FBXL18 (F-box/LRR-repeat protein 18, FBL18) is a member of the FBXL subfamily of F-box proteins, with an N-terminal F-box domain followed by an extensive C-terminal leucine-rich repeat (LRR) array. It serves as the substrate-recognition subunit of a Cullin-RING (SCF; SKP1-CUL1-F-box) E3 ubiquitin ligase, docking onto SKP1/CUL1 via its F-box domain and recruiting substrates through its LRRs. FBXL18 deploys two distinct ubiquitination modes. In a degradative (K48-linked) mode it targets another F-box protein, FBXL7, for polyubiquitination and proteasomal degradation, recognizing an N-terminal FQ motif in FBXL7 and conjugating ubiquitin onto FBXL7 Lys109; because FBXL7 is pro-apoptotic, this turnover limits apoptosis. SCF^FBXL18 (reconstituted with SKP1-CUL1-RBX1) also mediates K48-linked degradation of the TFIIH subunit XPB/ERCC3 in a drug-triggered, CDK7- and XPB-Ser90-dependent manner (spironolactone-induced), thereby impairing nucleotide-excision repair and transcription and sensitizing cells to platinum agents. In a second, non-degradative (K63-linked) mode FBXL18 ubiquitinates signaling proteins to modulate their activity rather than degrade them: it promotes K63-linked ubiquitination of AKT (driving AKT-FOXO3a-Bim survival signaling in glioma and ovarian cancer) and of PTEN (inhibiting PTEN and activating PI3K/AKT in non-small-cell lung cancer), and is frequently upregulated and pro-oncogenic in these tumors. Consistent with these roles, FBXL18 has been annotated in both the cytoplasm (AKT/PTEN signaling) and the nucleus (XPB/TFIIH). It is broadly expressed with enhancement in brain.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro/domain-based electronic assignment (FBXL18 F-box/LRR signature) that FBXL18 acts in SCF-dependent proteasomal degradation. This is the experimentally established core process (FBXL18 K48-polyubiquitinates and degrades FBXL7, and SCF^FBXL18 degrades the TFIIH subunit XPB/ERCC3). Reason: Core biological process; directly supported by the experimental demonstration that FBXL18 polyubiquitinates and targets FBXL7 for proteasomal degradation, and by reconstituted SCF^FBXL18-mediated K48 degradation of XPB. Note FBXL18 also performs non-degradative K63 ubiquitination of AKT and PTEN, which this catabolic term does not capture. Supporting Evidence: PMID:25654763 an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation file:human/FBXL18/FBXL18-deep-research-falcon.md SCF^FBXL18 was biochemically reconstituted/purified (Cul1, Skp1, Rbx1, FBXL18) and shown to ubiquitinate XPB in vitro, supporting direct E3/substrate compatibility. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:33234069 The FBXL family of F-box proteins: variations on a theme. | ACCEPT | Summary: Family/ComplexPortal NAS assignment of the same core SCF-dependent degradation process, redundant with the experimentally supported IEA annotation. Reason: Core biological process; supported experimentally (FBXL18 degrades FBXL7) and by family-level evidence. Supporting Evidence: PMID:25654763 an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation |
| GO:0042981 regulation of apoptotic process | NAS PMID:25654763 F-box protein Fbxl18 mediates polyubiquitylation and proteas... | KEEP AS NON CORE | Summary: FBXL18 regulates apoptosis by mediating the ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein FBXL7; FBXL18 depletion accentuates FBXL7-induced apoptosis, and FBXL18 overexpression limits it. Reason: Genuine biological consequence of FBXL18 activity, supported by the FBXL7 study, but it is an indirect, downstream outcome of the core SCF-dependent degradation function rather than a separate molecular role. Supporting Evidence: PMID:25654763 Fbxl18 regulates apoptosis by mediating ubiquitin-dependent proteasomal degradation of the pro-apoptotic protein Fbxl7 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8854051 | KEEP AS NON CORE | Summary: Reactome cytosol annotation tied to the curated reaction "SCF-FBXL18 ubiquitinates FBXL7", which reflects FBXL18's actual ligase reaction. The cytosol is a plausible compartment for this SCF activity. Reason: Plausible localization linked to the bona fide FBXL18-FBXL7 reaction, but derived from Reactome pathway curation rather than direct FBXL18 localization data. Supporting Evidence: PMID:25654763 an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation from the generic CRL1/neddylation reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic CRL1 neddylation reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic CRL (CAND1) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic CRL (COMMD/CAND1) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic CRL deneddylation (COP9) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic CRL1 (DCUN1D3) reaction set. Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic ubiquitination reaction set (transfer of Ub from E2 to substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic ubiquitination reaction set (release of E3 from substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic ubiquitination reaction set (polyubiquitination of substrate). Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 annotation from the generic ubiquitination reaction set (interaction of E3 with substrate and E2-Ub). Reason: Plausible but redundant generic-pathway localization; not FBXL18-specific. Supporting Evidence: file:human/FBXL18/FBXL18-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 determines whether FBXL18 attaches degradative K48 chains (FBXL7, XPB) versus non-degradative K63 chains (AKT, PTEN) to a given substrate, and is this substrate-intrinsic or context-dependent?
Q: Beyond FBXL7, XPB, AKT and PTEN, what is the broader FBXL18 substrate repertoire, and how is FBXL18-FBXL7 cross-regulation balanced given both are SCF F-box receptors?
Q: How is FBXL18 activity and substrate selection regulated across tissues (notably brain), and do its multiple isoforms have distinct substrate specificities?
Experiment: Reconstitute SCF-FBXL18 in vitro with FBXL7 and XPB to confirm direct K48-linked ubiquitination (FBXL7 Lys109, FQ-motif dependence) and contrast with K63-linked ubiquitination of AKT/PTEN, comparing wild-type FBXL18 to an F-box-deletion mutant.
Experiment: Identify endogenous FBXL18 substrates by AP-MS and by quantitative proteomics of FBXL18 knockout versus wild-type cells, classifying each by ubiquitin-chain linkage type, and test the apoptosis and PI3K/AKT-signaling phenotypes upon co-modulation of FBXL18 with FBXL7, AKT or PTEN.
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