FBXO6 (FBG2/FBS2, F-box protein that recognizes sugar chains 2) is a 293-amino-acid cytoplasmic F-box protein and a member of the FBA (F-box-associated) lectin family (FBXO2/FBXO6/FBXO17/FBXO27/FBXO44). It serves as the substrate-recognition subunit of SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complexes: its N-terminal F-box domain docks onto SKP1 (and thence CUL1-RBX1), while its C-terminal FBA/G domain is a carbohydrate-binding lectin module that recognizes N-linked glycans on client proteins. As an F-box protein FBXO6 has no intrinsic catalytic activity; catalysis is contributed by the RING subunit RBX1 within the assembled SCF complex, and FBXO6 confers substrate specificity. Through its FBA domain FBXO6 binds high-mannose oligosaccharides (with the chitobiose core being essential), complex-type glycans, and sulfated glycoproteins, and it preferentially engages denatured/misfolded glycoproteins. This lectin activity directs misfolded glycoproteins that have been retrotranslocated to the cytosol into the endoplasmic-reticulum-associated degradation (ERAD)/glycoprotein-quality-control pathway, promoting their ubiquitination and proteasomal degradation. FBXO6 also has a documented role in the DNA replication/damage checkpoint: it recognizes activated, S345-phosphorylated CHEK1 (CHK1) via its FBA domain and assembles an SCF(FBXO6) complex that ubiquitinates CHK1 and targets it for degradation, contributing to checkpoint termination and influencing cellular sensitivity to replication stress. FBXO6 is broadly but variably expressed (notably in liver and kidney) and interacts with VCP/p97. Among its glycoprotein clients, SCF(FBXO6/Fbs2) ubiquitinates the ER-membrane transcription factor NFE2L1/NRF1; in the absence of the cytoplasmic deglycosylase NGLY1, FBXO6-mediated ubiquitination of still-glycosylated NFE2L1 impairs its processing and nuclear function, blunting the proteasome "bounce-back" induction of new proteasome subunits, and genetic reduction of Fbs2/FBXO6 partially rescues Ngly1-knockout phenotypes in mice (with Fbs2-knockout mice otherwise healthy).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in ER-associated degradation, a core biological process of the FBA lectin family of F-box proteins. Reason: Core biological process; FBXO6 recognizes glycans on misfolded glycoproteins to direct them to ERAD/proteasomal degradation, supported by UniProt and ISS. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of cytoplasmic localization, consistent with the documented cytoplasmic site of FBXO6 action. Reason: Correct localization; SCF(FBXO6) acts in the cytosol on retrotranslocated glycoproteins and on cytoplasmic CHK1; supported by IDA (PMID:19716789) and UniProt subcellular location. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0006516 glycoprotein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in glycoprotein catabolism, a core process for this lectin F-box family that targets glycoproteins for degradation. Reason: Core biological process; FBXO6 recognizes glycans on misfolded glycoproteins and routes them to degradation. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation |
| GO:0019005 SCF ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment placing FBXO6 in the SCF (SKP1-CUL1-F-box) ubiquitin ligase complex, its defining structural context as an F-box protein. Reason: Core cellular-complex assignment; FBXO6 assembles into a canonical SCF complex (SKP1, CUL1, RBX1) via its F-box domain, supported experimentally. Supporting Evidence: PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in SCF-dependent proteasomal degradation, the core biological process executed by SCF(FBXO6). Reason: Core biological process; FBXO6 acts as the substrate receptor of an SCF complex that drives proteasomal degradation of its glycoprotein and CHK1 substrates. Supporting Evidence: PMID:19716789 an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 |
| GO:0044322 endoplasmic reticulum quality control compartment | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment to the ER quality-control compartment, inferred from the family's role in glycoprotein quality control/ERAD. Reason: Plausible localization inferred from the ERAD/glycoprotein-QC role, but FBXO6 is a cytoplasmic protein that engages substrates after retrotranslocation; direct ERQC localization is not demonstrated for FBXO6. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of ubiquitin protein ligase activity with a contributes_to qualifier, reflecting that FBXO6 is the substrate receptor that contributes to the activity of the assembled SCF E3 ligase rather than carrying catalytic activity itself. Reason: FBXO6 has no intrinsic catalytic ligase activity; catalysis resides in the RING subunit RBX1. The contributes_to qualifier is the correct way to capture that FBXO6 contributes substrate specificity to SCF ligase activity, but FBXO6's own core molecular function is carbohydrate binding, so this is retained as non-core rather than as the gene's primary function. Supporting Evidence: PMID:18203720 As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated electronic assignment of cytoplasmic localization, consistent with the experimentally documented cytoplasmic site of FBXO6. Reason: Correct localization; redundant with the IDA (PMID:19716789) and IBA cytoplasm annotations. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005515 protein binding | IPI PMID:23108047 FBXW7-mediated degradation of CCDC6 is impaired by ATM durin... | KEEP AS NON CORE | Summary: IntAct interaction with CUL1 (Q13616), the cullin scaffold of the SCF complex. A real and functionally relevant interaction, but the bare protein binding term is uninformative. Reason: Records the FBXO6-CUL1 SCF-assembly interaction, but bare protein binding is uninformative per curation guidelines; the SCF-complex membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390 |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: IntAct interaction with SKP1 (P63208), the adaptor that bridges the F-box domain to CUL1. A real SCF-assembly interaction, but bare protein binding is uninformative. Reason: Records the FBXO6-SKP1 interaction central to SCF assembly, but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput interactome interaction with CUL1 (Q13616). A real SCF-component interaction, but bare protein binding is uninformative. Reason: Records the FBXO6-CUL1 interaction but bare protein binding is uninformative; captured at the complex level by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390 |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | KEEP AS NON CORE | Summary: Interferon-stimulated-gene interactome capturing FBXO6 interactions with SKP1 (P63208), CUL1 (Q13616) and LGALS3BP (Q08380, a secreted glycoprotein). Bare protein binding is uninformative. Reason: Records SCF-component interactions plus a glycoprotein (LGALS3BP) interaction, but bare protein binding is uninformative; relevant functions are captured by the SCF-complex and carbohydrate-binding annotations. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-3938499, EBI-354956 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map capturing the FBXO6-SKP1 (P63208) interaction. Bare protein binding is uninformative. Reason: Records the FBXO6-SKP1 interaction but bare protein binding is uninformative; SCF membership is captured by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome capturing FBXO6 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. Reason: Records SCF-component interactions but bare protein binding is uninformative; captured at the complex level by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; P63208: SKP1; NbExp=10; IntAct=EBI-3938499, EBI-307486 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map interactome capturing FBXO6 interactions with SKP1 (P63208) and CUL1 (Q13616). Bare protein binding is uninformative. Reason: Records SCF-component interactions but bare protein binding is uninformative; captured at the complex level by GO:0019005. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Q9NRD1; Q13616: CUL1; NbExp=6; IntAct=EBI-3938499, EBI-359390 |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of ubiquitin-dependent protein catabolism, a parent process consistent with FBXO6's role as an SCF substrate receptor. Reason: Correct but generic; the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent catabolism) and GO:0036503 (ERAD) better capture the core role. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt promoting their ubiquitination and subsequent degradation |
| GO:0019005 SCF ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of SCF complex membership, the defining context of FBXO6 as an F-box protein. Reason: Core cellular-complex assignment; redundant with the IBA, NAS and IDA SCF-complex annotations and experimentally supported. Supporting Evidence: PMID:18203720 All FBA family members co-immunoprecipitated components of the SCF complex |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of carbohydrate binding, capturing the FBA/G-domain lectin activity that is the core molecular function distinguishing this F-box subfamily. Reason: Core molecular function; the FBA domain is a lectin that binds high-mannose, complex and sulfated glycans, directly demonstrated by glycan-array and pulldown assays. Supporting Evidence: PMID:18203720 FBXO6 bound high mannose glycans with relatively high affinity |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO6). Reason: Core biological process; redundant with the IBA, NAS and IDA annotations of the same term. Supporting Evidence: PMID:19716789 an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 |
| GO:0036503 ERAD pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of involvement in ERAD, a core biological process for FBXO6. Reason: Core biological process; redundant with the IBA and ISS ERAD annotations. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins |
| GO:0044322 endoplasmic reticulum quality control compartment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment to the ER quality-control compartment, inferred from the glycoprotein-QC/ERAD role. Reason: Plausible but not directly demonstrated for FBXO6, which is a cytoplasmic protein engaging substrates after retrotranslocation; the experimentally supported localization is cytoplasm. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of ubiquitin protein ligase activity with a contributes_to qualifier, reflecting FBXO6's contribution of substrate specificity to the SCF E3 ligase. Reason: FBXO6 has no intrinsic catalytic ligase activity (RBX1 is catalytic); the contributes_to qualifier correctly conveys that FBXO6 contributes substrate recognition to SCF ligase activity, but the gene's own core molecular function is carbohydrate binding. Supporting Evidence: PMID:18203720 As the substrate recognition subunits of multiprotein ubiquitin ligase complexes, F-box proteins have no intrinsic catalytic activity of their own. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination FBXO6 contributes to. Reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture FBXO6's role. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal/Reactome non-traceable author statement placing FBXO6 in an SCF E3 ubiquitin ligase complex; consistent with a defined ComplexPortal entry (CPX-7905, SCF FBXO6 variant). Reason: Core cellular-complex assignment; FBXO6 is a defined F-box substrate-receptor variant of the SCF complex, supported experimentally (PMID:18203720) and by ComplexPortal CPX-7905. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt ComplexPortal; CPX-7905; SCF E3 ubiquitin ligase complex, FBXO6 variant. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: ComplexPortal non-traceable author statement of involvement in SCF-dependent proteasomal degradation, the core process of SCF complexes including SCF(FBXO6). Reason: Core biological process; redundant with the IBA, IEA and IDA annotations of the same term. Supporting Evidence: PMID:34445249 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL1/neddylation reaction (NEDD8 transfer to CRL1). Consistent with the cytoplasmic localization of FBXO6 and its SCF complex. Reason: Correct localization; the cytosol is a child of cytoplasm and consistent with the experimentally supported cytoplasmic localization; these Reactome cytosol annotations reflect generic CRL/neddylation machinery reactions. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | ACCEPT | Summary: Reactome curation of cytosolic localization within a CRL1/neddylation reaction. Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization (cytosol is part of cytoplasm); reflects generic CRL/neddylation reactions and is redundant with the experimentally supported cytoplasm annotation. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL E3 ligases). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: Reactome curation of cytosolic localization (COMMDs displace CAND1 from cytosolic CRL complexes). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates cytosolic CRL complexes). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | ACCEPT | Summary: Reactome curation of cytosolic localization (MyrG-DCUN1D3 binds CRL1 complex). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic CRL-regulation machinery reactions. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (polyubiquitination of substrate). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | ACCEPT | Summary: Reactome curation of cytosolic localization within a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Consistent with FBXO6's cytoplasmic localization. Reason: Correct localization; redundant with the experimentally supported cytoplasm annotation; reflects generic SCF ubiquitination-reaction machinery. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19716789} |
| GO:0000077 DNA damage checkpoint signaling | TAS PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | KEEP AS NON CORE | Summary: Traceable author statement linking FBXO6 to the DNA damage/replication checkpoint via SCF(FBXO6)-mediated ubiquitination and degradation of activated CHK1, which terminates the checkpoint. Reason: Well-supported, genuine role (degradation of activated CHK1 contributes to checkpoint termination), but distinct from the gene's primary glycan-recognition/ERAD core function; retained as a non-core second process. Supporting Evidence: PMID:19716789 DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint |
| GO:0005515 protein binding | IPI PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | KEEP AS NON CORE | Summary: IPI interaction with CHEK1/CHK1 (O14757), a functionally important FBXO6 substrate engaged via the FBA domain. Bare protein binding is uninformative. Reason: Records the functionally meaningful FBXO6-CHK1 substrate interaction, but bare protein binding is uninformative; the CHK1-regulation role is captured by the checkpoint/SCF-catabolism annotations. Supporting Evidence: PMID:19716789 endogenous Fbx6 was co-immunoprecipitated with Chk1 in extracts from non-transfected cells |
| GO:0005737 cytoplasm | IDA PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | ACCEPT | Summary: Direct experimental evidence (immunolocalization) that FBXO6 is mainly localized to the cytoplasm, where it engages CHK1. Reason: Core localization with direct experimental support; FBXO6 acts in the cytoplasm/cytosol on its substrates. Supporting Evidence: PMID:19716789 The Fbx6-Chk1 interaction was only detected in the cytoplasmic compartment where Fbx6 is mainly localized |
| GO:0006281 DNA repair | TAS PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | MARK AS OVER ANNOTATED | Summary: Traceable author statement annotating FBXO6 to DNA repair, derived from its role in the ATR-CHK1 replication-checkpoint pathway that coordinates DNA damage/repair responses. Reason: FBXO6's documented role is checkpoint termination via CHK1 degradation, not DNA repair per se; CHK1 activation triggers repair responses, but FBXO6 acts to remove activated CHK1 and is not itself a repair factor. DNA damage checkpoint signaling (GO:0000077) more accurately captures the role; DNA repair is an over-annotation of the downstream pathway. Supporting Evidence: PMID:19716789 which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | ACCEPT | Summary: Direct experimental evidence that FBXO6 forms an SCF (SKP1-CUL1-FBXO6) complex, demonstrated by co-immunoprecipitation of SCF components. Reason: Core cellular-complex assignment with direct experimental support. Supporting Evidence: PMID:19716789 an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:19716789 The F box protein Fbx6 regulates Chk1 stability and cellular... | ACCEPT | Summary: Direct experimental evidence that SCF(FBXO6) drives the ubiquitination and proteasomal degradation of CHK1, demonstrating involvement in SCF-dependent proteasomal catabolism. Reason: Core biological process with direct experimental (IDA) support; FBXO6 FL supported CHK1 ubiquitination in vitro and FBXO6 depletion stabilized CHK1. Supporting Evidence: PMID:19716789 only the Fbx6 FL protein supported ubiquitination of Chk1 in vitro |
| GO:0036503 ERAD pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based assignment of involvement in ERAD, transferred from the mouse ortholog (Q9QZN4); a core biological process. Reason: Core biological process; consistent with the IBA and IEA ERAD annotations and the documented glycan-recognition/glycoprotein-degradation function. Supporting Evidence: file:human/FBXO6/FBXO6-uniprot.txt Involved in endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins |
| GO:0006508 proteolysis | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Early traceable author statement (F-box family identification paper) annotating FBXO6 to proteolysis, reflecting the general role of F-box proteins in SCF-mediated protein degradation. Reason: Correct but very generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture FBXO6's role. The abstract describes the F-box family broadly rather than FBXO6 specifically. Supporting Evidence: PMID:10531035 F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs |
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Download this section (compressed HTML)Q: Does FBXO6 recognize the CHK1 degron purely through a protein-protein (FBA-domain) interaction, or is glycan recognition also involved, and is the glycan-binding pocket (Y241/W242) dispensable for CHK1 targeting?
Q: What is the endogenous repertoire of glycoprotein substrates degraded specifically via SCF(FBXO6) (versus the paralog FBXO2), and how does FBXO6's broader specificity for complex and sulfated glycans translate into distinct in vivo substrates?
Q: How is partitioning between FBXO6's glycoprotein-ERAD role and its CHK1-checkpoint role regulated, and does the FBXO6-VCP/p97 interaction couple substrate recognition to retrotranslocation?
Q: Does SCF(FBXO6) ubiquitination of NFE2L1/NRF1 depend on the glycan-binding (FBA lectin) pocket, and is the proteasome bounce-back defect in NGLY1 deficiency driven specifically by FBXO6-mediated targeting of still-glycosylated NFE2L1?
Experiment: Perform quantitative ubiquitinome/proteome profiling in FBXO6-knockout versus wild-type cells, with and without ER stress and replication stress (e.g. camptothecin), to define the endogenous SCF(FBXO6) substrate repertoire and distinguish glycoprotein from CHK1-dependent effects.
Experiment: Reconstitute SCF(FBXO6) ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2 and FBXO6, comparing wild-type FBXO6 with the Y241A/W242A glycan-pocket mutant against a high-mannose glycoprotein substrate and against phospho-CHK1 to dissect glycan-dependent versus glycan-independent substrate targeting.
Experiment: Use glycan-array and structural (crystallography/cryo-EM) analysis of the FBXO6 FBA domain bound to defined oligosaccharides to map the determinants of its broader specificity (high-mannose, complex, sulfated glycans) relative to FBXO2.
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