FBXL16 (F-box/LRR-repeat protein 16, C16orf22) is a member of the FBXL subfamily of F-box proteins, with an N-terminal (proline-rich/disordered) region, an F-box domain, and a C-terminal leucine-rich repeat (LRR) array. Its F-box motif mediates SKP1 binding, but unlike canonical F-box proteins FBXL16 shows no detectable CUL1 interaction in reported assays, suggesting it may act non-canonically rather than as a conventional SCF (SKP1-CUL1-F-box) substrate receptor. FBXL16 is a context-dependent regulator of protein stability acting in the cytoplasm, with two opposing modes: it promotes ubiquitination-dependent proteasomal degradation of some clients (e.g. the transcription factor HIF1alpha, where it limits HIF1alpha-driven epithelial-mesenchymal transition and angiogenesis as a tumor suppressor in triple-negative breast cancer, and the amyloid precursor protein APP, where neuronal/hippocampal FBXL16 reduces APP and improves cognition in Alzheimer's disease models), but it stabilizes other signaling regulators by decreasing their ubiquitination or antagonizing other ligases (e.g. IRS1, sustaining IGF1/IRS1/AKT signaling and sotorasib resistance in KRAS-mutant lung adenocarcinoma; and estrogen receptor alpha (ERalpha), c-MYC, SRC-3 and beta-catenin in ER-positive breast cancer, where it antagonizes FBXO45-mediated ERalpha degradation). Both the F-box and LRR domains are required for its substrate effects. It is expressed most highly in brain.
Definition: A molecular function or process by which a protein increases the stability/half-life of a target protein by preventing or antagonizing its ubiquitination and consequent proteasomal degradation (e.g. by competing with or inhibiting a ubiquitin ligase). Proposed to capture the stabilizing, anti-degradative mode of FBXL16 on substrates such as IRS1 and ERalpha, which is not described by existing SCF/ligase-adaptor or generic protein-stabilization terms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:34818544 Suppression of breast cancer progression by FBXL16 via oxyge... | KEEP AS NON CORE | Summary: IntAct interaction with HIF1A (WITH/FROM UniProtKB:Q16665), the substrate FBXL16 binds and targets for degradation in the breast cancer study. The HIF1alpha interaction is functionally meaningful, but the bare protein binding term is uninformative. Reason: Records the functionally important FBXL16-HIF1alpha substrate interaction, but bare protein binding is uninformative per curation guidelines; the substrate relationship is better captured by the SCF-degradation process annotation. Supporting Evidence: file:human/FBXL16/FBXL16-uniprot.txt Q8N461; Q16665: HIF1A; NbExp=6; IntAct=EBI-7208098, EBI-447269; |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined automated electronic assignment of cytoplasmic localization, now corroborated by FBXL16-specific experimental evidence (FBXL16 co-localizes with APP in the cytoplasm of neuronal cell models), consistent with FBXL16 engaging substrates in the cytoplasm. Reason: Cytoplasm is where FBXL16 is reported to act on substrates (e.g. cytoplasmic colocalization with APP), but the generic cytoplasm term is broad; retained as a supporting, non-core localization. Supporting Evidence: file:human/FBXL16/FBXL16-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXL16/FBXL16-deep-research-falcon.md FBXL16 and APP co-localize in the cytoplasm in neuronal cell models and co-immunoprecipitate (Flag-FBXL16 with Myc-APP). |
| 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 assignment that FBXL16 acts in SCF-dependent proteasomal degradation. Consistent with reported FBXL16-driven ubiquitination and proteasomal degradation of HIF1alpha and of APP (in Alzheimer's models). However, FBXL16 binds SKP1 but shows no detectable CUL1 interaction, so whether it assembles a canonical SCF for these events is unresolved; and for several other clients (IRS1, ERalpha, c-MYC) FBXL16 stabilizes rather than degrades, an outcome not captured by this term. Reason: Ubiquitin-dependent proteasomal degradation of substrates is a documented FBXL16 function (HIF1alpha; APP). Retained as the core catabolic process, though the precise E3 architecture may be non-canonical (no detectable CUL1 binding) and FBXL16 also acts as a stabilizer for other substrates. Supporting Evidence: PMID:34818544 FBXL16 directly binds to HIF1Ξ± and induces its ubiquitination and degradation file:human/FBXL16/FBXL16-deep-research-falcon.md Promoting ubiquitination and proteasomal degradation of certain proteins (e.g., APP in AD models). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol annotation propagated across the generic CRL1/neddylation reaction set. Reason: Plausible localization for a cytosolic SCF component, but derived from generic CRL pathway membership rather than FBXL16-specific evidence. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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 FBXL16-specific. Supporting Evidence: file:human/FBXL16/FBXL16-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: Does FBXL16 assemble a canonical, catalytically productive SCF complex with CUL1/RBX1, or does its lack of detectable CUL1 binding mean it works through a non-canonical E3 mechanism or by modulating other ligases?
Q: What molecular features determine whether FBXL16 degrades a substrate (HIF1alpha, APP) versus stabilizes it (IRS1, ERalpha, c-MYC), and is the stabilizing mode mediated by antagonizing specific ligases such as FBXO45?
Q: Beyond these substrates, what are the FBXL16 substrates in brain (its highest-expression tissue), and what is its physiological role there?
Experiment: Test whether FBXL16 assembles a productive SCF (immunoprecipitate FBXL16 and probe for CUL1/RBX1/NEDD8) and whether neddylation inhibition (MLN4924) alters FBXL16-dependent turnover of HIF1alpha and APP versus stabilization of IRS1/ERalpha, distinguishing canonical-SCF from non-canonical mechanisms.
Experiment: Identify the endogenous FBXL16 substrate repertoire by AP-MS and quantitative proteomics in FBXL16 knockout versus wild-type cells across brain-derived and cancer models, classifying each interactor as stabilized or degraded, and test whether stabilization requires antagonism of competing ligases (e.g. FBXO45 for ERalpha).
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The exact E3-ligase architecture used by FBXL16 remains unresolved. FBXL16 can bind SKP1 and is mapped here to ubiquitin-like ligase-substrate adaptor activity, but reported failure to detect CUL1 leaves open whether the degradative HIF1alpha/APP activities use a canonical productive SCF complex, a non-canonical cullin/RBX module, or modulation of other ligases.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: The review supports FBXL16 as an F-box/LRR substrate-recognition factor that can promote proteasomal degradation of HIF1alpha and APP, while excluding catalytic ubiquitin ligase activity from the core function.
Significance: This boundary determines how confidently GO:1990756 and SCF-dependent-proteasomal-catabolism annotations should be propagated to FBXL16. Treating it as an ordinary Cul1-SCF receptor may overstate the molecular mechanism if FBXL16 instead acts through a non-canonical complex or through antagonism of other ligases.
What would resolve it: Endogenous and reconstituted FBXL16 complex profiling should test SKP1, CUL1, RBX1, neddylated cullin, and alternative ligase partners, then compare FBXL16-dependent HIF1alpha/APP turnover under cullin/neddylation inhibition and with F-box or LRR mutants.
Provenance (the field's own admissions):
Gap: The molecular basis of FBXL16's substrate-stabilizing mode is still dark. Current evidence indicates FBXL16 can degrade some clients while stabilizing others, but it is unresolved whether the stabilizing activity is direct substrate-adaptor behavior, competition with another E3 ligase, inhibition of ubiquitination, or an indirect signaling consequence.
OPEN BIOLOGYONTOLOGYCURATION MF_DARK
What is known: The review supports context-dependent regulation of substrate protein stability, including degradative and stabilizing modes, but the current GO molecular-function term captures the adaptor/degradative side better than anti-degradative stabilization.
Significance: This is the main ontology pressure point for FBXL16. Without a resolved mechanism and a precise GO term, the stabilizing activities on IRS1, ERalpha, c-MYC, SRC-3, and beta-catenin can only be represented awkwardly by a broad adaptor function or by a proposed, not-yet-real term.
What would resolve it: For each stabilized client, measure direct FBXL16 binding, client ubiquitination, half-life, competing ligase involvement, and dependence on the FBXL16 F-box/LRR domains; in parallel, submit or refine a GO term if the direct anti-degradative activity is experimentally supported.
Provenance (the field's own admissions):
Gap: The normal physiological substrate repertoire and tissue role of FBXL16, especially in brain, remain incompletely defined. APP and several cancer signaling proteins are useful leads, but it is not yet clear which clients and processes represent conserved endogenous FBXL16 biology rather than disease-model or tumor-context readouts.
OPEN BIOLOGYCURATION BP_DARK
What is known: APP degradation, HIF1alpha degradation, and stabilization of selected signaling regulators are captured as supported examples, and brain is noted as the highest-expression tissue, but the review does not convert those examples into a broad normal brain or disease-process annotation.
Significance: Resolving this gap would decide whether FBXL16 should receive additional biological-process annotations for neuronal proteostasis, cognition, neuroinflammation, cancer signaling, or drug resistance, or whether those claims should remain context-specific findings rather than core function.
What would resolve it: Combine FBXL16 loss-of-function and rescue in physiological brain-derived systems with quantitative substrate proteomics, ubiquitinomics, and phenotype assays, then compare the validated endogenous clients with the APP, HIF1alpha, IRS1, and ERalpha disease-model literature.
Provenance (the field's own admissions):
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