FBXW12

UniProt ID: Q6X9E4
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXW12 (F-box only protein 35; FBXO12/FBXO35) is a member of the F-box/WD40 (FBXW) family, with an N-terminal F-box motif and a C-terminal beta-propeller of WD40 repeats. F-box proteins are the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif binds SKP1 (which bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller recognizes substrates and presents them for ubiquitination and proteasomal degradation. FBXW12 is ubiquitously expressed. It binds SKP1 and assembles into an SCF complex, and in human epithelial cells it functions as a substrate receptor that ubiquitinates the interleukin-22 receptor subunit IL22RA1: ectopic FBXW12 accelerates IL22RA1 degradation in resting and IL-22-stimulated cells, and FBXW12 reconstitutes IL22RA1 ubiquitination in a defined cell-free SCF system. Through this activity FBXW12 dampens IL-22/STAT3 signaling and acts as an epithelial cell-growth suppressor, with its knockdown enhancing proliferation, cell-cycle progression and JNK/ERK activation.

Proposed New Ontology Terms

ubiquitin-like ligase-substrate adaptor activity

Definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW12's annotation set.

Justification: FBXW12 directly bridges the substrate IL22RA1 to the SCF E3 ligase, binding SKP1 and the substrate and facilitating substrate ubiquitination in a reconstituted system. This substrate-adaptor molecular function is experimentally supported (PMID:26171402) and is more informative than the existing bare protein binding/complex-membership annotations; GO:1990756 should be added as the molecular function for FBXW12 as an SCF substrate receptor.

Parent term: ubiquitin-like ligase-substrate adaptor activity

Supporting Evidence:

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: ARBA machine-learning electronic assignment of cytoplasmic localization, a generic compartment consistent with cytosolic SCF assembly.
Reason: Plausible generic localization but electronically inferred and not directly demonstrated for FBXW12; subsumed by the more specific cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0016567 protein ubiquitination
IEA
GO_REF:0000041 		ACCEPT
Summary: UniPathway-derived general protein ubiquitination process; FBXW12 facilitates ubiquitination of its substrate IL22RA1 in a defined cell-free SCF system.
Reason: Correct process; FBXW12 facilitates substrate ubiquitination as an SCF subunit, directly demonstrated in vitro for IL22RA1, though the more specific GO:0031146 captures the proteasomal-degradation context.
Supporting Evidence:
PMID:26171402
facilitates ubiquitination of IL-22R in vitro
file:human/FBXW12/FBXW12-deep-research-falcon.md
In a cell-free system, IL-22R ubiquitination is observed when ubiquitin machinery and SCF constituents (including FBXW12) are present
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:26171402
The Human IL-22 Receptor Is Regulated through the Action of ... 		ACCEPT
Summary: Assignment of SCF complex membership; FBXW12 binds SKP1 and CUL1 and assembles with Rbx1 into a functional SCF E3 ligase (ComplexPortal CPX-7822, SCF complex FBXW12 variant).
Reason: Core assembly annotation, experimentally supported by demonstrated SKP1 (and CUL1) binding and reconstitution of FBXW12 into an active SCF that ubiquitinates IL-22R in vitro.
Supporting Evidence:
PMID:26171402
FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination
file:human/FBXW12/FBXW12-deep-research-falcon.md
FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:26171402
The Human IL-22 Receptor Is Regulated through the Action of ... 		ACCEPT
Summary: Assignment of involvement in SCF-dependent proteasomal degradation; FBXW12 drives proteasomal degradation of IL22RA1, shortening its half-life from ~6 h to ~2 h.
Reason: Core biological process, experimentally supported by accelerated IL22RA1 degradation upon FBXW12 expression and stabilization upon FBXW12 knockdown.
Supporting Evidence:
PMID:26171402
In the presence of overexpressed FBXW12, we observe an accelerated degradation of IL-22R with half-life closer to 2 hours
file:human/FBXW12/FBXW12-deep-research-falcon.md
IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW12 as an SCF subunit.
Reason: Plausible cytosolic localization for an SCF substrate receptor, consistent with FBXW12 assembling SCF and acting on IL22RA1 in cells, but derived from generic CRL pathway reactions rather than FBXW12-specific localization data.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW12.
Reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
Supporting Evidence:
file:human/FBXW12/FBXW12-uniprot.txt
Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex

Core Functions

Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that binds SKP1 and bridges substrate to the ligase; it ubiquitinates the IL-22 receptor subunit IL22RA1, targeting it for SCF-dependent proteasomal degradation.

Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:26171402
    FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination

By degrading IL22RA1, FBXW12 negatively regulates IL-22/STAT3 cytokine signaling and acts as an epithelial cell-growth suppressor, restraining proliferation and cell-cycle progression.

Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Supporting Evidence:

References

GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
PMID:26171402
The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor.
  • FBXW12 destabilizes human IL-22R (IL22RA1) in lung epithelia, binds SKP1, and facilitates IL22RA1 ubiquitination in a defined cell-free SCF system; FBXW12 knockdown increases IL22RA1 abundance and IL-22-induced STAT3 phosphorylation, and FBXW12 acts as an epithelial cell-growth suppressor (knockdown increases proliferation, cell-cycle progression and JNK/ERK activation).
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/FBXW12/FBXW12-deep-research-falcon.md
Falcon deep research report for human FBXW12
  • FBXW12 is an SCF-family E3 ligase subunit that physically associates with SKP1 and CUL1 and with IL-22R (IL22RA1), and reconstitutes IL-22R ubiquitination in a cell-free system, confirming it as a substrate-recognition adaptor rather than an enzyme.
    "FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor"
  • Ectopic FBXW12 accelerates IL-22R turnover (half-life ~6 h to ~2 h), and FBXW12 knockdown increases IL-22R abundance and IL-22-induced STAT3, ERK and JNK signaling, defining FBXW12 as a negative post-translational regulator of IL-22 signaling and an epithelial growth suppressor.
    "IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression"
  • Beyond IL-22R no additional validated FBXW12 substrate, ubiquitin linkage type, or definitive subcellular localization has been established, so substrate scope remains open.
    "additional validated FBXW12 protein substrates, ubiquitin linkage types, and definitive subcellular localization were not identified in the retrieved materials"
  • A circular RNA (circ-FBXW12) from the FBXW12 locus is discussed in diabetic nephropathy, but this circRNA biology is distinct from and must not be conflated with the linear FBXW12 protein's E3-adaptor function.
    "This evidence concerns **circRNA biology**, and should not be conflated with the **linear FBXW12 protein**'s E3-ligase substrate receptor activity"

Suggested Questions for Experts

Q: What is the substrate-recognition determinant (e.g. a phosphodegron) on IL22RA1 recognized by the FBXW12 WD40 propeller, and does FBXW12 have additional epithelial substrates beyond IL22RA1?

Q: Does FBXW12 loss-of-function in vivo enhance IL-22-dependent mucosal host defense or epithelial proliferation, as predicted from the cell-based growth-suppressor phenotype?

Suggested Experiments

Experiment: Map the IL22RA1 region/residues required for FBXW12 binding and ubiquitination, and test whether dephosphorylation or degron mutation abolishes recognition by the FBXW12 WD40 propeller.

Experiment: Generate FBXW12-knockout epithelial cells and tissues and assess endogenous IL22RA1 stability, IL-22-induced STAT3 signaling, proliferation, and identify the broader SCF(FBXW12) substrate repertoire by ubiquitinome profiling.

Deep Research

Falcon

(FBXW12-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 23 citations 2 artifacts 2026-06-13T07:15:39.305532
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000012 The table entry for FBXW12 with UniProt accession Q6X9E4 and its domain annotations (F-box domain, WD repeats) can be found in Tabl (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 FBXW12 (UniProt Q6X9E4) — functional annotation

1) Target verification (gene/protein identity)

Target confirmed: The symbol FBXW12 corresponds to human F-box/WD repeat-containing protein 12, and is explicitly mapped to UniProt Q6X9E4 in an interactome resource table that annotates the protein as an E3 Cullin-RING ligase (CRL) adaptor with F-box and WD-repeat (WD40) domains—consistent with the user-provided UniProt description. (poirson2017mappingtheinteractome pages 23-23, poirson2017mappingtheinteractome media 39749cd6)

Why this matters: F-box proteins are substrate-recognition subunits of SCF-type CRLs (SKP1–CUL1–F-box), and WD40 repeats commonly mediate recognition of phosphorylated degrons in target proteins. This domain logic supports FBXW12 acting as a substrate receptor in ubiquitin-mediated proteolysis (general mechanism summarized in authoritative reviews). (yumimoto2020fboxproteinsand pages 3-5, zeng2025skp1‐cul1‐f‐boxkeymolecular pages 1-3)

2) Key concepts and current understanding

2.1 SCF/CRL E3 ligases and F-box proteins (definitions)

Cullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases composed of (i) a Cullin scaffold, (ii) a RING protein (RBX1/RBX2) that recruits E2~ubiquitin, and (iii) an adaptor plus substrate receptor module that determines substrate specificity. (zhang2023advancesinthe pages 1-2)

The SCF complex (SKP1–CUL1–F-box) is a canonical CRL in which the F-box protein binds SKP1 and confers substrate specificity. F-box proteins are commonly classified by their C-terminal substrate-binding domain (e.g., Fbxw = WD40 repeat-containing). (zeng2025skp1‐cul1‐f‐boxkeymolecular pages 1-3, yumimoto2020fboxproteinsand pages 3-5)

Functional implication for FBXW12: As an FBXW-class protein (F-box + WD repeats), FBXW12 is expected to function as a substrate receptor that recruits specific proteins to an SCF/CRL for ubiquitination and proteasome-directed degradation (or other ubiquitin-dependent fates). The primary experimental substrate currently supported for FBXW12 is IL-22 receptor (IL-22R/IL-22RA1). (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)

3) Molecular function, pathway placement, and localization context

3.1 Primary experimentally supported function: IL-22 receptor downregulation

A focused mechanistic study in human epithelial systems identified FBXW12 as a previously undescribed SCF-family E3 ligase subunit that destabilizes the human IL-22 receptor (IL-22R) by promoting its ubiquitination and degradation. (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 1-2)

Key mechanistic findings include:
- Physical association with IL-22R: FBXW12 and IL-22R co-immunoprecipitate in cells. (franz2015thehumanil22 pages 3-5)
- Association with SCF machinery: FBXW12 associates with SCF components including SKP1 and CUL1, consistent with being an SCF substrate receptor. (franz2015thehumanil22 pages 3-5)
- Direct ubiquitination capacity in vitro: In a cell-free system, IL-22R ubiquitination is observed when ubiquitin machinery and SCF constituents (including FBXW12) are present. (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)

Quantitative effect size: IL-22R half-life is reported to be ~6 hours at baseline and is accelerated to ~2 hours with FBXW12 overexpression, supporting a substantial increase in receptor turnover. (franz2015thehumanil22 pages 3-5)

Ubiquitin linkage note: The available excerpts demonstrate ubiquitination and proteasome-directed degradation but do not specify ubiquitin linkage topology (e.g., K48 vs K63). (franz2015thehumanil22 pages 6-8, franz2015thehumanil22 pages 3-5)

3.2 Downstream pathway consequences: IL-22 → STAT3 and MAPK signaling

IL-22 signaling is classically transduced via JAK/STAT3 in epithelial cells. In the epithelial models used, FBXW12 knockdown increases IL-22R abundance and enhances IL-22 responsiveness:
- Increased STAT3 phosphorylation in response to IL-22 upon FBXW12 depletion. (franz2015thehumanil22 pages 5-6, franz2015thehumanil22 pages 1-2)
- Increased MAPK signaling with enhanced ERK and JNK phosphorylation (more constitutive and inducible activation reported). (franz2015thehumanil22 pages 6-8, franz2015thehumanil22 pages 5-6)

These data position FBXW12 as a negative post-translational regulator of IL-22R abundance and IL-22–dependent epithelial signaling.

3.3 Cellular localization context

Direct subcellular localization mapping of FBXW12 (e.g., nuclear vs cytosolic distribution) was not identified in the retrieved excerpts. However, the mechanism demonstrated—SCF association and receptor ubiquitination leading to degradation—places FBXW12 function within the intracellular ubiquitin–proteasome system and in the context of IL-22R processing/turnover in epithelial cells. (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)

4) Recent developments (prioritizing 2023–2024)

4.1 2023 infectious disease/IL-22 review reinforces FBXW12 as IL-22R negative regulator

A 2023 review of Th22/IL-22 in infectious diseases summarizes that FBXW12 degrades IL-22R and restricts lung epithelial proliferation, and further proposes that silencing FBXW12 may be a therapeutic method for infection-induced epithelial damage (review-level claim referencing prior primary research). (zhang2023currentknowledgeof pages 11-12)

4.2 2024 reproductive biology review: testis-enriched expression signal

A 2024 review on F-box proteins in spermatogenesis reports FBXW12 among F-box genes with highest transcript levels in human testis, suggesting a potential (but as yet mechanistically unresolved) role in male germ cell biology. This is currently expression-based inference, not direct functional proof. (xuan2024theemergingand pages 7-8)

4.3 circRNA literature (important caveat: not the FBXW12 protein)

A 2023 mini-review of circRNAs in diabetic nephropathy discusses circ-FBXW12 (a circular RNA derived from the FBXW12 locus) as being overexpressed in diabetic nephropathy model systems; suppressing circ-FBXW12 reduced mesangial cell proliferation, oxidative stress, and extracellular matrix production via a miR-31-5p/LIN28B axis. This evidence concerns circRNA biology, and should not be conflated with the linear FBXW12 protein’s E3-ligase substrate receptor activity. (basudkar2023currentclinicalinsights pages 6-8)

5) Current applications and real-world implementations

5.1 Proposed therapeutic application: enhancing IL-22 signaling at mucosal surfaces

The primary FBXW12–IL-22R study explicitly suggests that therapeutic inhibition of FBXW12 could increase IL-22R abundance and augment IL-22 signaling, potentially bolstering mucosal host defense and infection containment. (franz2015thehumanil22 pages 1-2, franz2015thehumanil22 pages 6-8)

A 2023 infectious disease review reiterates a similar translational concept, proposing FBXW12 silencing as a strategy to mitigate infection-induced epithelial damage (review-level synthesis). (zhang2023currentknowledgeof pages 11-12)

Clinical trial landscape: A ClinicalTrials.gov search using FBXW12/FBXO35/FBW12 terms did not yield relevant FBXW12-targeted interventional trials in the retrieved results. (tool result; no relevant trial context IDs available)

5.2 Biomarkers and disease-network uses (circRNA context)

The circRNA diabetic nephropathy review frames circRNAs as potential diagnostic/therapeutic biomarkers and includes circ-FBXW12 among reported DN-associated circRNAs, but this is not yet a validated clinical biomarker implementation for FBXW12. (basudkar2023currentclinicalinsights pages 6-8, basudkar2023currentclinicalinsights pages 1-2)

6) Expert opinion and interpretation (evidence-weighted)

High-confidence function (direct evidence): FBXW12 is best-supported as an SCF/CRL substrate receptor that promotes ubiquitination and degradation of IL-22R, thereby attenuating IL-22–STAT3/MAPK signaling and acting as an epithelial growth suppressor in cell culture systems. (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)

Moderate-confidence biological roles (inference): Given its domain architecture (F-box + WD repeats) and SCF paradigm, FBXW12 likely recognizes additional substrates beyond IL-22R, potentially via WD-repeat mediated interactions with phosphorylated motifs; however, additional validated substrates were not identified in the retrieved corpus. (poirson2017mappingtheinteractome media 39749cd6, yumimoto2020fboxproteinsand pages 3-5)

Lower-confidence / hypothesis-generating signals: The testis-enriched transcript observation suggests reproductive roles but currently lacks mechanistic validation. (xuan2024theemergingand pages 7-8)

7) Relevant statistics and data (from recent studies / key sources)

From primary mechanistic FBXW12 study (2015):
- IL-22R half-life decreased from ~6 h to ~2 h with FBXW12 overexpression. (franz2015thehumanil22 pages 3-5)
- Baseline cell-cycle distribution in control: ~80% G0/G1, ~14% S, ~4% G2/M; proliferation differences significant by ANOVA (p<0.05) at 24 h and 40 h with 5 replicates/group in one reported experiment. (franz2015thehumanil22 pages 6-8)

From 2023 diabetic nephropathy circRNA mini-review (epidemiology):
- In the USA, ~1 in 3 people with diabetes have diabetic nephropathy; globally DN occurs in ~30–40% of patients with diabetes. (basudkar2023currentclinicalinsights pages 1-2)

Evidence summary table

Evidence type Finding Molecular partners/substrates Biological context (cell type/tissue/disease) Key quantitative/statistical data Publication (with year) URL/DOI Citation context ID
Primary Human FBXW12 functions as an SCF-family E3 ligase subunit that binds IL-22R and promotes its ubiquitination and degradation IL-22R/IL-22RA1; SKP1; CUL1 Human epithelial cells; Beas-2B and HeLa; mucosal/airway epithelial signaling IL-22R half-life shortened from ~6 h to ~2 h with FBXW12 overexpression; representative statistics include p<0.05, n=4 in degradation assays Franz et al. (2015) https://doi.org/10.1155/2015/912713 (franz2015thehumanil22 pages 3-5)
Primary FBXW12 knockdown increases IL-22R abundance and enhances downstream IL-22 signaling IL-22R; STAT3; ERK; JNK HeLa epithelial cells; IL-22-responsive epithelial signaling Relative p-STAT3 densitometry values reported as 0, 0.75, 1.5, 2.25 under assay conditions; IL-22 at 60 ng/mL for 60 min in signaling assays Franz et al. (2015) https://doi.org/10.1155/2015/912713 (franz2015thehumanil22 pages 5-6)
Primary FBXW12 behaves as an epithelial growth suppressor; depletion promotes proliferation and cell-cycle progression FBXW12-linked IL-22R/STAT3/MAPK axis HeLa epithelial cells Control cell-cycle distribution approximately 80% G0/G1, 14% S, 4% G2/M; growth differences significant at 24 h and 40 h by ANOVA (p<0.05), 5 replicates/group Franz et al. (2015) https://doi.org/10.1155/2015/912713 (franz2015thehumanil22 pages 6-8)
Review FBXW12 degrades IL-22R and restricts lung epithelial proliferation; silencing FBXW12 is proposed as a therapeutic strategy for infection-induced epithelial damage IL-22R Infectious disease / lung epithelium / IL-22 biology No new quantitative data reported in the review excerpt Zhang et al. (2023) https://doi.org/10.3390/pathogens12020176 (zhang2023currentknowledgeof pages 11-12)
Review FBXW12 is among F-box genes with high transcript levels in human testis, suggesting possible spermatogenesis-related roles, but direct mechanisms remain unresolved Not specified for FBXW12 in excerpt Human testis / spermatogenesis / male infertility context Qualitative expression statement only; no numeric values in excerpt Xuan et al. (2024) https://doi.org/10.1186/s13619-024-00196-9 (xuan2024theemergingand pages 7-8)
Bioinformatic/annotation FBXW12 maps to UniProt Q6X9E4 and is annotated as an E3 CRL adaptor with F-box and WD-repeat domains, supporting classification as an FBXW substrate receptor F-box domain; WD repeats Human protein annotation / domain architecture Length reported as 394 aa in table entry Poirson et al. (2017) https://doi.org/10.1111/febs.14193 (poirson2017mappingtheinteractome pages 23-23, poirson2017mappingtheinteractome media 39749cd6)
Review (circRNA, not linear protein) circ-FBXW12 is overexpressed in diabetic nephropathy models; its knockdown reduces proliferation, oxidative stress, and ECM production via the miR-31-5p/LIN28B axis circ-FBXW12; miR-31-5p; LIN28B Human mesangial cells / diabetic nephropathy Epidemiology in review: ~1 in 3 people with diabetes in the USA have DN; globally DN occurs in 30–40% of patients with diabetes Basudkar et al. (2023) https://doi.org/10.1515/dine-2023-0007 (basudkar2023currentclinicalinsights pages 6-8, basudkar2023currentclinicalinsights pages 1-2)

Table: This table summarizes direct and indirect evidence relevant to human FBXW12 (UniProt Q6X9E4), emphasizing experimentally supported function, pathway context, domain annotation, and translational implications. It distinguishes evidence on the linear FBXW12 protein from circ-FBXW12 literature to avoid gene-product conflation.

References (URLs and publication dates)

  • Franz J, Jerome J, Lear T, Gong Q, Weathington NM. The Human IL-22 Receptor Is Regulated through the Action of the Novel E3 Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor. Journal of Immunology Research. 2015-06. https://doi.org/10.1155/2015/912713 (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)
  • Zhang K, Chen L, Zhu C, Zhang M, Liang C. Current Knowledge of Th22 Cell and IL-22 Functions in Infectious Diseases. Pathogens. 2023-01. https://doi.org/10.3390/pathogens12020176 (zhang2023currentknowledgeof pages 11-12)
  • Basudkar V, Ajgaonkar S, Mehta D, Nair S. Current clinical insights into circRNAs and signal transduction in diabetic nephropathy. Diabetic Nephropathy. 2023-09 (received 2023-06-19; accepted 2023-07-28). https://doi.org/10.1515/dine-2023-0007 (basudkar2023currentclinicalinsights pages 1-2, basudkar2023currentclinicalinsights pages 6-8)
  • Xuan Z, Ruan J, Zhou C, Li ZM. The emerging and diverse roles of F-box proteins in spermatogenesis and male infertility. Cell Regeneration. 2024-06. https://doi.org/10.1186/s13619-024-00196-9 (xuan2024theemergingand pages 7-8)
  • Poirson J et al. Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system. The FEBS Journal. 2017-10. https://doi.org/10.1111/febs.14193 (FBXW12: UniProt Q6X9E4; F-box and WD repeats shown in table) (poirson2017mappingtheinteractome media 39749cd6)
  • Yumimoto K, Yamauchi Y, Nakayama KI. F-Box Proteins and Cancer. Cancers. 2020-05. https://doi.org/10.3390/cancers12051249 (SCF definitions and Fbxw phosphodegron recognition paradigm) (yumimoto2020fboxproteinsand pages 3-5)
  • Zhang X et al. Advances in the potential roles of Cullin-RING ligases in regulating autoimmune diseases. Frontiers in Immunology. 2023-03. https://doi.org/10.3389/fimmu.2023.1125224 (CRL definitions; immune pathway context) (zhang2023advancesinthe pages 1-2, zhang2023advancesinthe pages 10-12)

Limitations of the current evidence base

  • Beyond IL-22R, additional validated FBXW12 protein substrates, ubiquitin linkage types, and definitive subcellular localization were not identified in the retrieved materials; further targeted proteomics/biochemistry literature may exist but was not captured here. (franz2015thehumanil22 pages 3-5, franz2015thehumanil22 pages 6-8)
  • Several 2023 sources discuss circ-FBXW12, which is biologically distinct from the FBXW12 protein; conclusions about circRNA function should not be attributed to the protein without direct evidence. (basudkar2023currentclinicalinsights pages 6-8)

References

  1. (poirson2017mappingtheinteractome pages 23-23): Juline Poirson, Elise Biquand, Marie‐Laure Straub, Patricia Cassonnet, Yves Nominé, Louis Jones, Sylvie van der Werf, Gilles Travé, Katia Zanier, Yves Jacob, Caroline Demeret, and Murielle Masson. Mapping the interactome of hpv e6 and e7 oncoproteins with the ubiquitin‐proteasome system. The FEBS Journal, 284:3171-3201, Oct 2017. URL: https://doi.org/10.1111/febs.14193, doi:10.1111/febs.14193. This article has 74 citations.

  2. (poirson2017mappingtheinteractome media 39749cd6): Juline Poirson, Elise Biquand, Marie‐Laure Straub, Patricia Cassonnet, Yves Nominé, Louis Jones, Sylvie van der Werf, Gilles Travé, Katia Zanier, Yves Jacob, Caroline Demeret, and Murielle Masson. Mapping the interactome of hpv e6 and e7 oncoproteins with the ubiquitin‐proteasome system. The FEBS Journal, 284:3171-3201, Oct 2017. URL: https://doi.org/10.1111/febs.14193, doi:10.1111/febs.14193. This article has 74 citations.

  3. (yumimoto2020fboxproteinsand pages 3-5): Kanae Yumimoto, Yuhei Yamauchi, and Keiichi I. Nakayama. F-box proteins and cancer. Cancers, 12:1249, May 2020. URL: https://doi.org/10.3390/cancers12051249, doi:10.3390/cancers12051249. This article has 70 citations.

  4. (zeng2025skp1‐cul1‐f‐boxkeymolecular pages 1-3): Xiangrong Zeng, Jiaying Cao, Juan Xu, Zihua Zhou, Chen Long, Yanhong Zhou, and Jingqiong Tang. Skp1‐cul1‐f‐box: key molecular targets affecting disease progression. The FASEB Journal, Jan 2025. URL: https://doi.org/10.1096/fj.202402816rr, doi:10.1096/fj.202402816rr. This article has 15 citations.

  5. (zhang2023advancesinthe pages 1-2): Xiaoying Zhang, Yu’e Liu, Tong Zhang, Yuying Tan, Xiangpeng Dai, Yong-Guang Yang, and Xiaoling Zhang. Advances in the potential roles of cullin-ring ligases in regulating autoimmune diseases. Frontiers in Immunology, Mar 2023. URL: https://doi.org/10.3389/fimmu.2023.1125224, doi:10.3389/fimmu.2023.1125224. This article has 14 citations and is from a peer-reviewed journal.

  6. (franz2015thehumanil22 pages 3-5): Joseph Franz, Jacob Jerome, Travis Lear, Qiaoke Gong, and Nathaniel M. Weathington. The human il-22 receptor is regulated through the action of the novel e3 ligase subunit fbxw12, which functions as an epithelial growth suppressor. Journal of Immunology Research, 2015:1-9, Jun 2015. URL: https://doi.org/10.1155/2015/912713, doi:10.1155/2015/912713. This article has 13 citations and is from a peer-reviewed journal.

  7. (franz2015thehumanil22 pages 6-8): Joseph Franz, Jacob Jerome, Travis Lear, Qiaoke Gong, and Nathaniel M. Weathington. The human il-22 receptor is regulated through the action of the novel e3 ligase subunit fbxw12, which functions as an epithelial growth suppressor. Journal of Immunology Research, 2015:1-9, Jun 2015. URL: https://doi.org/10.1155/2015/912713, doi:10.1155/2015/912713. This article has 13 citations and is from a peer-reviewed journal.

  8. (franz2015thehumanil22 pages 1-2): Joseph Franz, Jacob Jerome, Travis Lear, Qiaoke Gong, and Nathaniel M. Weathington. The human il-22 receptor is regulated through the action of the novel e3 ligase subunit fbxw12, which functions as an epithelial growth suppressor. Journal of Immunology Research, 2015:1-9, Jun 2015. URL: https://doi.org/10.1155/2015/912713, doi:10.1155/2015/912713. This article has 13 citations and is from a peer-reviewed journal.

  9. (franz2015thehumanil22 pages 5-6): Joseph Franz, Jacob Jerome, Travis Lear, Qiaoke Gong, and Nathaniel M. Weathington. The human il-22 receptor is regulated through the action of the novel e3 ligase subunit fbxw12, which functions as an epithelial growth suppressor. Journal of Immunology Research, 2015:1-9, Jun 2015. URL: https://doi.org/10.1155/2015/912713, doi:10.1155/2015/912713. This article has 13 citations and is from a peer-reviewed journal.

  10. (zhang2023currentknowledgeof pages 11-12): Kunyu Zhang, Lei Chen, Chenyu Zhu, Meng Zhang, and Chaozhao Liang. Current knowledge of th22 cell and il-22 functions in infectious diseases. Pathogens, 12:176, Jan 2023. URL: https://doi.org/10.3390/pathogens12020176, doi:10.3390/pathogens12020176. This article has 55 citations.

  11. (xuan2024theemergingand pages 7-8): Zhuang Xuan, Jun Ruan, Canquan Zhou, and Zhi-ming Li. The emerging and diverse roles of f-box proteins in spermatogenesis and male infertility. Cell Regeneration, Jun 2024. URL: https://doi.org/10.1186/s13619-024-00196-9, doi:10.1186/s13619-024-00196-9. This article has 5 citations.

  12. (basudkar2023currentclinicalinsights pages 6-8): Vivek Basudkar, Saiprasad Ajgaonkar, Dilip Mehta, and Sujit Nair. Current clinical insights into circrnas and signal transduction in diabetic nephropathy. Diabetic Nephropathy, 3:58-67, Sep 2023. URL: https://doi.org/10.1515/dine-2023-0007, doi:10.1515/dine-2023-0007. This article has 3 citations.

  13. (basudkar2023currentclinicalinsights pages 1-2): Vivek Basudkar, Saiprasad Ajgaonkar, Dilip Mehta, and Sujit Nair. Current clinical insights into circrnas and signal transduction in diabetic nephropathy. Diabetic Nephropathy, 3:58-67, Sep 2023. URL: https://doi.org/10.1515/dine-2023-0007, doi:10.1515/dine-2023-0007. This article has 3 citations.

  14. (zhang2023advancesinthe pages 10-12): Xiaoying Zhang, Yu’e Liu, Tong Zhang, Yuying Tan, Xiangpeng Dai, Yong-Guang Yang, and Xiaoling Zhang. Advances in the potential roles of cullin-ring ligases in regulating autoimmune diseases. Frontiers in Immunology, Mar 2023. URL: https://doi.org/10.3389/fimmu.2023.1125224, doi:10.3389/fimmu.2023.1125224. This article has 14 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. zhang2023advancesinthe pages 1-2
  2. zhang2023currentknowledgeof pages 11-12
  3. xuan2024theemergingand pages 7-8
  4. basudkar2023currentclinicalinsights pages 6-8
  5. basudkar2023currentclinicalinsights pages 1-2
  6. yumimoto2020fboxproteinsand pages 3-5
  7. poirson2017mappingtheinteractome pages 23-23
  8. zhang2023advancesinthe pages 10-12
  9. https://doi.org/10.1155/2015/912713
  10. https://doi.org/10.3390/pathogens12020176
  11. https://doi.org/10.1186/s13619-024-00196-9
  12. https://doi.org/10.1111/febs.14193
  13. https://doi.org/10.1515/dine-2023-0007
  14. https://doi.org/10.3390/cancers12051249
  15. https://doi.org/10.3389/fimmu.2023.1125224
  16. https://doi.org/10.1111/febs.14193,
  17. https://doi.org/10.3390/cancers12051249,
  18. https://doi.org/10.1096/fj.202402816rr,
  19. https://doi.org/10.3389/fimmu.2023.1125224,
  20. https://doi.org/10.1155/2015/912713,
  21. https://doi.org/10.3390/pathogens12020176,
  22. https://doi.org/10.1186/s13619-024-00196-9,
  23. https://doi.org/10.1515/dine-2023-0007,

📚 Additional Documentation

Pn Notes

(FBXW12-pn-notes.md)

FBXW12 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q6X9E4
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • Description: FBXW12 (F-box only protein 35; FBXO12/FBXO35) is a member of the F-box/WD40 (FBXW) family, with an N-terminal F-box motif and a C-terminal beta-propeller of WD40 repeats. F-box proteins are the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes: the F-box motif binds SKP1 (which bridges to CUL1 and the RBX1-bound catalytic RING), while the WD40 propeller recognizes substrates and presents them for ubiquitination and proteasomal degradation. FBXW12 is ubiquitously expressed. It binds SKP1 and assembles into an SCF complex, and in human epithelial cells it functions as a substrate receptor that ubiquitinates the interleukin-22 receptor subunit IL22RA1: ectopic FBXW12 accelerates IL22RA1 degradation in resting and IL-22-stimulated cells, and FBXW12 reconstitutes IL22RA1 ubiquitination in a defined cell-free SCF system. Through this activity FBXW12 dampens IL-22/STAT3 signaling and acts as an epithelial cell-growth suppressor, with its knockdown enhancing proliferation, cell-cycle progression and JNK/ERK activation.
  • Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 11

PN Consistency Summary

  • Consistency: Fully consistent. Deep research, review YAML, PN annotation and PN-node mapping all agree FBXW12 is an SCF F-box/WD40 substrate receptor. Better characterized than FBXW10: experimentally binds SKP1/CUL1 and reconstitutes IL22RA1 ubiquitination in a cell-free SCF system. Review proposes GO:1990756, matching the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts GO:1990756 (substrate-adaptor MF), absent from GOA (goa.tsv has only generic GO:0016567 IEA, no MF adaptor term). GO:1990756 verified real (OLS). Verdict: ADD GO:1990756 — strongly supported (direct IL22RA1 substrate, in vitro SCF reconstitution) and already proposed in the review.
  • Evidence alignment: Aligned. PN ref 15340381 (Jin et al. F-box family review) is generic family context. The review's load-bearing PMID is 26171402 (Franz et al., IL-22R / FBXW12 growth suppressor), full-text-available, relevance HIGH / VERIFIED — stronger and more specific than the PN's cited reference. Falcon corroborates; circ-FBXW12 correctly excluded as distinct gene product.
  • Verdict: Consistent; PN GO:1990756 add well-supported and already mirrored in the review. No changes needed.

Full Consistency Review

  • UniProt: Q6X9E4 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40 ; PN-node mapping: group=mapped, ok_for_propagation_to_go, GO:1990756; subtype/type=no_mapping; projected GO:1990756 goa_status=new_to_goa.
  • Consistency: Fully consistent. Deep research, review YAML, PN annotation and PN-node mapping all agree FBXW12 is an SCF F-box/WD40 substrate receptor. Better characterized than FBXW10: experimentally binds SKP1/CUL1 and reconstitutes IL22RA1 ubiquitination in a cell-free SCF system. Review proposes GO:1990756, matching the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts GO:1990756 (substrate-adaptor MF), absent from GOA (goa.tsv has only generic GO:0016567 IEA, no MF adaptor term). GO:1990756 verified real (OLS). Verdict: ADD GO:1990756 — strongly supported (direct IL22RA1 substrate, in vitro SCF reconstitution) and already proposed in the review.
  • Mapping strategy: Correct. FBXW12 is a Cul1/SCF F-box receptor; GO:1990756 is the right MF category (receptor, not scaffold/catalytic). Scope ok_for_propagation. Class-level GO:0061630 correctly held context_only/too_broad.
  • Evidence alignment: Aligned. PN ref 15340381 (Jin et al. F-box family review) is generic family context. The review's load-bearing PMID is 26171402 (Franz et al., IL-22R / FBXW12 growth suppressor), full-text-available, relevance HIGH / VERIFIED — stronger and more specific than the PN's cited reference. Falcon corroborates; circ-FBXW12 correctly excluded as distinct gene product.
  • Verdict: Consistent; PN GO:1990756 add well-supported and already mirrored in the review. No changes needed.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXW12/FBXW12-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | WD40

  • UniProt: Q6X9E4
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR001680
  • 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|WD40
      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: Q6X9E4
gene_symbol: FBXW12
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW12 (F-box only protein 35; FBXO12/FBXO35) is a member of the F-box/WD40
  (FBXW) family, with an N-terminal F-box motif and a C-terminal beta-propeller of
  WD40 repeats. F-box proteins are the interchangeable substrate-recognition
  subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase
  complexes: the F-box motif binds SKP1 (which bridges to CUL1 and the RBX1-bound
  catalytic RING), while the WD40 propeller recognizes substrates and presents
  them for ubiquitination and proteasomal degradation. FBXW12 is ubiquitously
  expressed. It binds SKP1 and assembles into an SCF complex, and in human
  epithelial cells it functions as a substrate receptor that ubiquitinates the
  interleukin-22 receptor subunit IL22RA1: ectopic FBXW12 accelerates IL22RA1
  degradation in resting and IL-22-stimulated cells, and FBXW12 reconstitutes
  IL22RA1 ubiquitination in a defined cell-free SCF system. Through this activity
  FBXW12 dampens IL-22/STAT3 signaling and acts as an epithelial cell-growth
  suppressor, with its knockdown enhancing proliferation, cell-cycle progression
  and JNK/ERK activation.
existing_annotations:
- 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, a generic compartment consistent with cytosolic SCF assembly.
    action: KEEP_AS_NON_CORE
    reason: Plausible generic localization but electronically inferred and not directly demonstrated for FBXW12; subsumed by the more specific cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein ubiquitination process; FBXW12 facilitates ubiquitination of its substrate IL22RA1 in a defined cell-free SCF system.
    action: ACCEPT
    reason: Correct process; FBXW12 facilitates substrate ubiquitination as an SCF subunit, directly demonstrated in vitro for IL22RA1, though the more specific GO:0031146 captures the proteasomal-degradation context.
    additional_reference_ids:
    - file:human/FBXW12/FBXW12-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:26171402
      supporting_text: facilitates ubiquitination of IL-22R in vitro
    - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md
      supporting_text: In a cell-free system, IL-22R ubiquitination is observed when ubiquitin machinery and SCF constituents (including FBXW12) are present
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:26171402
  qualifier: part_of
  review:
    summary: Assignment of SCF complex membership; FBXW12 binds SKP1 and CUL1 and assembles with Rbx1 into a functional SCF E3 ligase (ComplexPortal CPX-7822, SCF complex FBXW12 variant).
    action: ACCEPT
    reason: Core assembly annotation, experimentally supported by demonstrated SKP1 (and CUL1) binding and reconstitution of FBXW12 into an active SCF that ubiquitinates IL-22R in vitro.
    additional_reference_ids:
    - file:human/FBXW12/FBXW12-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:26171402
      supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination
    - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md
      supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:26171402
  qualifier: involved_in
  review:
    summary: Assignment of involvement in SCF-dependent proteasomal degradation; FBXW12 drives proteasomal degradation of IL22RA1, shortening its half-life from ~6 h to ~2 h.
    action: ACCEPT
    reason: Core biological process, experimentally supported by accelerated IL22RA1 degradation upon FBXW12 expression and stabilization upon FBXW12 knockdown.
    additional_reference_ids:
    - file:human/FBXW12/FBXW12-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:26171402
      supporting_text: In the presence of overexpressed FBXW12, we observe an accelerated degradation of IL-22R with half-life closer to 2 hours
    - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md
      supporting_text: IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW12 as an SCF subunit.
    action: KEEP_AS_NON_CORE
    reason: Plausible cytosolic localization for an SCF substrate receptor, consistent with FBXW12 assembling SCF and acting on IL22RA1 in cells, but derived from generic CRL pathway reactions rather than FBXW12-specific localization data.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW12.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; redundant with the other cytosol annotations.
    supported_by:
    - reference_id: file:human/FBXW12/FBXW12-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
references:
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:26171402
  title: The Human IL-22 Receptor Is Regulated through the Action of the Novel E3
    Ligase Subunit FBXW12, Which Functions as an Epithelial Growth Suppressor.
  findings:
  - statement: FBXW12 destabilizes human IL-22R (IL22RA1) in lung epithelia, binds SKP1, and facilitates IL22RA1 ubiquitination in a defined cell-free SCF system; FBXW12 knockdown increases IL22RA1 abundance and IL-22-induced STAT3 phosphorylation, and FBXW12 acts as an epithelial cell-growth suppressor (knockdown increases proliferation, cell-cycle progression and JNK/ERK activation).
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; full text available. Sole functional study, providing experimental support for SCF assembly (SKP1 binding, in vitro reconstitution), IL22RA1 ubiquitination, and SCF-dependent proteasomal degradation. Basis for proposing the substrate-adaptor molecular function term.
- 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/FBXW12/FBXW12-deep-research-falcon.md
  title: Falcon deep research report for human FBXW12
  findings:
  - statement: FBXW12 is an SCF-family E3 ligase subunit that physically associates with SKP1 and CUL1 and with IL-22R (IL22RA1), and reconstitutes IL-22R ubiquitination in a cell-free system, confirming it as a substrate-recognition adaptor rather than an enzyme.
    supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor
  - statement: Ectopic FBXW12 accelerates IL-22R turnover (half-life ~6 h to ~2 h), and FBXW12 knockdown increases IL-22R abundance and IL-22-induced STAT3, ERK and JNK signaling, defining FBXW12 as a negative post-translational regulator of IL-22 signaling and an epithelial growth suppressor.
    supporting_text: IL-22R half-life is reported to be ~**6 hours** at baseline and is accelerated to ~**2 hours** with FBXW12 overexpression
  - statement: Beyond IL-22R no additional validated FBXW12 substrate, ubiquitin linkage type, or definitive subcellular localization has been established, so substrate scope remains open.
    supporting_text: additional validated FBXW12 protein substrates, ubiquitin linkage types, and definitive subcellular localization were not identified in the retrieved materials
  - statement: A circular RNA (circ-FBXW12) from the FBXW12 locus is discussed in diabetic nephropathy, but this circRNA biology is distinct from and must not be conflated with the linear FBXW12 protein's E3-adaptor function.
    supporting_text: This evidence concerns **circRNA biology**, and should not be conflated with the **linear FBXW12 protein**'s E3-ligase substrate receptor activity
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis grounded chiefly in Franz et al. 2015 (J Immunol Res, doi:10.1155/2015/912713 = PMID:26171402; full text available and already the basis of this review), which provides SKP1/CUL1 association, IL22RA1 co-IP, cell-free SCF reconstitution of IL22RA1 ubiquitination, accelerated IL22RA1 turnover, and the epithelial growth-suppressor phenotype. Cross-checked against UniProt Q6X9E4 FUNCTION/SUBUNIT statements and ComplexPortal CPX-7822. The 2024 spermatogenesis review (Xuan) reports FBXW12 among high-testis-transcript F-box genes, which is a transcript-level observation that does not override the UniProt 'ubiquitously expressed' tissue-specificity statement; the circ-FBXW12 (diabetic nephropathy) literature is explicitly excluded as it concerns a distinct gene product. No annotation action changed by the falcon report.
core_functions:
- description: Substrate-recognition subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that binds SKP1 and bridges substrate to the ligase; it ubiquitinates the IL-22 receptor subunit IL22RA1, targeting it for SCF-dependent proteasomal degradation.
  supported_by:
  - reference_id: PMID:26171402
    supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: By degrading IL22RA1, FBXW12 negatively regulates IL-22/STAT3 cytokine signaling and acts as an epithelial cell-growth suppressor, restraining proliferation and cell-cycle progression.
  supported_by:
  - reference_id: PMID:26171402
    supporting_text: FBXW12 functions as a cell growth suppressor
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms:
- proposed_name: ubiquitin-like ligase-substrate adaptor activity
  proposed_definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW12's annotation set.
  justification: FBXW12 directly bridges the substrate IL22RA1 to the SCF E3 ligase, binding SKP1 and the substrate and facilitating substrate ubiquitination in a reconstituted system. This substrate-adaptor molecular function is experimentally supported (PMID:26171402) and is more informative than the existing bare protein binding/complex-membership annotations; GO:1990756 should be added as the molecular function for FBXW12 as an SCF substrate receptor.
  proposed_parent:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: PMID:26171402
    supporting_text: FBXW12 is a bona fide SCF E3 ligase constituent that can bind to IL-22R and other components of SCF to mediate IL-22R ubiquitination
  - reference_id: file:human/FBXW12/FBXW12-deep-research-falcon.md
    supporting_text: FBXW12 associates with SCF components including **SKP1** and **CUL1**, consistent with being an SCF substrate receptor
suggested_questions:
- question: What is the substrate-recognition determinant (e.g. a phosphodegron) on IL22RA1 recognized by the FBXW12 WD40 propeller, and does FBXW12 have additional epithelial substrates beyond IL22RA1?
- question: Does FBXW12 loss-of-function in vivo enhance IL-22-dependent mucosal host defense or epithelial proliferation, as predicted from the cell-based growth-suppressor phenotype?
suggested_experiments:
- description: Map the IL22RA1 region/residues required for FBXW12 binding and ubiquitination, and test whether dephosphorylation or degron mutation abolishes recognition by the FBXW12 WD40 propeller.
- description: Generate FBXW12-knockout epithelial cells and tissues and assess endogenous IL22RA1 stability, IL-22-induced STAT3 signaling, proliferation, and identify the broader SCF(FBXW12) substrate repertoire by ubiquitinome profiling.