling-scaffold mode: FBXO17 can regulate signaling independently of its canonical SCF function by recruiting PP2A to the transcription factor IRF3 to promote IRF3 dephosphorylation and suppress type I interferon signaling. This is explicitly described as not requiring the F-box domain and using the “F-box associated region.” (peng2017anovelfunction pages 1-2)

3) Experimentally supported molecular functions

3.1 FBXO17 as an SCF adaptor that targets GSK3β for degradation

A detailed biochemical study in lung epithelial cells shows that FBXO17 associates with GSK3β, promotes polyubiquitination of GSK3β, and drives proteasome-dependent turnover of GSK3β. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 2-3)

Mechanistic details supported by experiments include:
- FBXO17 being an “authentic subunit” of SCF E3 ligase machinery and identifying GSK3β as an SCF^FBXO17 substrate. (suber2017scffbxo17e3ligase pages 4-5)
- Cytoplasmic colocalization of FBXO17 and GSK3β (cellular localization for the functional interaction). (suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase media b09b278e)
- Mapping a putative GSK3β-binding region in FBXO17 (amino acids 151–200 required for association in the reported assays). (suber2017scffbxo17e3ligase pages 4-5)

Visual evidence: Cropped figure panels show co-immunoprecipitation and cytoplasmic colocalization of FBXO17 with GSK3β, plus downstream cytokine outcomes (see §3.2). (suber2017scffbxo17e3ligase media b09b278e)

3.2 Functional consequence in lung epithelia: dampening inflammatory cytokines

In lung epithelial cells, overexpression of FBXO17 reduces pro-inflammatory cytokine production after innate immune stimuli, consistent with FBXO17 limiting a GSK3β-dependent inflammatory program:
- FBXO17 overexpression reduces TNFα- and LPS-induced IL-6 and KC/CXCL1. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 4-5)
- Re-expression of GSK3β partially rescues the KC suppression, linking the phenotype to the FBXO17→GSK3β axis. (suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase media b09b278e)

Visual evidence: Cropped cytokine panels (IL-6 and KC) following TNFα/LPS stimulation are shown in the retrieved figure crops. (suber2017scffbxo17e3ligase media b09b278e)

3.3 Antiviral innate immunity: negative regulation of type I IFN signaling (IRF3/PP2A)

A mechanistic immunology study reports that FBXO17 specifically interacts with IRF3 and negatively regulates type I interferon signaling by recruiting PP2A to promote IRF3 dephosphorylation, and emphasizes that this action is independent of canonical SCF E3 ligase function (does not require the F-box domain). (peng2017anovelfunction pages 1-2)

This positions FBXO17 as a dual-function regulator: a classical E3-adaptor in some contexts and a phosphatase-recruiting scaffold in others. (peng2017anovelfunction pages 1-2)

3.4 Cancer cell biology contexts: divergent pathway effects across models

Available primary studies suggest FBXO17 can be pro- or anti-proliferative depending on context:

Lung adenocarcinoma (A549): FBXO17 overexpression increases proliferation and is associated with increased activation of Akt/PDK1, ERK1/2, and downstream signaling (e.g., RPS6, CREB), while knockdown reduces growth and reduces ERK phosphorylation. (suber2018fbxo17promotescell pages 4-7)

Endometrial cancer model (Ishikawa cells): FBXO17 overexpression suppresses proliferation and is associated with reduced Wnt/β-catenin output (reduced β-catenin targets such as cyclin D1 and c-Myc, reduced Axin2 mRNA) and altered EMT markers (↑E-cadherin, ↓N-cadherin). (zheng2022fbxo17inhibitsthe pages 4-7)

Interpretation: these studies indicate FBXO17 influences major signaling hubs (GSK3β, Akt/ERK, Wnt/β-catenin), but the directionality of pathway changes is model-dependent and not yet reconciled into a single unified mechanism across tissues. (zheng2022fbxo17inhibitsthe pages 4-7, suber2018fbxo17promotescell pages 4-7)

4) Subcellular localization (where the protein acts)

Direct experimental localization in the mechanistic SCF substrate study indicates cytoplasmic colocalization of FBXO17 with its demonstrated substrate GSK3β. (suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase media b09b278e)

In the interferon/IRF3 context, the functional description implies FBXO17 engages cytosolic antiviral signaling components (IRF3 prior to nuclear translocation), consistent with a cytoplasm-accessible regulatory role, though the excerpted evidence is primarily functional/interaction-based rather than microscopy-based. (peng2017anovelfunction pages 1-2)

5) Pathways and biological processes implicated

5.1 Ubiquitin–proteasome system (UPS) / SCF E3 ligases

FBXO17 is part of the F-box protein family that serves as substrate adaptors for SCF E3 ubiquitin ligases. This is both generally described in authoritative reviews and experimentally demonstrated for FBXO17 via SCF^FBXO17-mediated ubiquitination/degradation of GSK3β. (skaar2013mechanismsandfunction pages 1-2, suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16)

5.2 GSK3β-centered signaling

GSK3β is a multifunctional kinase connected to inflammatory signaling and Wnt/β-catenin regulation. FBXO17 directly controls GSK3β abundance through proteasomal degradation in lung epithelium. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16)

5.3 Type I interferon signaling (IRF3 axis)

FBXO17 negatively regulates type I IFN signaling by recruiting PP2A to deactivate IRF3 via dephosphorylation, described explicitly as a non-canonical F-box protein function. (peng2017anovelfunction pages 1-2)

5.4 Wnt/β-catenin pathway in cancer contexts

In an endometrial cancer model, FBXO17 overexpression suppresses Wnt/β-catenin pathway markers and proliferation. (zheng2022fbxo17inhibitsthe pages 4-7)

6) Recent developments (prioritizing 2023–2024)

6.1 2023–2024 literature availability specific to FBXO17 mechanisms

Within the retrieved corpus, FBXO17-focused mechanistic primary papers in 2023–2024 were not identified; the most direct mechanistic evidence remains from 2017–2018 primary work plus a 2022 cancer model paper. (suber2017scffbxo17e3ligase pages 1-2, peng2017anovelfunction pages 1-2, suber2018fbxo17promotescell pages 4-7, zheng2022fbxo17inhibitsthe pages 4-7)

However, FBXO17 appears in recent (2024) systems-level and pathway/therapeutics discussions that contextualize SCF/CRL regulation as druggable:
- A 2024 review of E3 ligases in hepatocellular carcinoma (HCC) frames the therapeutic potential of E3 ligase targeting in tumor microenvironment modulation (general E3/UPS context rather than FBXO17-specific mechanism). (wang2024roleandtherapeutic pages 1-3)
- A 2024 cancer bioinformatics paper on neddylation landscapes explicitly includes FBXO17 among neddylation-related genes, placing it within the broader CRL/UPS regulatory ecosystem that is pharmacologically targetable via NAE inhibition (MLN4924/pevonedistat). (liu2024evaluatingtherole pages 2-4)

6.2 2023–2024 quantitative cohort/omics implementations where FBXO17 is a feature

A 2024 multi-omics glioma classification study reports that FBXO17 is among the gene features contributing to discrimination of glioblastoma vs lower-grade gliomas in a supervised multi-omics integration framework, demonstrating real-world usage as a potential biomarker feature in computational pipelines (not a mechanistic validation). (vieira2024integrationofmultiomics pages 4-5)

7) Current applications and real-world implementations

1) Biomarker nomination in computational oncology: FBXO17 is used as a discriminative feature in multi-omics models distinguishing glioma types, exemplifying how FBXO17 expression can be incorporated into diagnostic/prognostic ML workflows (implementation-level use rather than causal biology). (vieira2024integrationofmultiomics pages 4-5)

2) UPS/CRL pathway therapeutic strategies relevant to FBXO17 biology:
- Neddylation inhibition (e.g., MLN4924/pevonedistat) is widely used in experimental oncology to inactivate cullin-RING ligases (CRLs). Since SCF complexes are CRLs (CUL1-based), this strategy is mechanistically relevant to FBXO17-dependent SCF activity even if not FBXO17-specific. (liu2024evaluatingtherole pages 2-4)

3) Target/disease association resources: Open Targets links FBXO17 to disease areas including hepatocellular carcinoma (evidence-backed association score and literature link), offering a starting point for translational prioritization. (OpenTargets Search: hepatocellular carcinoma,glioma,type 2 diabetes mellitus,infection,neoplasm-FBXO17)

8) Expert opinions and authoritative synthesis

A highly cited Nature Reviews Molecular Cell Biology review emphasizes that substrate recognition by F-box proteins is central to SCF specificity, and that many F-box proteins historically lacked known substrates (“orphan” adaptors). This contextualizes why experimentally validated substrates like GSK3β are particularly valuable for FBXO17 annotation. (skaar2013mechanismsandfunction pages 1-2)
The “cytosolic N-glycans” review highlights that F-box proteins act as SCF substrate-recognition subunits and places FBXO17 in a phylogenetic context with related glycan-recognizing FBXOs, consistent with the idea that FBXO17 may possess carbohydrate-recognition-like features (though substrate glycan recognition is not directly validated in the retrieved core mechanistic papers). (yoshida2018cytosolicnglycanstriggers pages 5-6)

9) Relevant statistics and quantitative data from recent studies

From primary mechanistic FBXO17 studies (quantitative directionality reported; numeric effect sizes are largely in figures rather than extracted in the text snippets):
- FBXO17 overexpression reduces TNFα/LPS-induced cytokines (IL-6, KC) and this is partially rescued by GSK3β re-expression. (suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase media b09b278e)

From 2023–2024 computational/clinical cohort studies (non-mechanistic):
- Glioblastoma long-term survival prediction ROC AUCs for top genes reported (contextual example of the kind of metrics used in real-world TCGA analyses; not FBXO17-specific in that paper section). AUC values include ATP5C1 0.682 (2.5-year) and 0.814 (5-year), etc. (yoon2023thegenessignificantly pages 8-10)
- Glioma multi-omics classifier reports overall accuracy ~98% and identifies FBXO17 among influential GBM-discriminating gene features. (vieira2024integrationofmultiomics pages 4-5)

From Open Targets association scoring:
- FBXO17–hepatocellular carcinoma association score is reported (0.0358) with linked literature evidence. (OpenTargets Search: hepatocellular carcinoma,glioma,type 2 diabetes mellitus,infection,neoplasm-FBXO17)

10) Evidence summary table (key studies)

Biological context/model (cell type/organism)	Molecular role	Direct substrates/interactors	Downstream pathway effects	Key readouts/quantitative outcomes	Evidence type	Publication (authors, journal)	Year	DOI/URL	Notes/limitations
Lung epithelium; MLE-12 cells / mouse, with human FBXO17 constructs	SCF substrate receptor	GSK3β; Skp1	Promotes K48-linked proteasomal turnover of GSK3β; dampens pro-inflammatory signaling	FBXO17 overexpression lowers GSK3β protein; FBXO17 silencing increases GSK3β half-life; reduced TNFα/LPS-induced IL-6 and KC/CXCL1; KC suppression partially rescued by GSK3β re-expression (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase pages 2-3, suber2017scffbxo17e3ligase media b09b278e)	Co-IP, IF colocalization, CHX chase, MG132 rescue, ubiquitination assay, siRNA knockdown, cytokine assays (suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 7-8, suber2017scffbxo17e3ligase media b09b278e)	Suber et al., J. Biol. Chem. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16)	2017	https://doi.org/10.1074/jbc.m116.771667	Strongest direct mechanistic evidence for FBXO17 as SCF adaptor; primary functional work is in murine lung epithelial cells rather than human tissues (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16)
Antiviral innate immune signaling; mammalian cells / human-focused signaling study	Non-canonical scaffold (SCF-independent for this function)	IRF3; PP2A	Negative regulation of type I IFN signaling via IRF3 dephosphorylation/inactivation	FBXO17 specifically interacts with IRF3 and recruits PP2A; this recruitment uses the F-box-associated region and is reported as independent of canonical SCF E3 ligase function, enhancing IRF3 dephosphorylation and suppressing IFN-I signaling (peng2017anovelfunction pages 1-2)	Interaction assays and signaling/functional immune assays summarized in text evidence (peng2017anovelfunction pages 1-2)	Peng et al., J. Immunol. (peng2017anovelfunction pages 1-2)	2017	https://doi.org/10.4049/jimmunol.1601009	Evidence supports a signaling-scaffold role rather than a demonstrated ubiquitin substrate in this context; quantitative effect sizes not available in provided context (peng2017anovelfunction pages 1-2)
Lung adenocarcinoma; A549 and other lung cancer cell lines / human	Likely SCF-linked regulator; mechanistically tied to GSK3β turnover	GSK3β; Akt-pathway mediators (PDK1, ERK1/2, RPS6, CREB as downstream readouts)	Activates Akt/ERK/mTOR-related signaling and promotes proliferation/survival	FBXO17 overexpression increases cell number, metabolic activity, and S-phase fraction; increases p-Akt (Thr308, modestly Ser473), PDK1, p-ERK1/2, p-CREB, and p-RPS6; knockdown reduces growth and p-ERK1/2, with trend toward reduced p-Akt Ser473; 212 genes altered after knockdown (suber2018fbxo17promotescell pages 1-2, suber2018fbxo17promotescell pages 4-7)	Overexpression/knockdown, immunoblotting, BrdU/MTS/cell-cycle assays, transcriptomics (suber2018fbxo17promotescell pages 4-7)	Suber et al., Respir. Res. (suber2018fbxo17promotescell pages 1-2, suber2018fbxo17promotescell pages 4-7)	2018	https://doi.org/10.1186/s12931-018-0910-0	Direct SCF assembly was not biochemically shown in the provided excerpt; pathway links are strong but substrate causality beyond prior GSK3β work is indirect here (suber2018fbxo17promotescell pages 4-7)
Endometrial carcinoma; Ishikawa cells / human	Putative SCF-linked tumor suppressive regulator	Wnt/β-catenin pathway components; β-catenin, GSK3β, pGSK3β measured as affected proteins	Inhibits Wnt/β-catenin signaling; suppresses proliferation and EMT-like changes	FBXO17 overexpression reduces proliferation (CCK-8, RTCA, colony formation, EdU), increases apoptosis and G1 arrest; decreases β-catenin, GSK3β, pGSK3β, cyclin D1, c-Myc, and Axin2 mRNA; increases E-cadherin and decreases N-cadherin (zheng2022fbxo17inhibitsthe pages 4-7)	Lentiviral overexpression, proliferation/apoptosis/cell-cycle assays, western blotting, qPCR, bioinformatics pathway analysis (zheng2022fbxo17inhibitsthe pages 4-7)	Zheng et al., Int. J. Med. Sci. (zheng2022fbxo17inhibitsthe pages 4-7)	2022	https://doi.org/10.7150/ijms.60335	Functional evidence is strong for pathway/cell phenotype, but no direct ubiquitination substrate or Co-IP evidence for FBXO17 targets was provided in the excerpt; reported decrease in total GSK3β differs from expectation based on lung studies and may be context-dependent (zheng2022fbxo17inhibitsthe pages 4-7)

Table: This table summarizes the main experimentally supported functions of human FBXO17 across the four key studies available in context. It separates canonical SCF-associated substrate-receptor activity from non-canonical signaling-scaffold behavior and highlights the strongest evidence, readouts, and study limitations.

11) Conclusions and research gaps

Best-supported primary function: FBXO17 is an SCF-type E3 ubiquitin ligase substrate adaptor that can directly bind and promote proteasomal degradation of GSK3β, thereby modulating inflammatory signaling in lung epithelium. (suber2017scffbxo17e3ligase pages 1-2, suber2017scffbxo17e3ligase pages 14-16, suber2017scffbxo17e3ligase pages 4-5, suber2017scffbxo17e3ligase media b09b278e)

Additional validated role: FBXO17 negatively regulates antiviral type I interferon signaling by recruiting PP2A to IRF3 for dephosphorylation, a mechanism explicitly described as independent of the canonical SCF function. (peng2017anovelfunction pages 1-2)

Major open questions:
- Tissue-specific directionality (oncogenic vs tumor-suppressive) and reconciliation of pathway effects across cancer models remain unresolved. (zheng2022fbxo17inhibitsthe pages 4-7, suber2018fbxo17promotescell pages 4-7)
- Beyond GSK3β and IRF3/PP2A scaffolding, additional direct substrates of FBXO17 in human tissues are not established in the retrieved corpus and represent a key opportunity for future work. (skaar2013mechanismsandfunction pages 1-2, suber2017scffbxo17e3ligase pages 4-5)

Key URLs (publication landing pages)

Suber et al., J Biol Chem (2017-03): https://doi.org/10.1074/jbc.m116.771667 (suber2017scffbxo17e3ligase pages 1-2)
Peng et al., J Immunol (2017-01): https://doi.org/10.4049/jimmunol.1601009 (peng2017anovelfunction pages 1-2)
Suber et al., Respir Res (2018-10): https://doi.org/10.1186/s12931-018-0910-0 (suber2018fbxo17promotescell pages 1-2)
Zheng et al., Int J Med Sci (2022-08): https://doi.org/10.7150/ijms.60335 (zheng2022fbxo17inhibitsthe pages 4-7)
Wang et al., Front Immunol (2024-10-31): https://doi.org/10.3389/fimmu.2024.1483721 (wang2024roleandtherapeutic pages 1-3)
Liu et al., Pharmaceuticals (2024-05): https://doi.org/10.3390/ph17050635 (liu2024evaluatingtherole pages 2-4)
Vieira et al., Bioinformatics and Biology Insights (2024-01): https://doi.org/10.1177/11779322241249563 (vieira2024integrationofmultiomics pages 4-5)
Open Targets FBXO17 associations (accessed via tool; evidence-linked): https://platform.opentargets.org/target/ENSG00000269190 (OpenTargets Search: hepatocellular carcinoma,glioma,type 2 diabetes mellitus,infection,neoplasm-FBXO17)

References

(suber2017scffbxo17e3ligase pages 4-5): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(skaar2013mechanismsandfunction pages 1-2): Jeffrey R. Skaar, Julia K. Pagan, and Michele Pagano. Mechanisms and function of substrate recruitment by f-box proteins. Nature Reviews Molecular Cell Biology, 14:369-381, May 2013. URL: https://doi.org/10.1038/nrm3582, doi:10.1038/nrm3582. This article has 818 citations and is from a domain leading peer-reviewed journal.
(suber2017scffbxo17e3ligase pages 1-2): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(suber2017scffbxo17e3ligase pages 14-16): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(suber2017scffbxo17e3ligase pages 2-3): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(peng2017anovelfunction pages 1-2): Di Peng, Zining Wang, Anfei Huang, Yong Zhao, and F. Xiao-Feng Qin. A novel function of f-box protein fbxo17 in negative regulation of type i ifn signaling by recruiting pp2a for ifn regulatory factor 3 deactivation. The Journal of Immunology, 198:808-819, Jan 2017. URL: https://doi.org/10.4049/jimmunol.1601009, doi:10.4049/jimmunol.1601009. This article has 38 citations.
(suber2017scffbxo17e3ligase media b09b278e): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(suber2018fbxo17promotescell pages 4-7): Tomeka L. Suber, Ina Nikolli, Michael E. O’Brien, James Londino, Jing Zhao, Kong Chen, Rama K. Mallampalli, and Yutong Zhao. Fbxo17 promotes cell proliferation through activation of akt in lung adenocarcinoma cells. Respiratory Research, Oct 2018. URL: https://doi.org/10.1186/s12931-018-0910-0, doi:10.1186/s12931-018-0910-0. This article has 33 citations and is from a domain leading peer-reviewed journal.
(zheng2022fbxo17inhibitsthe pages 4-7): Zi-Meng Zheng, Ying-Ying Wang, Min Chen, Hui-Li Yang, Zhen-Zhen Lai, Ming-Qing Li, and Jun Shao. Fbxo17 inhibits the wnt/β-catenin pathway and proliferation of ishikawa cells. International Journal of Medical Sciences, 19:1430-1441, Aug 2022. URL: https://doi.org/10.7150/ijms.60335, doi:10.7150/ijms.60335. This article has 5 citations and is from a peer-reviewed journal.
(wang2024roleandtherapeutic pages 1-3): Hailin Wang, Qiang Li, Qinqin Tang, Gang Shi, Guo Wu, Xingbo Mao, Changkang Wu, Lixin Zhang, Jie Liu, Jingdong Li, and Bo Li. Role and therapeutic potential of e3s in the tumor microenvironment of hepatocellular carcinoma. Frontiers in Immunology, Oct 2024. URL: https://doi.org/10.3389/fimmu.2024.1483721, doi:10.3389/fimmu.2024.1483721. This article has 5 citations and is from a peer-reviewed journal.
(liu2024evaluatingtherole pages 2-4): Dequan Liu, Guangzhen Wu, Shijin Wang, Xu Zheng, and Xiangyu Che. Evaluating the role of neddylation modifications in kidney renal clear cell carcinoma: an integrated approach using bioinformatics, mln4924 dosing experiments, and rna sequencing. Pharmaceuticals, 17:635, May 2024. URL: https://doi.org/10.3390/ph17050635, doi:10.3390/ph17050635. This article has 4 citations.
(vieira2024integrationofmultiomics pages 4-5): Francisca G. Vieira, Regina Bispo, and Marta B. Lopes. Integration of multi-omics data for the classification of glioma types and identification of novel biomarkers. Bioinformatics and Biology Insights, Jan 2024. URL: https://doi.org/10.1177/11779322241249563, doi:10.1177/11779322241249563. This article has 19 citations and is from a peer-reviewed journal.
(OpenTargets Search: hepatocellular carcinoma,glioma,type 2 diabetes mellitus,infection,neoplasm-FBXO17): Open Targets Query (hepatocellular carcinoma,glioma,type 2 diabetes mellitus,infection,neoplasm-FBXO17, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(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.
(yoon2023thegenessignificantly pages 8-10): Hong Gyu Yoon, Jin Hwan Cheong, Je Il Ryu, Yu Deok Won, Kyueng-Whan Min, and Myung-Hoon Han. The genes significantly associated with an improved prognosis and long-term survival of glioblastoma. PLOS ONE, 18:e0295061, Nov 2023. URL: https://doi.org/10.1371/journal.pone.0295061, doi:10.1371/journal.pone.0295061. This article has 9 citations and is from a peer-reviewed journal.
(suber2017scffbxo17e3ligase pages 7-8): Tomeka Suber, Jianxin Wei, Anastasia M. Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, and Rama K. Mallampalli. Scffbxo17 e3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia. The Journal of Biological Chemistry, 292:7452-7461, Mar 2017. URL: https://doi.org/10.1074/jbc.m116.771667, doi:10.1074/jbc.m116.771667. This article has 32 citations.
(suber2018fbxo17promotescell pages 1-2): Tomeka L. Suber, Ina Nikolli, Michael E. O’Brien, James Londino, Jing Zhao, Kong Chen, Rama K. Mallampalli, and Yutong Zhao. Fbxo17 promotes cell proliferation through activation of akt in lung adenocarcinoma cells. Respiratory Research, Oct 2018. URL: https://doi.org/10.1186/s12931-018-0910-0, doi:10.1186/s12931-018-0910-0. This article has 33 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

skaar2013mechanismsandfunction pages 1-2
peng2017anovelfunction pages 1-2
wang2024roleandtherapeutic pages 1-3
liu2024evaluatingtherole pages 2-4
vieira2024integrationofmultiomics pages 4-5
yoshida2018cytosolicnglycanstriggers pages 5-6
yoon2023thegenessignificantly pages 8-10
https://doi.org/10.1074/jbc.m116.771667
https://doi.org/10.4049/jimmunol.1601009
https://doi.org/10.1186/s12931-018-0910-0
https://doi.org/10.7150/ijms.60335
https://doi.org/10.3389/fimmu.2024.1483721
https://doi.org/10.3390/ph17050635
https://doi.org/10.1177/11779322241249563
https://platform.opentargets.org/target/ENSG00000269190
https://doi.org/10.1074/jbc.m116.771667,
https://doi.org/10.1038/nrm3582,
https://doi.org/10.4049/jimmunol.1601009,
https://doi.org/10.1186/s12931-018-0910-0,
https://doi.org/10.7150/ijms.60335,
https://doi.org/10.3389/fimmu.2024.1483721,
https://doi.org/10.3390/ph17050635,
https://doi.org/10.1177/11779322241249563,
https://doi.org/10.1002/bies.201700215,
https://doi.org/10.1371/journal.pone.0295061,

📚 Additional Documentation

Pn Notes

(FBXO17-pn-notes.md)

FBXO17 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96EF6
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXO17/FBXO17-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXO17/FBXO17-ai-review.html
Gene notes: missing - genes/human/FBXO17/FBXO17-notes.md
GOA TSV: present - genes/human/FBXO17/FBXO17-goa.tsv
UniProt record: present - genes/human/FBXO17/FBXO17-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXO17.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXO17.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXO17/FBXO17-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXO17 (also FBG4, FBXO26) is a cytoplasmic F-box protein of the FBA/FBG (F-box-associated, "sugar-recognizing") lectin subfamily that also includes FBXO2, FBXO6, FBXO27 and FBXO44. It is built from an N-terminal F-box domain, which binds the adaptor SKP1 and thereby docks the protein into a canonical SCF (SKP1-CUL1-F-box, with RBX1) E3 ubiquitin-protein ligase complex, and a C-terminal FBA/G domain that functions as a carbohydrate-binding (lectin) module. Within the SCF complex FBXO17 acts as the interchangeable substrate-recognition subunit: it has no intrinsic catalytic activity, and ubiquitin transfer is carried out by an E2 enzyme recruited through the RBX1 RING subunit. The FBA/G domain uses a conserved hydrophobic pocket (the Ser-Trp pair around residues 257-258) to recognize glycans on target glycoproteins. Unlike the high-mannose-binding members FBXO2 and FBXO6, FBXO17 does not bind high-mannose glycans; instead it binds complex-type N-glycans on glycoproteins and sulfated glycans (e.g. heparin), placing it in the glycoprotein quality-control / glycoprotein catabolism arm of the ubiquitin-proteasome system. FBXO17 is expressed across several tissues with notable expression in liver, kidney, heart, skeletal muscle and brain. By selecting substrates and delivering them to the SCF machinery it contributes to SCF-dependent, proteasome-mediated protein turnover. Beyond a family-level lectin role, the best-validated FBXO17 substrate is a protein rather than a glycan: in lung epithelium SCF(FBXO17) binds and polyubiquitinates the kinase GSK3-beta (GSK3B), driving its proteasomal degradation and thereby dampening GSK3-beta-dependent pro-inflammatory cytokine production (IL-6, CXCL1). FBXO17 also has a documented non-canonical, SCF-independent mode in antiviral innate immunity: through its F-box-associated region (not its F-box) it binds the transcription factor IRF3 and recruits protein phosphatase 2A (PP2A) to promote IRF3 dephosphorylation, negatively regulating type I interferon signaling.
Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 10; MARK_AS_OVER_ANNOTATED: 1; NEW: 1

PN Consistency Summary

Consistency: Largely consistent, with a deliberate MF divergence. PN projects the generic adaptor MF (GO:1990756); the review instead makes GO:0030246 carbohydrate binding the core MF (NEW, IDA PMID:18203720) — correct for an FBA/lectin F-box, and a refinement of, not a contradiction with, the PN family story. DR (GSK3beta substrate, IRF3/PP2A non-canonical mode) ↔ YAML agree.
PN story / NEW pressure: SPECIAL CASE re-examined. ERAD IBA (GO:0036503, verified real) is correctly MARK_AS_OVER_ANNOTATED: PMID:18203720 shows FBXO17 does NOT bind high-mannose glycans (only FBXO2/FBXO6 do GERAD), so the family ERAD propagation over-reaches — review call stands. Review ADDs GO:0030246 carbohydrate binding (verified real) — defensible, evidence-backed lectin MF absent from GOA. GO:0006516 glycoprotein catabolic process (verified real) ACCEPTed. Validated PROTEIN substrate exists (GSK3beta, Suber 2017) so not substrate-less.
Evidence alignment: PN cites only 15340381. Review anchors on PMID:18203720 (HIGH, full text, the lectin/SCF characterization) plus many interactome PMIDs (all non-core protein binding) and Falcon GSK3beta/IRF3 leads (VERIFIED notes). Strong divergence in depth, no conflict.
Verdict: Consistent; ERAD over-annotation call confirmed (no high-mannose binding). PN's generic GO:1990756 under-specifies the FBA lectin MF — review's GO:0030246 is the better gene-level MF.

Full Consistency Review

UniProt: Q96EF6 · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|FBA (lectin subfamily, aux domain IPR007397) ; PN-node mapping: subtype/type no_mapping; group Cul1 substrate receptor=mapped / ok_for_propagation_to_go → GO:1990756 (new_to_goa); class context_only/too_broad (GO:0061630).
Consistency: Largely consistent, with a deliberate MF divergence. PN projects the generic adaptor MF (GO:1990756); the review instead makes GO:0030246 carbohydrate binding the core MF (NEW, IDA PMID:18203720) — correct for an FBA/lectin F-box, and a refinement of, not a contradiction with, the PN family story. DR (GSK3beta substrate, IRF3/PP2A non-canonical mode) ↔ YAML agree.
PN story / NEW pressure: SPECIAL CASE re-examined. ERAD IBA (GO:0036503, verified real) is correctly MARK_AS_OVER_ANNOTATED: PMID:18203720 shows FBXO17 does NOT bind high-mannose glycans (only FBXO2/FBXO6 do GERAD), so the family ERAD propagation over-reaches — review call stands. Review ADDs GO:0030246 carbohydrate binding (verified real) — defensible, evidence-backed lectin MF absent from GOA. GO:0006516 glycoprotein catabolic process (verified real) ACCEPTed. Validated PROTEIN substrate exists (GSK3beta, Suber 2017) so not substrate-less.
Mapping strategy: Gene refines the node's MF: PN's GO:1990756 is generic; for the FBA leaf the more informative MF is the lectin GO:0030246 (review) and the family adaptor role is still captured by the contributes_to GO:0061630. PN-projected GO:1990756 is broader than the review's chosen core MF — flag as the one place where PN altitude is less specific than the gene-level call.
Evidence alignment: PN cites only 15340381. Review anchors on PMID:18203720 (HIGH, full text, the lectin/SCF characterization) plus many interactome PMIDs (all non-core protein binding) and Falcon GSK3beta/IRF3 leads (VERIFIED notes). Strong divergence in depth, no conflict.
Verdict: Consistent; ERAD over-annotation call confirmed (no high-mannose binding). PN's generic GO:1990756 under-specifies the FBA lectin MF — review's GO:0030246 is the better gene-level MF.
Recommended edits: none to FBXO17-ai-review.yaml (ERAD MARK_AS_OVER_ANNOTATED and NEW carbohydrate-binding are sound). [MAP] for the FBA subfamily, prefer GO:0030246 (lectin) as the informative MF at gene level rather than propagating the generic GO:1990756; do not propagate ERAD (GO:0036503) from the FBA node to FBXO17.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXO17/FBXO17-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: Q96EF6
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.

📄 View Raw YAML

id: Q96EF6
gene_symbol: FBXO17
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXO17 (also FBG4, FBXO26) is a cytoplasmic F-box protein of the FBA/FBG
  (F-box-associated, "sugar-recognizing") lectin subfamily that also includes
  FBXO2, FBXO6, FBXO27 and FBXO44. It is built from an N-terminal F-box domain,
  which binds the adaptor SKP1 and thereby docks the protein into a canonical SCF
  (SKP1-CUL1-F-box, with RBX1) E3 ubiquitin-protein ligase complex, and a
  C-terminal FBA/G domain that functions as a carbohydrate-binding (lectin)
  module. Within the SCF complex FBXO17 acts as the interchangeable
  substrate-recognition subunit: it has no intrinsic catalytic activity, and
  ubiquitin transfer is carried out by an E2 enzyme recruited through the RBX1
  RING subunit. The FBA/G domain uses a conserved hydrophobic pocket (the
  Ser-Trp pair around residues 257-258) to recognize glycans on target
  glycoproteins. Unlike the high-mannose-binding members FBXO2 and FBXO6,
  FBXO17 does not bind high-mannose glycans; instead it binds complex-type
  N-glycans on glycoproteins and sulfated glycans (e.g. heparin), placing it in
  the glycoprotein quality-control / glycoprotein catabolism arm of the
  ubiquitin-proteasome system. FBXO17 is expressed across several tissues with
  notable expression in liver, kidney, heart, skeletal muscle and brain. By
  selecting substrates and delivering them to the SCF machinery it
  contributes to SCF-dependent, proteasome-mediated protein turnover. Beyond a
  family-level lectin role, the best-validated FBXO17 substrate is a protein rather
  than a glycan: in lung epithelium SCF(FBXO17) binds and polyubiquitinates the
  kinase GSK3-beta (GSK3B), driving its proteasomal degradation and thereby
  dampening GSK3-beta-dependent pro-inflammatory cytokine production (IL-6, CXCL1).
  FBXO17 also has a documented non-canonical, SCF-independent mode in antiviral
  innate immunity: through its F-box-associated region (not its F-box) it binds the
  transcription factor IRF3 and recruits protein phosphatase 2A (PP2A) to promote
  IRF3 dephosphorylation, negatively regulating type I interferon signaling.
existing_annotations:
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (PAN-GO/PANTHER) transfer of an ERAD role from the FBA lectin-ligase family.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      ERAD/GERAD is the role of the high-mannose-binding members of this family
      (FBXO2, FBXO6), which recognize the high-mannose signal on
      retrotranslocated misfolded ER glycoproteins. The experimental
      characterization of FBXO17 shows it does NOT bind high-mannose glycans and
      instead binds complex-type and sulfated glycans, so the authors
      explicitly conclude only FBXO2 and FBXO6 are likely to function in GERAD.
      The more general glycoprotein catabolic process / SCF-dependent catabolism
      terms better capture FBXO17's role; the specific ERAD assignment is a
      family-level over-propagation.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: Our results lead us to conclude that only some members of the FBA family (FBXO2 and FBXO6) could function in GERAD by recognizing the signature high mannose glycan moiety present on retrotranslocated ER proteins.
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: Does not bind high-mannose glycoproteins.
- 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 localization, consistent with FBXO17 being a cytoplasmic SCF substrate-recognition subunit.
    action: ACCEPT
    reason: >-
      FBA proteins are described as cytoplasmic F-box proteins; the localization
      is consistent with cytosolic SCF assembly. Correct but generic relative to
      the SCF complex annotation.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0006516
    label: glycoprotein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic transfer of a glycoprotein-catabolism role; FBXO17 recognizes glycans on glycoprotein substrates and feeds them to the SCF/proteasome system.
    action: ACCEPT
    reason: >-
      Captures the core biological role of the FBA family in glycoprotein
      quality control. FBXO17 binds complex and sulfated glycoproteins via its
      FBA/G domain and is a substrate receptor that targets glycoproteins for
      degradation, consistent with this term.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: These differences in substrate recognition, SCF complex formation, and tissue distribution suggest that FBA proteins play diverse roles in glycoprotein quality control.
- 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 SCF complex membership, the defining cellular context for FBXO17 as an F-box protein.
    action: ACCEPT
    reason: >-
      Core localization/context. Directly demonstrated experimentally for FBXO17
      (co-precipitates SKP1, CUL1 and RBX1) and supported by ComplexPortal
      (CPX-7927, SCF E3 ubiquitin ligase complex, FBXO17 variant).
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex.
- 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 complexes containing FBXO17.
    action: ACCEPT
    reason: >-
      Core biological process. As an F-box substrate receptor, FBXO17 directs
      target glycoproteins into SCF-dependent, proteasome-mediated degradation.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: When an SCF complex binds a substrate protein, a ubiquitin-conjugating enzyme associates with the complex via Rbx1 and ubiquitinates the substrate protein.
- 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 that the F-box subunit contributes substrate specificity to the catalytically active SCF complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      F-box proteins have no intrinsic catalytic activity; ubiquitin transfer is
      performed by the E2 enzyme recruited through the RBX1 RING subunit. The
      contributes_to qualifier correctly attributes the holo-complex activity to
      FBXO17 as a substrate receptor, but FBXO17 itself is not the catalytic
      entity, so this is retained as non-core rather than as a core molecular
      function (the lectin/carbohydrate-binding activity is the core MF).
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: ARBA machine-learning electronic assignment of cytoplasmic localization, redundant with the IBA cytoplasm annotation.
    action: ACCEPT
    reason: Consistent with FBXO17 being a cytoplasmic F-box/SCF substrate receptor; redundant with the IBA cytoplasm annotation.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145461
  qualifier: enables
  review:
    summary: IntAct interaction with CUL1 (Q13616) from a quantitative proteomics survey of cullin-RING ligase networks; CUL1 is the scaffold of the SCF complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the functionally meaningful FBXO17-CUL1 interaction (SCF scaffold),
      but bare protein binding is uninformative per curation guidelines; the SCF
      membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) from a proteome-scale interactome map; SKP1 is the F-box adaptor that links FBXO17 into the SCF complex.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the core SKP1 interaction, but bare protein binding is uninformative;
      the SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  qualifier: enables
  review:
    summary: IntAct interaction with SKP1 (P63208) captured in a Polycomb complexome AP-MS map. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from a large-scale interactome (BioPlex). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the SKP1/CUL1 SCF interactions but bare protein binding is uninformative; captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map capturing numerous FBXO17 partners (SKP1 plus many candidate substrates/Y2H hits such as ADAMTSL4, KRT75, RUNX1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-throughput binary interactome; many partners may be candidate
      glycoprotein substrates but bare protein binding is uninformative and not a
      core function.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome capturing FBXO17 partners SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; Q13616: CUL1; NbExp=11; IntAct=EBI-2510157, EBI-359390;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map study capturing FBXO17 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records SCF-component interactions but bare protein binding is uninformative; captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:34445249
  qualifier: part_of
  review:
    summary: ComplexPortal (NAS) assignment of SCF complex membership, consistent with the FBXO17-variant SCF complex (CPX-7927).
    action: ACCEPT
    reason: >-
      Core context; FBXO17 is the F-box substrate-recognition subunit of an SCF
      complex, supported experimentally and by ComplexPortal CPX-7927.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'ComplexPortal; CPX-7927; SCF E3 ubiquitin ligase complex, FBXO17 variant.'
- 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: ComplexPortal (NAS) assignment of SCF-dependent proteasomal degradation, the generic process executed by SCF complexes.
    action: ACCEPT
    reason: >-
      Core biological process for an F-box substrate receptor; SCF complexes
      poly-ubiquitinate substrates to target them for proteasomal degradation.
    supported_by:
    - reference_id: PMID:34445249
      supporting_text: The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization within the CRL1/SCF neddylation pathway. Consistent with cytoplasmic SCF assembly.
    action: ACCEPT
    reason: Correct localization; cytosol is the compartment of SCF assembly/neddylation. Redundant with the cytoplasm annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CRL1 neddylation reaction). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CAND1 binding to cytosolic CRL ligases). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COMMD displacement of CAND1 from cytosolic CRL ligases). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylation of cytosolic CRL ligases). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (DCUN1D3 binding to CRL1). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate, antigen processing/proteasome pathway). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub complex). Redundant cytosol annotation.
    action: ACCEPT
    reason: Correct localization; redundant with other cytoplasm/cytosol annotations.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: how glycoproteins processed by the Golgi might become available to interact with cytoplasmic FBA proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IDA
  original_reference_id: PMID:18203720
  qualifier: enables
  review:
    summary: Direct experimental demonstration that FBXO17 binds SCF components (SKP1, CUL1) by co-immunoprecipitation. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: >-
      Records the experimentally demonstrated FBXO17-SCF interaction, but bare
      protein binding is uninformative; SCF membership is captured by GO:0019005.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18203720
  qualifier: enables
  review:
    summary: IntAct interactions with SKP1 (P63208) and CUL1 (Q13616) from the FBXO17 characterization study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the core SKP1/CUL1 SCF interactions, but bare protein binding is uninformative; captured by GO:0019005.
    supported_by:
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: 'Q96EF6; P63208: SKP1; NbExp=20; IntAct=EBI-2510157, EBI-307486;'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:18203720
  qualifier: part_of
  review:
    summary: Direct experimental evidence that FBXO17 assembles into an SCF complex (co-precipitation of SKP1, CUL1 and RBX1; mutagenesis of the glycan-binding pocket). Core cellular context.
    action: ACCEPT
    reason: >-
      Core, experimentally demonstrated localization/context. FBXO17 binds SKP1
      directly via its F-box domain and incorporates into a full SCF complex.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: All FBA family members co-immunoprecipitated components of the SCF complex
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: Interacts with SKP1 and CUL1. {ECO:0000269|PubMed:18203720}.
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IDA
  original_reference_id: PMID:18203720
  qualifier: enables
  review:
    summary: >-
      Proposed annotation for FBXO17's core lectin molecular function, which is
      not currently in GOA. The FBA/G domain directly binds glycans
      (complex-type glycoproteins and sulfated glycans such as heparin) via a
      conserved hydrophobic pocket; FBXO17 does not bind high-mannose glycans.
    action: NEW
    reason: >-
      The defining molecular function of FBXO17 as a sugar-recognizing F-box
      protein is carbohydrate binding, demonstrated experimentally by glycan
      arrays and glycoprotein pulldowns (heparin, chondroitin sulfate,
      lactoferrin), yet there is no corresponding molecular-function annotation
      in the existing GOA set. Adding GO:0030246 captures this lectin activity.
    supported_by:
    - reference_id: PMID:18203720
      supporting_text: FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans.
    - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
      supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:18203720
  title: Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.
  findings:
  - statement: >-
      FBXO17 is a member of the FBA lectin family of F-box proteins; it does NOT
      bind high-mannose glycans but binds complex-type glycoproteins (e.g.
      lactoferrin) and sulfated glycans (heparin strongly, chondroitin sulfate
      weakly) via a conserved hydrophobic pocket in the FBA/G domain, and it
      assembles into a canonical SCF complex with SKP1, CUL1 and RBX1.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available (PMC2442310). Definitive experimental characterization
      of human FBXO17 substrate binding and SCF complex formation; establishes
      that FBXO17 binds complex and sulfated glycans, NOT high-mannose glycans,
      and that FBA F-box proteins have no intrinsic catalytic activity. Source of
      the SCF complex (IDA) and substrate-binding annotations.
- id: PMID:21145461
  title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Quantitative CRL-network proteomics; source of the FBXO17-CUL1 (Q13616) interaction. Abstract-only in cache.
- 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 the FBXO17-SKP1 (P63208) 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: AP-MS complexome map; source of an FBXO17-SKP1 (P63208) bare protein binding annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex-type interactome; source of FBXO17-SKP1/CUL1 bare protein binding annotations.
- 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 many FBXO17 bare protein binding annotations (SKP1 plus diverse Y2H hits).
- 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 FBXO17-SKP1/CUL1 bare protein binding annotations.
- id: PMID:34445249
  title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability.
  findings:
  - statement: SCF (SKP1-CUL1-F-box) complexes are E3 ubiquitin ligases that modify substrates with poly-ubiquitin chains for proteasomal degradation, with the variable F-box protein conferring substrate specificity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review of SCF biology; basis for the ComplexPortal NAS SCF complex and SCF-dependent catabolism annotations. Abstract-only in cache.
- 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 FBXO17-SKP1/CUL1 bare protein binding annotations.
- 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/FBXO17/FBXO17-deep-research-falcon.md
  title: Falcon deep research report for human FBXO17
  findings:
  - statement: FBXO17 (also known as FBG4) is the substrate-recognition adaptor of an SCF-type E3 ubiquitin ligase (SCF^FBXO17), with the ~40-aa F-box domain binding SKP1 to link the substrate-recognition module to the CUL1-RBX1 catalytic core.
    supporting_text: SCF E3 ubiquitin ligases use F-box proteins as substrate adaptors**; the ~40-aa **F-box domain** binds **SKP1**, linking the variable substrate-recognition module to the CUL1-RBX1 catalytic core.
  - statement: The best-validated FBXO17 substrate is the protein kinase GSK3-beta; SCF^FBXO17 associates with GSK3-beta, promotes its polyubiquitination, and drives proteasome-dependent turnover in lung epithelial cells.
    supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β.
  - statement: By degrading GSK3-beta, FBXO17 dampens GSK3-beta-dependent pro-inflammatory cytokine production; FBXO17 overexpression reduces TNF-alpha/LPS-induced IL-6 and KC/CXCL1, partially rescued by GSK3-beta re-expression.
    supporting_text: FBXO17 overexpression reduces **TNFα- and LPS-induced IL-6 and KC/CXCL1**.
  - statement: FBXO17 has a non-canonical, SCF-independent mode that does not require the F-box domain - it binds IRF3 and recruits PP2A to promote IRF3 dephosphorylation, negatively regulating type I interferon signaling.
    supporting_text: FBXO17 can regulate signaling **independently of its canonical SCF function** by recruiting **PP2A** to the transcription factor **IRF3** to promote IRF3 dephosphorylation and suppress type I interferon signaling. This is explicitly described as not requiring the F-box domain and using the "F-box associated region."
  - statement: FBXO17 and its demonstrated substrate GSK3-beta colocalize in the cytoplasm, consistent with a cytoplasmic site of action.
    supporting_text: Direct experimental localization in the mechanistic SCF substrate study indicates **cytoplasmic colocalization** of FBXO17 with its demonstrated substrate GSK3β.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis anchored on primary mechanistic papers (Suber et al. J Biol Chem 2017 for SCF^FBXO17-GSK3beta degradation/inflammation; Peng et al. J Immunol 2017 for the non-canonical IRF3/PP2A scaffold) and the Skaar 2013 SCF review. These establish a validated PROTEIN substrate (GSK3beta) and a non-canonical signaling-scaffold role, both absent from current GOA; cross-checked against UniProt (which records the complex/sulfated-glycan lectin activity). Cancer association studies are model-dependent and treated as leads only.
core_functions:
- description: >-
    Carbohydrate-binding (lectin) substrate-recognition subunit of an SCF
    (SKP1-CUL1-F-box) E3 ubiquitin ligase complex. The C-terminal FBA/G domain
    binds glycans on glycoprotein substrates (complex-type N-glycans and sulfated
    glycans such as heparin, but not high-mannose glycans) via a conserved
    hydrophobic pocket, selecting glycosylated targets for the SCF machinery.
  molecular_function:
    id: GO:0030246
    label: carbohydrate binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18203720
    supporting_text: FBXO17 bound heparin strongly and chondroitin sulfate weakly, suggesting that FBXO17 binds sulfated glycans.
  - reference_id: file:human/FBXO17/FBXO17-uniprot.txt
    supporting_text: Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides. Also recognizes sulfated glycans.
  directly_involved_in:
  - id: GO:0006516
    label: glycoprotein catabolic process
- description: >-
    F-box substrate receptor that links selected glycoprotein substrates into a
    SKP1-CUL1-RBX1 SCF complex (binding SKP1 via its F-box domain), contributing
    substrate specificity to SCF-dependent, proteasome-mediated protein
    degradation. FBXO17 has no intrinsic catalytic activity; ubiquitin transfer
    is performed by the SCF-associated E2/RBX1 module.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18203720
    supporting_text: All FBA proteins co-precipitated components of the canonical SCF complex (Skp1, Cullin1, and Rbx1)
  - reference_id: file:human/FBXO17/FBXO17-deep-research-falcon.md
    supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: >-
    Beyond glycoprotein recognition, SCF(FBXO17) targets at least one validated
    protein substrate, the kinase GSK3-beta (GSK3B): FBXO17 binds GSK3-beta and
    promotes its polyubiquitination and proteasomal degradation in lung epithelium,
    thereby restraining GSK3-beta-dependent pro-inflammatory cytokine production
    (IL-6, CXCL1). This indicates FBXO17's substrate scope is not limited to its
    lectin/glycan-recognition activity.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/FBXO17/FBXO17-deep-research-falcon.md
    supporting_text: A detailed biochemical study in lung epithelial cells shows that **FBXO17 associates with GSK3β**, promotes **polyubiquitination** of GSK3β, and drives **proteasome-dependent turnover** of GSK3β.
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: What are the physiological glycoprotein substrates that FBXO17 selects for SCF-dependent ubiquitination, and through which complex-type or sulfated glycan determinants are they recognized?
- question: In which subcellular/secretory context do cytoplasmic FBXO17 and its Golgi-processed (sulfated/complex) glycoprotein substrates meet, given that sulfation and complex-glycan maturation occur in the Golgi?
- question: Is recognition of the validated protein substrate GSK3-beta glycan-dependent (requiring the FBA/G-domain pocket and the 151-200 region) or glycan-independent, and how broad is FBXO17's protein-substrate repertoire relative to its glycoprotein substrates?
- question: How is FBXO17's non-canonical, F-box-independent IRF3/PP2A scaffolding function partitioned from its canonical SCF substrate-receptor activity, and which domains/post-translational signals switch FBXO17 between these modes?
suggested_experiments:
- description: Identify endogenous FBXO17 substrates by comparing the ubiquitinome/proteome of FBXO17-knockout versus wild-type cells, with parallel glycoproteomics to test enrichment for complex-type and sulfated glycoproteins, and to confirm GSK3-beta as an endogenous substrate.
- description: Reconstitute SCF(FBXO17) in vitro with SKP1, CUL1, RBX1 and an E2 to test ubiquitination of candidate complex/sulfated glycoproteins and of GSK3-beta, using the FBA/G-domain pocket mutant (S257A/W258A) and the 151-200 deletion as substrate-recognition-deficient controls to dissect glycan-dependent versus protein-dependent recognition.
- description: Dissect the non-canonical IRF3/PP2A scaffold mode by testing whether F-box-deletion and FBA-region mutants of FBXO17 still recruit PP2A to IRF3 and suppress type I interferon reporter activity, separating it from SCF-dependent ubiquitination.

FBXO17

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human FBXO17 (UniProt Q96EF6) Functional Annotation

1) Target verification and identity (critical disambiguation)

2) Key concepts and current understanding

2.1 What FBXO17 is (conceptual definition)

2.2 Two mechanistic “modes” of FBXO17 function

3) Experimentally supported molecular functions

3.1 FBXO17 as an SCF adaptor that targets GSK3β for degradation

3.2 Functional consequence in lung epithelia: dampening inflammatory cytokines

3.3 Antiviral innate immunity: negative regulation of type I IFN signaling (IRF3/PP2A)

3.4 Cancer cell biology contexts: divergent pathway effects across models

4) Subcellular localization (where the protein acts)

5) Pathways and biological processes implicated

5.1 Ubiquitin–proteasome system (UPS) / SCF E3 ligases

5.2 GSK3β-centered signaling

5.3 Type I interferon signaling (IRF3 axis)

5.4 Wnt/β-catenin pathway in cancer contexts

6) Recent developments (prioritizing 2023–2024)

6.1 2023–2024 literature availability specific to FBXO17 mechanisms

6.2 2023–2024 quantitative cohort/omics implementations where FBXO17 is a feature

7) Current applications and real-world implementations

8) Expert opinions and authoritative synthesis

9) Relevant statistics and quantitative data from recent studies

10) Evidence summary table (key studies)

11) Conclusions and research gaps

Key URLs (publication landing pages)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXO17 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (1)

Note

📄 View Raw YAML