FBXO15

FBXO15 is an F-box protein that assembles into an SCF(FBXO15) E3 ubiquitin ligase complex (with Skp1 and Cullin1) to direct selective substrates toward proteasomal degradation (PMID:23465077). It targets a structurally diverse set of substrates whose recognition is frequently gated by post-translational modification: P-glycoprotein/ABCB1, ubiquitinated using the E2 enzyme Ube2r1/Cdc34 (PMID:23465077); cardiolipin synthase 1, recognized via a PINK1-generated phosphodegron at Thr219 during bacterial infection (PMID:24703837); the KBP protein (Kif1bp), recognized after GCN5L1-dependent acetylation of Lys501 (PMID:28319092); and the transcription factor CHOP (PMID:33159144). Through degradation of KBP, FBXO15 restrains mitochondrial biogenesis in embryonic stem cells, with its loss causing unscheduled mitochondrial expansion, elevated respiration and ROS, and impaired proliferation (PMID:28319092). Its degradation of P-gp is embedded in MAPK signaling, where RSK1 phosphorylation of Ube2r1 modulates the pathway, and FBXO15 is required for MEK-inhibitor-induced P-gp downregulation (PMID:27786305). In embryonic stem cells, Fbxo15 transcription is directly activated by cooperative Oct3/4–Sox2 binding to an 18-bp enhancer upstream of its transcription start site, placing it within the pluripotency regulatory circuit (PMID:12665572, PMID:15557334); despite this, Fbxo15 is dispensable for ES cell self-renewal and mouse development (PMID:12665572).

1. 2003 High

   Established that Fbxo15 is a direct transcriptional output of the core pluripotency factors, answering how this gene is wired into the ES cell program.

   Evidence Luciferase reporter and EMSA with site-directed mutagenesis plus inducible Oct3/4 knockout in ES cells, defining an 18-bp Oct3/4–Sox2 enhancer

   PMID:12665572

   Open questions at the time

   • Does not define a molecular function for the FBXO15 protein itself
   • Enhancer mapping does not address the protein's biochemical role
2. 2003 High

   Determined the loss-of-function consequence, showing Fbxo15 is not required for pluripotency or development despite its ES-cell-specific expression.

   Evidence Germline beta-galactosidase knock-in knockout mice and null ES cells with phenotypic analysis

   PMID:12665572

   Open questions at the time

   • Lack of phenotype leaves the protein's molecular activity undefined
   • Possible functional redundancy not tested
3. 2004 High

   Independently confirmed cooperative Oct3/4–Sox2 control of Fbxo15 and positioned it within a shared regulatory circuit with Fgf-4, Utf1 and Sox2.

   Evidence EMSA with ES-derived extracts and luciferase reporter assays in a separate lab

   PMID:15557334

   Open questions at the time

   • Reinforces transcriptional regulation but adds no mechanism for the protein
4. 2013 High

   Defined the core biochemical identity of FBXO15 as an SCF E3 ligase substrate-recognition subunit and identified its first substrate and cognate E2 enzyme.

   Evidence Reciprocal Co-IP, MALDI-TOF MS, gain/loss-of-function, and MG132 rescue identifying P-glycoprotein as substrate and Ube2r1/Cdc34 as E2

   PMID:23465077

   Open questions at the time

   • Degron on P-gp not mapped
   • No structural model of the SCF(FBXO15)–substrate interaction
5. 2014 High

   Revealed that FBXO15 substrate recognition can be gated by upstream kinase-generated phosphodegrons, linking it to mitochondrial lipid metabolism during infection.

   Evidence Co-IP, Thr219 phospho-mutant mutagenesis, PINK1 manipulation and Pink1 knockout mice, proteasome inhibitor assays in lung epithelia

   PMID:24703837

   Open questions at the time

   • How FBXO15 distinguishes phosphorylated CLS1 structurally not defined
   • Physiological scope beyond S. aureus infection unclear
6. 2016 Medium

   Placed FBXO15-mediated P-gp degradation downstream of MAPK signaling and showed the pathway is tuned by RSK1 phosphorylation of the E2 enzyme.

   Evidence siRNA knockdown, Thr162 UBE2R1 phospho-mutagenesis, proteasome rescue, and drug/rhodamine 123 accumulation assays

   PMID:27786305

   Open questions at the time

   • FBXO15's role shown by epistasis/knockdown rather than direct reconstitution
   • Direct effect of RSK1 on FBXO15 itself not tested
7. 2017 High

   Connected FBXO15 to control of mitochondrial biogenesis in ES cells via acetylation-dependent recognition of the KBP substrate.

   Evidence AP-MS interactome, Co-IP, Lys501 acetylation mutagenesis, GCN5L1 link, knockdown/rescue, and mitochondrial mass/respiration assays

   PMID:28319092

   Open questions at the time

   • Whether this reconciles with the lack of developmental phenotype not addressed
   • Structural basis for acetyl-degron recognition undefined
8. 2020 Medium

   Extended FBXO15 substrate repertoire to the transcription factor CHOP, implicating it in resolving sepsis-associated immunoparalysis.

   Evidence Co-IP, overexpression/knockdown, CLP mouse model and cytokine measurements following Oroxylin A induction

   PMID:33159144

   Open questions at the time

   • CHOP degron not mapped
   • Limited biochemical reconstitution of the ubiquitination event
9. 2024 Medium

   Demonstrated the FBXO15–P-gp interaction is pharmacologically targetable, with direct ligand binding modulating P-gp levels at the blood-brain barrier.

   Evidence Molecular docking/MD simulations, MST direct binding, Co-IP, western blot, and APP/PS1 mouse behavioral assays with Gastrodin

   PMID:39541666

   Open questions at the time

   • Binding site on FBXO15 not validated by mutagenesis
   • Single lab, limited reconstitution detail

• The structural basis by which a single F-box protein recognizes its diverse modified degrons (phospho-, acetyl-) and how its multiple substrate-specific roles are coordinated in vivo remain unresolved.
• No structural model of SCF(FBXO15) bound to any substrate
• Reconciliation of substrate diversity with the dispensable knockout phenotype not established
• Tissue-specific substrate selection mechanisms unknown