FBXO16

FBXO16 is an F-box protein that serves as the substrate-recognition subunit of SCF (SKP1–Cullin1–FBXO16) E3 ubiquitin ligase complexes, directing diverse substrates toward K48-linked polyubiquitination and 26S proteasomal degradation (PMID:30530053, PMID:34333526). A recurrent theme across studies is its tumor-suppressive role through control of nuclear signaling pools: its C-terminal region binds nuclear β-catenin and drives its degradation in a GSK-3β-independent manner, restraining TCF4/LEF1-dependent Wnt signaling, with depletion promoting EMT, invasion, and tumor growth (PMID:30530053, PMID:30714168). FBXO16 also constitutively targets the RNA-binding protein hnRNPL—via its RRM3 domain—for degradation, and its loss leads to hnRNPL accumulation and activation of oncogenic signaling in ovarian cancer (PMID:34333526). Beyond cancer signaling, FBXO16 acts as the substrate receptor that delivers the NF-κB p65 subunit for ubiquitination, suppressing NF-κB transactivation and proinflammatory cytokine production in dendritic cells, with substrate specificity confirmed by its failure to degrade STAT3 or STAT4 (PMID:40529355). It additionally limits autophagy by degrading ULK1; this brake is relieved when miR-937-5p represses FBXO16 expression (PMID:39384743). FBXO16 was originally identified as a human F-box gene on chromosome 8p12 (PMID:12243353).

1. 2002 Medium

   Before any functional role was known, the question was whether FBXO16 was a bona fide F-box gene; cloning established it as a novel human F-box protein with a defined genomic structure and tissue expression.

   Evidence cDNA cloning from a human fetal brain library, Northern blot, RT-PCR, and genomic mapping to chromosome 8p12

   PMID:12243353

   Open questions at the time

   • No substrate or biochemical activity assigned at this stage
   • F-box partner subunits (SKP1/Cullin1) not yet demonstrated
2. 2018 Medium

   The first substrate question—what does FBXO16 ubiquitinate—was answered by showing it targets nuclear β-catenin for K48-linked degradation independently of GSK-3β, defining a tumor-suppressive node in Wnt signaling.

   Evidence Co-IP, K48-specific ubiquitination assays, and nuclear fractionation with loss/gain-of-function in glioblastoma cells

   PMID:30530053

   Open questions at the time

   • Mechanism of nuclear targeting/recruitment of FBXO16 to β-catenin unclear
   • Single-lab finding in one tumor context
3. 2019 Medium

   Extending the β-catenin model, this work confirmed assembly of the SKP1-Cullin1-FBXO16 SCF complex on β-catenin's C-terminal domain and linked its loss to EMT and metastatic phenotypes in breast cancer.

   Evidence Reciprocal Co-IP, in vivo ubiquitination assay, siRNA knockdown with invasion/proliferation readouts, and clinical sample analysis

   PMID:30714168

   Open questions at the time

   • Did not resolve whether nuclear vs cytoplasmic β-catenin pools are differentially targeted
   • Upstream regulation of FBXO16 abundance not addressed
4. 2021 High

   The substrate repertoire was broadened beyond β-catenin by demonstrating that FBXO16 constitutively degrades the RNA-binding protein hnRNPL via its RRM3 domain, connecting the ligase to control of oncogenic RNA-processing activity.

   Evidence Reciprocal Co-IP with domain mapping, in vivo ubiquitination, CRISPR/siRNA depletion with KO rescue, and in vitro/in vivo ovarian tumor models

   PMID:34333526

   Open questions at the time

   • Downstream oncogenic pathways activated by hnRNPL not fully delineated
   • Whether β-catenin and hnRNPL are degraded by the same cellular pool of FBXO16 unknown
5. 2024 Medium

   How FBXO16 itself is suppressed in cancer, and what this releases, was addressed by showing miR-937-5p represses FBXO16 to stabilize ULK1 and enhance autophagy—implicating FBXO16 as an autophagy brake.

   Evidence 3' UTR luciferase binding assay, CRISPR deletion of MIR937, rescue and autophagy-flux measurements in high-grade serous ovarian cancer cells

   PMID:39384743

   Open questions at the time

   • Direct ubiquitination of ULK1 by an SCF-FBXO16 complex not biochemically mapped here
   • Single-lab epistasis model
6. 2025 High

   A distinct immune role was established by identifying FBXO16 as the p65 substrate receptor within a PDLIM2-Cullin1-Skp1 ligase, with degradation specificity validated against STAT3/STAT4 negative controls, linking it to NF-κB-mediated inflammation.

   Evidence siRNA screen of F-box proteins, Co-IP, ubiquitination assay, and Fbxo16 KO dendritic cells with cytokine and nuclear-fractionation readouts

   PMID:40529355

   Open questions at the time

   • Relationship between the canonical SKP1-Cullin1 and the PDLIM2-containing complex not reconciled
   • In vivo inflammatory phenotype of organismal Fbxo16 loss not characterized

• How FBXO16 selects among its multiple unrelated substrates (β-catenin, hnRNPL, p65, ULK1) and whether these activities operate in the same cells or are context-restricted remains unresolved.
• No structural model of FBXO16 substrate-binding interface
• No unifying recognition motif or post-translational trigger identified across substrates
• Physiological (non-cancer) roles largely uncharacterized