Affinage

FBXO6

F-box only protein 6 · UniProt Q9NRD1

Length
293 aa
Mass
33.9 kDa
Annotated
2026-06-09
22 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FBXO6 (Fbs2/FBG2) is the substrate-recognition F-box subunit of an SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase that selects glycoproteins and other substrates for K48-linked polyubiquitination and proteasomal degradation (PMID:12939278, PMID:33767133). Through its FBA domain it binds high-mannose N-glycans (Man3-9GlcNAc2) on misfolded glycoproteins, marking them for ERAD-coupled destruction; crystallography of the FBS2-SKP1 complex bound to the core Man3GlcNAc2 pentasaccharide defines the structural basis of this sugar recognition and reveals a druggable pocket (PMID:12939278, PMID:39171510), and a glycan-recognition-defective FBA mutant loses substrate binding across multiple cell lines (PMID:22268729). FBXO6 thereby controls the abundance of a broad substrate set: it degrades Chk1 to terminate the S-phase replication checkpoint in response to DNA damage, an activity that modulates sensitivity to genotoxic chemotherapy (PMID:19716789, PMID:31140586); it degrades the ER oxidase Ero1L to restrain ER stress-induced apoptosis (PMID:27855403); and it targets MMP14 to limit MMP13 activation and protect cartilage, a protective axis placed downstream of TGFβ-SMAD2/3 signaling that transcriptionally upregulates FBXO6, with knockout mice developing accelerated osteoarthritis (PMID:32409323). FBXO6 also acts in immune and oncogenic contexts, degrading IRF3 through a non-canonical SCF-independent mechanism to suppress type I interferon signaling (PMID:31308089) and degrading NLRX1 to promote influenza-induced macrophage apoptosis (PMID:36217277). Beyond ubiquitin ligase activity, FBXO6 interacts with the spindle checkpoint proteins Mad2 and BubR1 to regulate mitotic exit, and is itself phosphorylated during mitosis (PMID:30526252).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    Established FBXO6's foundational identity as an SCF E3 ligase subunit that recognizes a glycan signal, answering how the cell links N-glycan structure to degradation of misfolded glycoproteins in ERAD.

    Evidence Oligosaccharide pull-down defining sugar specificity, co-IP, siRNA knockdown and dominant-negative FBX mutant scored against TCRα degradation

    PMID:12939278

    Open questions at the time
    • Did not resolve the atomic basis of glycan recognition
    • Substrate repertoire beyond TCRα unknown at this stage
  2. 2009 High

    Identified Chk1 as a physiological substrate, showing FBXO6 terminates the S-phase replication checkpoint and that low FBXO6 confers genotoxic drug resistance.

    Evidence Reciprocal co-IP, in vivo ubiquitination assay, RNAi and stability assays in cancer cells and breast tumor tissue

    PMID:19716789

    Open questions at the time
    • Whether Chk1 recognition is glycan-dependent or via a distinct C-terminal degron
    • Relationship to canonical SCF assembly for this substrate
  3. 2012 Medium

    Generalized the glycan-recognition mechanism by mapping a high-confidence N-glycoprotein interactome dependent on an intact FBA domain.

    Evidence Affinity purification with LC-MS across 293T, HeLa, Jurkat comparing wild-type vs glycan-recognition mutant FBXO6

    PMID:22268729

    Open questions at the time
    • Interactions not validated as productive ubiquitination substrates
    • Functional consequence of each interaction not tested
  4. 2016 Medium

    Connected FBXO6 to ER redox homeostasis by showing degradation of Ero1L restrains ER stress-induced apoptosis.

    Evidence In vivo ubiquitination, stability western blots, CCK8/FACS apoptosis assays with overexpression and RNAi

    PMID:27855403

    Open questions at the time
    • Single lab; reciprocal validation limited
    • Whether degradation is glycan-dependent not addressed
  5. 2018 Medium

    Revealed a degradation-independent mitotic role, with FBXO6 binding Mad2 and BubR1 to inactivate the spindle assembly checkpoint.

    Evidence Co-IP, overexpression in HeLa, nocodazole arrest/release, flow cytometry and microscopy of segregation defects

    PMID:30526252

    Open questions at the time
    • Whether the interaction is ubiquitination-coupled or purely scaffolding unclear
    • Endogenous-level requirement not established
  6. 2019 Medium

    Defined a non-canonical, SCF-independent activity in which FBXO6 degrades IRF3 to suppress type I interferon antiviral signaling.

    Evidence Co-IP with FBA-IAD domain mapping, ubiquitination and IFN-I reporter assays in HEK293T and A549

    PMID:31308089

    Open questions at the time
    • Mechanism of SCF-independent ubiquitin transfer unresolved
    • In vivo antiviral consequence not tested in this study
  7. 2019 Medium

    Corroborated Chk1 as a substrate in an independent cancer context, linking FBXO6 to cisplatin sensitization in NSCLC.

    Evidence Cell-based assays, Chk1 protein/phospho western blots, cisplatin sensitivity with overexpression and knockdown

    PMID:31140586

    Open questions at the time
    • No in vivo validation
    • Direct ubiquitination not re-demonstrated
  8. 2020 High

    Established a TGFβ-SMAD2/3 → FBXO6 → MMP14 protective axis in cartilage with strong genetic causality for osteoarthritis.

    Evidence Reciprocal co-IP, in vivo ubiquitination, global and Col2a1-CreER conditional knockout mice, SMAD2/3 epistasis, rescue

    PMID:32409323

    Open questions at the time
    • Whether MMP14 recognition uses the glycan-binding pocket not resolved
    • Generalizability of TGFβ-driven induction to other tissues
  9. 2021 Medium

    Identified RNASET2 as a K48-linked ubiquitination substrate, linking FBXO6 to ovarian cancer progression.

    Evidence Co-IP, K48-specific in vivo ubiquitination, FBA domain deletion, siRNA and rescue in ovarian cancer cells

    PMID:33767133

    Open questions at the time
    • Single lab
    • In vivo tumor validation limited
  10. 2022 Medium

    Showed FBXO6 activity is itself regulated by competing chaperone interactions, with HSP90 binding FBXO6 to protect CD147 and confer radioresistance.

    Evidence Proteomics, co-IP, ubiquitination assay, 17-AAG HSP90 inhibition, clonogenic survival in cervical cancer cells

    PMID:35043518

    Open questions at the time
    • Structural basis of HSP90-FBXO6 competition unknown
    • Single lab
  11. 2022 Medium

    Extended the antiviral role in vivo, with FBXO6 degrading NLRX1 to promote influenza-induced macrophage apoptosis and dampen type I IFN.

    Evidence Co-IP, FBXO6 knockout mice and macrophage shRNA, in vivo IAV infection, flow cytometry, IFN measurement

    PMID:36217277

    Open questions at the time
    • Direct ubiquitination of NLRX1 not fully demonstrated
    • Relationship to the IRF3 axis not reconciled
  12. 2023 Low

    Implicated an RNA-binding cofactor, MSI2, cooperating with FBXO6 to ubiquitinate RNASET2 in vascular smooth muscle phenotypic switching.

    Evidence RIP, co-IP, siRNA, migration assays and atherosclerosis mouse model

    PMID:37633478

    Open questions at the time
    • Single Co-IP for MSI2-FBXO6; not reciprocally validated
    • FBXO6-mediated ubiquitination inferred rather than directly shown here
  13. 2024 High

    Resolved the atomic mechanism of glycan recognition, providing the structural basis for SCFFbs2 sugar binding and a druggable pocket.

    Evidence X-ray crystal structure of bovine FBS2-SKP1 with Man3GlcNAc2, complemented by NMR and in silico docking

    PMID:39171510

    Open questions at the time
    • No structure of FBXO6 bound to a full glycoprotein substrate
    • Druggability not yet validated by chemical probes
  14. 2026 Low

    Expanded the substrate set to ITGB1, SLC3A2, and STARD3NL, linking FBXO6 degradation activity to colorectal cancer invasion, colitis ferroptosis, and Wnt-driven osteogenesis respectively.

    Evidence Co-IP/MS substrate identification, K48 ubiquitination assays, knockdown/overexpression rescue, xenograft and disease models

    PMID:41483826 PMID:41741720 PMID:41857001

    Open questions at the time
    • SLC3A2 and STARD3NL findings are single-lab with limited orthogonal validation
    • STARD3NL degradation mechanism not fully reconstituted
    • Whether each substrate is recognized via the glycan pocket unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FBXO6 discriminates among its many reported substrates — glycan-dependent versus degron-based versus SCF-independent recognition — and what governs context-specific substrate choice across tissues remains unresolved.
  • No unified model reconciling glycan recognition with non-glycan substrates like Chk1 and IRF3
  • Structural basis of substrate selection beyond the glycan pocket unknown
  • Mechanism of SCF-independent ubiquitination not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2
Partners
BUBR1CHK1HSP90IRF3MAD2MMP14NLRX1SKP1
Complex memberships
SCF (Skp1-Cul1-F-box) E3 ubiquitin ligase

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 FBXO6 (Fbs2/FBG2) forms an SCF E3 ubiquitin ligase complex (SCFFbs2) that specifically recognizes high-mannose N-glycans (Man3-9GlcNAc2) on misfolded glycoproteins and targets them for ubiquitylation and proteasomal degradation as part of the ERAD pathway. Pull-down with various oligosaccharides defined the sugar-binding specificity; siRNA knockdown and dominant-negative FBX deletion mutant both inhibited TCRα degradation. Pull-down assay with defined oligosaccharides, co-immunoprecipitation, siRNA knockdown, dominant-negative overexpression, western blot The Journal of biological chemistry High 12939278
2009 The SCF-Fbx6 E3 ubiquitin ligase complex mediates ubiquitination and proteasomal degradation of Chk1 in response to DNA damage, thereby terminating the S-phase replication checkpoint. DNA damage exposes a degron-like region at the C-terminus of Chk1 that is recognized by Fbx6. Low Fbx6 levels impair Chk1 degradation and correlate with camptothecin resistance. Co-immunoprecipitation, in vivo ubiquitination assay, RNAi-mediated knockdown, overexpression, western blot, protein stability assays in cultured cancer cells and breast tumor tissues Molecular cell High 19716789
2012 FBXO6 interacts with 29 high-confidence N-glycoproteins in an N-glycan-dependent manner across three cell lines (293T, HeLa, Jurkat), as identified by affinity purification combined with LC-MS. A glycan-recognition-defective FBXO6 mutant lost these interactions, confirming that the FBA domain mediates substrate recognition. Affinity purification, LC-MS proteomics, comparison of wild-type vs. glycan-recognition mutant FBXO6 Journal of proteome research Medium 22268729
2016 FBXO6 ubiquitinates and promotes proteasomal degradation of Ero1L (a protein disulfide oxidase in the ER), thereby inhibiting ER stress-induced apoptosis. Overexpression of FBXO6 increased Ero1L polyubiquitination and decreased its stability, while FBXO6 inhibition prolonged Ero1L half-life. In vivo ubiquitination assay, western blot for protein stability, CCK8 and FACS apoptosis assays, overexpression and RNAi knockdown Cellular physiology and biochemistry Medium 27855403
2018 Overexpression of Fbxo6 inactivates the spindle assembly checkpoint by physically interacting with the checkpoint proteins Mad2 and BubR1, leading to premature exit from nocodazole-induced mitotic arrest, premature sister chromatid separation, and formation of binuclear/multilobed nuclei. Fbxo6 itself is phosphorylated during mitosis. Co-immunoprecipitation, overexpression in HeLa cells, nocodazole arrest/release assay, flow cytometry, microscopy for chromosome segregation defects Cell cycle Medium 30526252
2019 FBXO6 promotes ubiquitination and proteasomal degradation of IRF3 independently of the canonical SCF complex, through its FBA region interacting with the IAD domain of IRF3. This non-canonical activity suppresses IFN-I antiviral signaling in HEK293T and A549 cells. Co-immunoprecipitation, domain-mapping experiments (structure-function), ubiquitination assay, overexpression and knockdown in HEK293T and A549 cells, IFN-I reporter assays Journal of immunology Medium 31308089
2019 Fbxo6 reduces Chk1 protein levels and phosphorylation in non-small cell lung cancer cells, sensitizing them to cisplatin, consistent with its role as an SCF E3 ligase subunit mediating Chk1 degradation. In vitro cell-based assays, western blot for Chk1 protein and phosphorylation levels, cisplatin sensitivity assays, overexpression and knockdown FEBS letters Medium 31140586
2020 FBXO6 directly ubiquitinates and promotes proteasomal degradation of MMP14, reducing proteolytic activation of MMP13 and thereby protecting cartilage from degradation. TGFβ-SMAD2/3 signaling upregulates FBXO6 transcription, placing FBXO6 downstream of TGFβ in this protective pathway. Global and conditional (Col2a1-CreER) FBXO6 knockout mice showed accelerated experimental OA. Co-immunoprecipitation, in vivo ubiquitination assay, global and conditional knockout mouse models (ACLT-induced and spontaneous OA), SMAD2/3 knockout, overexpression rescue experiments, western blot Annals of the rheumatic diseases High 32409323
2021 FBXO6 acts as the E3 ubiquitin ligase for RNASET2, promoting its K48-linked ubiquitination and proteasomal degradation via the FBA domain. FBXO6 depletion stabilizes RNASET2 and suppresses ovarian cancer cell proliferation, migration, and invasion. Co-immunoprecipitation, in vivo ubiquitination assay (K48 linkage specified), domain deletion analysis, siRNA knockdown, overexpression rescue experiments in ovarian cancer cells Cell death & disease Medium 33767133
2022 FBXO6 promotes proteasomal degradation of NLRX1 (a mitochondrial protein that counteracts virus-induced apoptosis), thereby facilitating IAV-induced alveolar macrophage apoptosis and impairing type I IFN production. FBXO6-deficient mice showed decreased pulmonary viral replication and enhanced type I IFN in the lungs. Co-immunoprecipitation, gain- and loss-of-function studies (FBXO6 knockout mice, shRNA knockdown in macrophages), in vivo IAV infection model, flow cytometry, IFN measurement Journal of medical virology Medium 36217277
2022 HSP90 interacts with FBXO6 and reduces FBXO6-mediated polyubiquitination and proteasomal degradation of CD147, thereby stabilizing CD147 and promoting radioresistance in cervical cancer cells. FBXO6 overexpression sensitizes radioresistant cells to irradiation. Proteomics screen, co-immunoprecipitation, ubiquitination assay, overexpression and HSP90 inhibitor (17-AAG) treatment, clonogenic survival assays Cancer science Medium 35043518
2023 MSI2 (Musashi-2) binds FBXO6 and cooperates with it to induce RNASET2 ubiquitination in vascular smooth muscle cells, regulating chemokine signaling and VSMC phenotypic switching in atherosclerosis. RNA-binding protein immunoprecipitation, co-immunoprecipitation, siRNA knockdown, western blot, CCK-8, wound healing and transwell assays, in vivo AS mouse model Cellular signalling Low 37633478
2024 Crystal structure of bovine FBS2 (FBXO6 ortholog) in complex with SKP1 and the core N-glycan pentasaccharide Man3GlcNAc2 revealed the structural basis of sugar recognition by SCFFbs2 and identified a druggable pocket. NMR data complemented crystallographic findings to define disparate sugar-binding specificities between FBS family members. X-ray crystallography, NMR spectroscopy, in silico docking FEBS letters High 39171510
2026 FBXO6 binds ITGB1 at its glycoprotein recognition site, promotes ITGB1 ubiquitination and degradation, and thereby attenuates downstream FAK/PI3K/AKT/ERK signaling, suppressing colorectal cancer cell migration and invasion. ITGB1 overexpression counteracts these effects. Co-immunoprecipitation, mass spectrometry substrate identification, in vitro ubiquitination/degradation assays, overexpression and knockdown, in vivo xenograft models, rescue experiments Cell death & disease Medium 41857001
2026 FBXO6 directly binds SLC3A2 and induces its degradation through K48-linked ubiquitination, promoting ferroptosis and epithelial barrier disruption in ulcerative colitis. Co-immunoprecipitation, K48-linked ubiquitination assay, LPS-stimulated HT29 cell model, western blot, machine-learning-guided candidate prioritization Inflammation research Low 41741720
2026 FBXO6 interacts with STARD3NL and promotes its destabilization, activating the Wnt/β-catenin signaling pathway to drive osteogenic differentiation of bone marrow mesenchymal stem cells. Label-free quantitative proteomics, co-immunoprecipitation, overexpression and siRNA knockdown, osteogenic differentiation assays (ALP, calcium nodules, osteogenic marker mRNA), Wnt/β-catenin inhibitor (DKK1) rescue, in vivo femoral defect model Biochemical pharmacology Low 41483826

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress. Molecular cell 153 19716789
2003 Fbs2 is a new member of the E3 ubiquitin ligase family that recognizes sugar chains. The Journal of biological chemistry 138 12939278
2020 TGFβ attenuates cartilage extracellular matrix degradation via enhancing FBXO6-mediated MMP14 ubiquitination. Annals of the rheumatic diseases 77 32409323
2012 Proteomic identification of common SCF ubiquitin ligase FBXO6-interacting glycoproteins in three kinds of cells. Journal of proteome research 39 22268729
2021 FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer. Cell death & disease 33 33767133
2016 FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 27855403
2022 HSP90 promotes radioresistance of cervical cancer cells via reducing FBXO6-mediated CD147 polyubiquitination. Cancer science 23 35043518
2021 Role of the miR-133a-5p/FBXO6 axis in the regulation of intervertebral disc degeneration. Journal of orthopaedic translation 19 34249610
2014 FBXO6 attenuates cadmium toxicity in HEK293 cells by inhibiting ER stress and JNK activation. The Journal of toxicological sciences 19 25374377
2009 A study on the functions of ubiquitin metabolic system related gene FBG2 in gastric cancer cell line. Journal of experimental & clinical cancer research : CR 18 19515249
2022 FBXO6 regulates the antiviral immune responses via mediating alveolar macrophages survival. Journal of medical virology 16 36217277
2019 Noncanonical Role of FBXO6 in Regulating Antiviral Immunity. Journal of immunology (Baltimore, Md. : 1950) 16 31308089
2019 Fbxo6 confers drug-sensitization to cisplatin via inhibiting the activation of Chk1 in non-small cell lung cancer. FEBS letters 15 31140586
2017 Genetic Analysis of FBXO2, FBXO6, FBXO12, and FBXO41 Variants in Han Chinese Patients with Sporadic Parkinson's Disease. Neuroscience bulletin 12 28341977
2018 Overexpression of Fbxo6 inactivates spindle checkpoint by interacting with Mad2 and BubR1. Cell cycle (Georgetown, Tex.) 11 30526252
2022 The USP18-FBXO6 axis maintains the malignancy of ovarian cancer. Biochemical and biophysical research communications 10 35063764
2024 Structural basis of sugar recognition by SCFFBS2 ubiquitin ligase involved in NGLY1 deficiency. FEBS letters 3 39171510
2023 Musashi-2 binds with Fbxo6 to induce Rnaset2 ubiquitination and chemokine signaling pathway during vascular smooth muscle cell phenotypic switch in atherosclerosis. Cellular signalling 3 37633478
2024 Delivery of FBXO6 with highly branched poly(β-amino ester)s to modulate the inflammatory environment for the treatment of osteoarthritis. Journal of controlled release : official journal of the Controlled Release Society 1 39674232
2026 Accelerating bone healing in femoral defect model using FBXO6-modified bone marrow-derived mesenchymal stem cells on a collagen scaffold. Biochemical pharmacology 0 41483826
2026 FBXO6 mediated ubiquitination of SLC3A2 drives ferroptosis in ulcerative colitis: a machine learning and SHAP discovery. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 41741720
2026 FBXO6 regulates colon cancer migration and invasion via ITGB1 ubiquitination and downstream signaling. Cell death & disease 0 41857001

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