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.
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:
| 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 |
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Download this section (compressed HTML)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?
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.
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