FBXL18

FBXL18 is the substrate-recognition subunit of an SCF (Skp1–Cul1–Rbx1–FBXL18) E3 ubiquitin ligase that governs cell survival and proliferation by conjugating distinct ubiquitin chain types to different substrates. It mediates K48-linked polyubiquitination and proteasomal degradation of the pro-apoptotic F-box protein FBXL7 (via an FQ degron and Lys109 acceptor), phosphorylated LRRK2 (in a PKC-enhanced, phosphorylation-dependent manner), XPB/TFIIH (primed by CDK7-dependent Ser90 phosphorylation), and DUSP16 (relieving JNK pathway suppression) (PMID:25654763, PMID:27890708, PMID:30762924, PMID:40382593). In parallel, FBXL18 catalyzes non-degradative K63-linked ubiquitination of Akt to promote its activation and downstream FOXO3a/BCL2L11 or CCND1 signaling, and K63-linked ubiquitination of RPS15A to stabilize it and drive SMAD3 nuclear translocation (PMID:27926990, PMID:38883375, PMID:37378633). FBXL18 also mediates K11-linked ubiquitination of BST2 at Lys109/Lys110, stabilizing BST2 and hyperactivating NF-κB/IL-6 inflammatory signaling during rabies virus infection (PMID:41390767).

1. 2015 High

   Establishing that FBXL18 is a functional SCF E3 ligase subunit resolved whether FBXL18 possesses ubiquitin ligase activity and identified its first substrate—the pro-apoptotic F-box protein FBXL7—targeted via K48-linked ubiquitination for proteasomal degradation.

   Evidence In vitro ubiquitination, site-directed mutagenesis of Lys109 and FQ degron, siRNA knockdown with apoptosis rescue in HeLa cells

   PMID:25654763

   Open questions at the time

   • No structural basis for FBXL18–FBXL7 recognition via the FQ motif
   • Whether other F-box proteins are similarly regulated by FBXL18 is unknown
   • Physiological tissues where FBXL18–FBXL7 axis operates are not defined
2. 2016 Medium

   Demonstrating that FBXL18 also catalyzes non-degradative K63-linked ubiquitination of Akt for its activation revealed a linkage-type switch capability—K48 for degradation versus K63 for signaling—and connected FBXL18 to pro-survival Akt signaling in glioma.

   Evidence K63-specific ubiquitination assay, siRNA knockdown with Akt pathway Western blotting and apoptosis assays in glioma cells

   PMID:27926990

   Open questions at the time

   • The ubiquitin acceptor lysine(s) on Akt were not identified
   • How FBXL18 selects between K48 and K63 chain assembly on different substrates is unknown
   • Single-lab finding at the time of publication
3. 2016 High

   Showing phosphorylation-dependent recognition of LRRK2 by FBXL18 established that SCF^FBXL18 uses a canonical phosphodegron mechanism and linked this E3 ligase to Parkinson's disease-relevant LRRK2 turnover.

   Evidence Reciprocal Co-IP, phosphatase treatment blocking FBXL18 association, PKC activation enhancing degradation, caspase/cell-death rescue assays

   PMID:27890708

   Open questions at the time

   • Specific phosphorylation site(s) on LRRK2 recognized by FBXL18 were not mapped
   • In vivo relevance in dopaminergic neurons or animal PD models not tested
   • Chain linkage type on LRRK2 not explicitly determined
4. 2019 High

   Identifying XPB as a spironolactone-induced substrate of SCF^FBXL18, dependent on CDK7-mediated Ser90 phosphorylation, revealed a pharmacologically triggerable phosphodegron and connected FBXL18 to transcription/NER factor turnover.

   Evidence siRNA library screen, Co-IP confirming SCF complex, CDK7 inhibitor epistasis, XPB Ser90 mutagenesis

   PMID:30762924

   Open questions at the time

   • Whether FBXL18 degrades XPB under physiological (non-drug) conditions is unclear
   • Direct binding interface between FBXL18 LRR domain and phospho-XPB not resolved
   • Consequences for NER and transcription in vivo not assessed
5. 2023 Medium

   Demonstrating K63-linked ubiquitination of RPS15A by FBXL18 that stabilizes the substrate and activates SMAD3 signaling expanded the non-degradative substrate repertoire and linked FBXL18 to TGF-β/SMAD-driven hepatocellular carcinoma proliferation.

   Evidence K63-ubiquitination assay, FBXL18 transgenic mouse model, siRNA epistasis with RPS15A and SMAD3 in HCC cells

   PMID:37378633

   Open questions at the time

   • Mechanism by which K63-ubiquitinated RPS15A stabilizes SMAD3 protein is undefined
   • Whether this reflects a ribosomal or extra-ribosomal function of RPS15A is unknown
   • Single-lab observation
6. 2024 Medium

   Independent replication of FBXL18-mediated K63-linked Akt ubiquitination in ovarian cancer, with pharmacological rescue by the Akt inhibitor MK-2206, strengthened confidence in the Akt–K63 ubiquitination axis across tumor types.

   Evidence Co-IP, K63-specific ubiquitination assay, MK-2206 rescue of FBXL18-driven proliferation/migration in ovarian cancer cells

   PMID:38883375

   Open questions at the time

   • Akt ubiquitin acceptor sites still unmapped
   • Whether FBXL18 directly ubiquitinates Akt or acts through an adaptor is not resolved
   • No in vivo validation in ovarian cancer models
7. 2025 High

   Discovery that FBXL18 catalyzes K11-linked ubiquitination of BST2 to stabilize it and drive NF-κB/IL-6 inflammation during rabies virus infection introduced a third chain-linkage type to FBXL18's repertoire and linked it to innate immune/inflammatory signaling.

   Evidence siRNA screen, K11-specific ubiquitination with K109/K110 mutagenesis, NF-κB reporter, in vivo mouse RABV infection model

   PMID:41390767

   Open questions at the time

   • How FBXL18 directs K11 versus K48 versus K63 chain assembly mechanistically is unknown
   • Whether BST2 stabilization by K11 chains occurs outside viral infection is untested
   • The E2 conjugating enzyme(s) partnering with FBXL18 for each chain type are not identified
8. 2025 Medium

   Identification of DUSP16 as a degradative substrate whose loss activates JNK/c-JUN signaling extended FBXL18's substrate range to MAP kinase phosphatases and linked it to endometrial carcinoma progression.

   Evidence Co-IP, ubiquitination assay, DUSP16 overexpression rescue of JNK activation, Transwell and colony assays in endometrial carcinoma cells

   PMID:40382593

   Open questions at the time

   • Ubiquitin chain type on DUSP16 not specified
   • Degron or phosphodegron on DUSP16 not mapped
   • Single-lab finding without in vivo model
9. 2025 Medium

   A third independent study confirmed FBXL18-mediated K63 ubiquitination of Akt, now linked to radioresistance in esophageal squamous cell carcinoma via AKT/CCND1, consolidating Akt as a bona fide non-degradative substrate across multiple cancer types.

   Evidence Co-IP, K63 polyubiquitination assay, siRNA knockdown with radiosensitivity assay in ESCC cells

   PMID:41655990

   Open questions at the time

   • Direct in vitro reconstitution of FBXL18-Akt ubiquitination with purified components is lacking
   • Whether K63-Akt ubiquitination drives radioresistance through membrane recruitment or kinase conformational change is unknown

• A central open question is how a single F-box protein directs three distinct ubiquitin chain types (K48, K63, K11) on different substrates, and whether this reflects E2 switching, substrate-intrinsic determinants, or cofactor-dependent mechanisms.
• No E2 conjugating enzyme partners have been identified for FBXL18
• No structural model of the FBXL18 LRR domain or substrate-binding interface exists
• Physiological regulation of FBXL18 expression or activity (transcriptional, post-translational) is uncharacterized