{"gene":"FBXL17","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FBXL17 (Fbxl17) is the substrate-recognition subunit of an SCF E3 ubiquitin ligase that ubiquitylates Sufu (Suppressor of fused) in the nucleus, targeting it for proteasomal degradation. This ubiquitylation releases Gli1 from Sufu repression, thereby activating Hedgehog signaling. Depletion of Fbxl17 impairs Hh signaling and reduces cancer cell proliferation and medulloblastoma tumor growth. A Gorlin-syndrome Sufu mutation increases Fbxl17-mediated polyubiquitylation, causing sustained Hh activation.","method":"Co-immunoprecipitation, ubiquitylation assays, siRNA/shRNA knockdown, in vivo tumor models (medulloblastoma), mutant Sufu functional analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, KD phenotype, disease mutation validation across multiple orthogonal methods in one study","pmids":["27234298"],"is_preprint":false},{"year":2017,"finding":"SCF-FBXL17 recognizes PRMT1 via a tandem IKxxxIK acetyldegron motif. Sirt1-mediated deacetylation and p300-mediated acetylation at K200 and K205 within this motif collaboratively enable FBXL17 binding and drive PRMT1 polyubiquitylation at K117, leading to proteasomal degradation. LPS downregulates Sirt1 and p300, blocking the acetyldegron and protecting PRMT1 from degradation.","method":"Co-immunoprecipitation, ubiquitylation assays, site-directed mutagenesis (K117, K200, K205), half-life/cycloheximide chase, siRNA knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitylation assay, mutagenesis of degron residues, Co-IP, multiple orthogonal methods in one study","pmids":["28883095"],"is_preprint":false},{"year":2019,"finding":"Fbxl17's LRR domain mediates its association with SCF holoenzyme subunits Skp1, Cul1, and Rbx1; truncation of the LRRs impairs this association and decreases ubiquitination activity. Fbxl17 directly binds UAP1 (an O-GlcNAcylation pathway enzyme) and inhibits its phosphorylation; knockdown of Fbxl17 elevates global O-GlcNAcylation in breast cancer cells.","method":"Yeast two-hybrid screen (37 binding partners identified), Co-immunoprecipitation, truncation/deletion constructs, siRNA knockdown with O-GlcNAcylation measurement","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid, Co-IP, KD phenotype; UAP1 phosphorylation inhibition inferred but mechanism not fully reconstituted","pmids":["31560077"],"is_preprint":false},{"year":2022,"finding":"FBXL17 is the substrate-recognition subunit of an SCF E3 ligase complex that binds the BTB domain at the N-terminus of SPAST-M1 (spastin isoform M1) and mediates its proteasome-dependent degradation specifically in the nuclear fraction. CK2-mediated phosphorylation of SPAST in the cytoplasmic fraction promotes poly-ubiquitination. A disease-associated SPAST Y52C mutation (BTB domain) abrogates FBXL17 binding, escaping SCF-FBXL17 regulation. Inhibition of SCF-FBXL17 stabilizes SPAST-M1 and rescues axonal extension phenotypes.","method":"Protein chip analysis, Co-immunoprecipitation (BTB domain mapping), fractionation assays, proteasome inhibitor rescue, CK2 kinase assay, shRNA knockdown, 3D neuronal differentiation model, small chemical inhibitor","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping, fractionation, KD phenotype, disease mutant validation; single lab","pmids":["35869491"],"is_preprint":false},{"year":2025,"finding":"SCF-FBXL17 acts as a dimerization quality control E3 ligase for BTB domain-containing proteins (including KEAP1, KLHL12, PATZ1). Translation-driven temporal control via coupled ribosomes enables nascent chain segments to adopt folding-assembly pathways that bypass closed monomeric BTB states; SCF-FBXL17-mediated quality control operates in concert with this cotranslational mechanism.","method":"Disome Selective Profiling, optical tweezers, ribosome profiling; mechanistic analysis of BTB domain folding states","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, FBXL17 role inferred in concert with cotranslational mechanism; direct ubiquitylation assay for FBXL17 not explicitly described in abstract","pmids":["bio_10.1101_2025.08.25.672138"],"is_preprint":true}],"current_model":"FBXL17 is the substrate-recognition F-box subunit of an SCF-type E3 ubiquitin ligase complex that targets multiple substrates—including Sufu (via nuclear ubiquitylation to activate Hedgehog signaling), PRMT1 (via an acetylation-regulated IKxxxIK acetyldegron), and SPAST-M1 (via its BTB domain, in the nuclear fraction)—for proteasomal degradation, while also binding UAP1 to regulate O-GlcNAcylation; substrate recognition by FBXL17 requires its LRR domain and can be governed by post-translational modifications (acetylation, phosphorylation) on the substrate."},"narrative":{"mechanistic_narrative":"FBXL17 is the substrate-recognition F-box subunit of an SCF (Skp1–Cul1–Rbx1) E3 ubiquitin ligase that selects specific substrates for polyubiquitylation and proteasomal degradation across multiple signaling contexts [PMID:27234298, PMID:31560077]. Its leucine-rich repeat (LRR) domain mediates both incorporation into the SCF holoenzyme and substrate engagement, and LRR truncation abolishes both holoenzyme association and ubiquitination activity [PMID:31560077]. Through this activity FBXL17 promotes Hedgehog signaling by ubiquitylating Sufu in the nucleus, releasing Gli1 from repression; its loss impairs Hh signaling and reduces medulloblastoma growth, and a Gorlin-syndrome Sufu mutation enhances FBXL17-mediated polyubiquitylation to sustain Hh activation [PMID:27234298]. Substrate recognition is gated by post-translational modifications: FBXL17 reads an acetylation-dependent IKxxxIK acetyldegron on PRMT1—jointly controlled by p300 acetylation and Sirt1 deacetylation at K200/K205—to drive its degradation [PMID:28883095], and it targets the M1 isoform of spastin (SPAST-M1) by binding its N-terminal BTB domain in the nuclear fraction, with CK2 phosphorylation promoting ubiquitination and a disease-associated Y52C BTB mutation escaping regulation [PMID:35869491]. FBXL17 also binds the O-GlcNAcylation enzyme UAP1 and inhibits its phosphorylation, with FBXL17 depletion elevating global O-GlcNAcylation in breast cancer cells [PMID:31560077].","teleology":[{"year":2016,"claim":"Established FBXL17 as a bona fide SCF substrate-recognition subunit and connected it to a signaling output by showing it ubiquitylates nuclear Sufu to de-repress Gli1 and activate Hedgehog signaling.","evidence":"Reciprocal Co-IP, ubiquitylation assays, siRNA/shRNA knockdown, medulloblastoma tumor models, and Gorlin-syndrome Sufu mutant analysis","pmids":["27234298"],"confidence":"High","gaps":["Does not resolve how FBXL17 is restricted to the nuclear Sufu pool","Degron/recognition determinants on Sufu not mapped"]},{"year":2017,"claim":"Defined a modification-gated recognition logic for FBXL17 by showing it reads an acetylation-dependent IKxxxIK acetyldegron, explaining how substrate PTM state controls degradation timing.","evidence":"In vitro ubiquitylation assays, site-directed mutagenesis of K117/K200/K205, Co-IP, and cycloheximide chase on PRMT1","pmids":["28883095"],"confidence":"High","gaps":["Whether the acetyldegron logic generalizes to other FBXL17 substrates untested","Structural basis of acetyl-lysine recognition by the LRR not determined"]},{"year":2019,"claim":"Mapped the LRR domain as the structural element required for both SCF holoenzyme assembly and ligase activity, and broadened the interactome to include UAP1, linking FBXL17 to O-GlcNAcylation control.","evidence":"Yeast two-hybrid screen, Co-IP, LRR truncation constructs, and siRNA knockdown with O-GlcNAcylation measurement in breast cancer cells","pmids":["31560077"],"confidence":"Medium","gaps":["UAP1 phosphorylation inhibition inferred, not reconstituted","Unclear whether UAP1 is a degradation substrate or a non-degradative binding partner"]},{"year":2022,"claim":"Showed FBXL17 recognizes substrates through BTB-domain binding and operates in a fractionation- and phosphorylation-dependent manner, extending its targeting repertoire to SPAST-M1 with disease relevance.","evidence":"Protein chip, Co-IP with BTB domain mapping, fractionation, proteasome inhibitor rescue, CK2 assay, shRNA, and a 3D neuronal differentiation model with disease mutant and chemical inhibitor","pmids":["35869491"],"confidence":"Medium","gaps":["Single-lab evidence","Why degradation is confined to the nuclear fraction not mechanistically explained"]},{"year":2025,"claim":"Proposed a unifying role for SCF-FBXL17 as a dimerization quality-control ligase for BTB-domain proteins acting alongside cotranslational folding control.","evidence":"Disome selective profiling, optical tweezers, and ribosome profiling on BTB folding states (preprint)","pmids":["bio_10.1101_2025.08.25.672138"],"confidence":"Low","gaps":["Preprint; direct FBXL17 ubiquitylation assay not described","FBXL17 role inferred in concert with cotranslational mechanism rather than directly demonstrated"]},{"year":null,"claim":"How FBXL17 substrate selection is partitioned between subcellular compartments and integrated across its diverse PTM-gated degrons remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FBXL17 LRR bound to a substrate degron","Mechanism restricting activity to the nuclear fraction unknown","Relationship between BTB-binding and acetyldegron-reading modes not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":["SCF (Skp1-Cul1-Rbx1) E3 ubiquitin ligase"],"partners":["SUFU","PRMT1","SPAST","UAP1","SKP1","CUL1","RBX1","KEAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UF56","full_name":"F-box/LRR-repeat protein 17","aliases":["F-box and leucine-rich repeat protein 17","F-box only protein 13"],"length_aa":701,"mass_kda":75.7,"function":"Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex, a key component of a quality control pathway required to ensure functional dimerization of BTB domain-containing proteins (dimerization quality control, DQC) (PubMed:30190310). FBXL17 specifically recognizes and binds a conserved degron of non-consecutive residues present at the interface of BTB dimers of aberrant composition: aberrant BTB dimer are then ubiquitinated by the SCF(FBXL17) complex and degraded by the proteasome (PubMed:30190310). The ability of the SCF(FBXL17) complex to eliminate compromised BTB dimers is required for the differentiation and survival of neural crest and neuronal cells (By similarity). The SCF(FBXL17) complex mediates ubiquitination and degradation of BACH1 (PubMed:24035498, PubMed:30190310). The SCF(FBXL17) complex is also involved in the regulation of the hedgehog/smoothened (Hh) signaling pathway by mediating the ubiquitination and degradation of SUFU, allowing the release of GLI1 from SUFU for proper Hh signal transduction (PubMed:27234298). The SCF(FBXL17) complex mediates ubiquitination and degradation of PRMT1 (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UF56/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXL17","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXL17","total_profiled":1310},"omim":[{"mim_id":"609083","title":"F-BOX AND LEUCINE-RICH REPEAT PROTEIN 17; FBXL17","url":"https://www.omim.org/entry/609083"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FBXL17"},"hgnc":{"alias_symbol":["DKFZP434C1715","Fbx13","Fbl17"],"prev_symbol":["FBXO13"]},"alphafold":{"accession":"Q9UF56","domains":[{"cath_id":"-","chopping":"326-363","consensus_level":"medium","plddt":89.06,"start":326,"end":363},{"cath_id":"3.80.10.10","chopping":"366-442","consensus_level":"medium","plddt":94.7318,"start":366,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UF56","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UF56-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UF56-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXL17","jax_strain_url":"https://www.jax.org/strain/search?query=FBXL17"},"sequence":{"accession":"Q9UF56","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UF56.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UF56/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UF56"}},"corpus_meta":[{"pmid":"18948957","id":"PMC_18948957","title":"Control of plant germline proliferation by SCF(FBL17) degradation of cell cycle inhibitors.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18948957","citation_count":166,"is_preprint":false},{"pmid":"27234298","id":"PMC_27234298","title":"SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/27234298","citation_count":57,"is_preprint":false},{"pmid":"28883095","id":"PMC_28883095","title":"Lipopolysaccharide modulates p300 and Sirt1 to promote PRMT1 stability via an SCFFbxl17-recognized acetyldegron.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28883095","citation_count":26,"is_preprint":false},{"pmid":"32414898","id":"PMC_32414898","title":"The F-Box-Like Protein FBL17 Is a Regulator of DNA-Damage Response and Colocalizes with RETINOBLASTOMA RELATED1 at DNA Lesion Sites.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32414898","citation_count":22,"is_preprint":false},{"pmid":"24778558","id":"PMC_24778558","title":"RTN4 and FBXL17 Genes are Associated with Coronary Heart Disease in Genome-Wide Association Analysis of Lithuanian Families.","date":"2013","source":"Balkan journal of medical genetics : BJMG","url":"https://pubmed.ncbi.nlm.nih.gov/24778558","citation_count":16,"is_preprint":false},{"pmid":"31560077","id":"PMC_31560077","title":"Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/31560077","citation_count":9,"is_preprint":false},{"pmid":"35869491","id":"PMC_35869491","title":"FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/35869491","citation_count":6,"is_preprint":false},{"pmid":"41706863","id":"PMC_41706863","title":"Tuning of the RBR1-E2F/DP transcriptional module by the F-box protein FBL17.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41706863","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.25.672138","title":"Translation-driven temporal control for intertwined protein assembly","date":"2025-08-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.672138","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6522,"output_tokens":1730,"usd":0.022758,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8498,"output_tokens":2454,"usd":0.05192,"stage2_stop_reason":"end_turn"},"total_usd":0.074678,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"FBXL17 (Fbxl17) is the substrate-recognition subunit of an SCF E3 ubiquitin ligase that ubiquitylates Sufu (Suppressor of fused) in the nucleus, targeting it for proteasomal degradation. This ubiquitylation releases Gli1 from Sufu repression, thereby activating Hedgehog signaling. Depletion of Fbxl17 impairs Hh signaling and reduces cancer cell proliferation and medulloblastoma tumor growth. A Gorlin-syndrome Sufu mutation increases Fbxl17-mediated polyubiquitylation, causing sustained Hh activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, siRNA/shRNA knockdown, in vivo tumor models (medulloblastoma), mutant Sufu functional analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitylation assay, KD phenotype, disease mutation validation across multiple orthogonal methods in one study\",\n      \"pmids\": [\"27234298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SCF-FBXL17 recognizes PRMT1 via a tandem IKxxxIK acetyldegron motif. Sirt1-mediated deacetylation and p300-mediated acetylation at K200 and K205 within this motif collaboratively enable FBXL17 binding and drive PRMT1 polyubiquitylation at K117, leading to proteasomal degradation. LPS downregulates Sirt1 and p300, blocking the acetyldegron and protecting PRMT1 from degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, site-directed mutagenesis (K117, K200, K205), half-life/cycloheximide chase, siRNA knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitylation assay, mutagenesis of degron residues, Co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28883095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fbxl17's LRR domain mediates its association with SCF holoenzyme subunits Skp1, Cul1, and Rbx1; truncation of the LRRs impairs this association and decreases ubiquitination activity. Fbxl17 directly binds UAP1 (an O-GlcNAcylation pathway enzyme) and inhibits its phosphorylation; knockdown of Fbxl17 elevates global O-GlcNAcylation in breast cancer cells.\",\n      \"method\": \"Yeast two-hybrid screen (37 binding partners identified), Co-immunoprecipitation, truncation/deletion constructs, siRNA knockdown with O-GlcNAcylation measurement\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid, Co-IP, KD phenotype; UAP1 phosphorylation inhibition inferred but mechanism not fully reconstituted\",\n      \"pmids\": [\"31560077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FBXL17 is the substrate-recognition subunit of an SCF E3 ligase complex that binds the BTB domain at the N-terminus of SPAST-M1 (spastin isoform M1) and mediates its proteasome-dependent degradation specifically in the nuclear fraction. CK2-mediated phosphorylation of SPAST in the cytoplasmic fraction promotes poly-ubiquitination. A disease-associated SPAST Y52C mutation (BTB domain) abrogates FBXL17 binding, escaping SCF-FBXL17 regulation. Inhibition of SCF-FBXL17 stabilizes SPAST-M1 and rescues axonal extension phenotypes.\",\n      \"method\": \"Protein chip analysis, Co-immunoprecipitation (BTB domain mapping), fractionation assays, proteasome inhibitor rescue, CK2 kinase assay, shRNA knockdown, 3D neuronal differentiation model, small chemical inhibitor\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping, fractionation, KD phenotype, disease mutant validation; single lab\",\n      \"pmids\": [\"35869491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SCF-FBXL17 acts as a dimerization quality control E3 ligase for BTB domain-containing proteins (including KEAP1, KLHL12, PATZ1). Translation-driven temporal control via coupled ribosomes enables nascent chain segments to adopt folding-assembly pathways that bypass closed monomeric BTB states; SCF-FBXL17-mediated quality control operates in concert with this cotranslational mechanism.\",\n      \"method\": \"Disome Selective Profiling, optical tweezers, ribosome profiling; mechanistic analysis of BTB domain folding states\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, FBXL17 role inferred in concert with cotranslational mechanism; direct ubiquitylation assay for FBXL17 not explicitly described in abstract\",\n      \"pmids\": [\"bio_10.1101_2025.08.25.672138\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"FBXL17 is the substrate-recognition F-box subunit of an SCF-type E3 ubiquitin ligase complex that targets multiple substrates—including Sufu (via nuclear ubiquitylation to activate Hedgehog signaling), PRMT1 (via an acetylation-regulated IKxxxIK acetyldegron), and SPAST-M1 (via its BTB domain, in the nuclear fraction)—for proteasomal degradation, while also binding UAP1 to regulate O-GlcNAcylation; substrate recognition by FBXL17 requires its LRR domain and can be governed by post-translational modifications (acetylation, phosphorylation) on the substrate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FBXL17 is the substrate-recognition F-box subunit of an SCF (Skp1–Cul1–Rbx1) E3 ubiquitin ligase that selects specific substrates for polyubiquitylation and proteasomal degradation across multiple signaling contexts [#0, #2]. Its leucine-rich repeat (LRR) domain mediates both incorporation into the SCF holoenzyme and substrate engagement, and LRR truncation abolishes both holoenzyme association and ubiquitination activity [#2]. Through this activity FBXL17 promotes Hedgehog signaling by ubiquitylating Sufu in the nucleus, releasing Gli1 from repression; its loss impairs Hh signaling and reduces medulloblastoma growth, and a Gorlin-syndrome Sufu mutation enhances FBXL17-mediated polyubiquitylation to sustain Hh activation [#0]. Substrate recognition is gated by post-translational modifications: FBXL17 reads an acetylation-dependent IKxxxIK acetyldegron on PRMT1—jointly controlled by p300 acetylation and Sirt1 deacetylation at K200/K205—to drive its degradation [#1], and it targets the M1 isoform of spastin (SPAST-M1) by binding its N-terminal BTB domain in the nuclear fraction, with CK2 phosphorylation promoting ubiquitination and a disease-associated Y52C BTB mutation escaping regulation [#3]. FBXL17 also binds the O-GlcNAcylation enzyme UAP1 and inhibits its phosphorylation, with FBXL17 depletion elevating global O-GlcNAcylation in breast cancer cells [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established FBXL17 as a bona fide SCF substrate-recognition subunit and connected it to a signaling output by showing it ubiquitylates nuclear Sufu to de-repress Gli1 and activate Hedgehog signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitylation assays, siRNA/shRNA knockdown, medulloblastoma tumor models, and Gorlin-syndrome Sufu mutant analysis\",\n      \"pmids\": [\"27234298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how FBXL17 is restricted to the nuclear Sufu pool\", \"Degron/recognition determinants on Sufu not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a modification-gated recognition logic for FBXL17 by showing it reads an acetylation-dependent IKxxxIK acetyldegron, explaining how substrate PTM state controls degradation timing.\",\n      \"evidence\": \"In vitro ubiquitylation assays, site-directed mutagenesis of K117/K200/K205, Co-IP, and cycloheximide chase on PRMT1\",\n      \"pmids\": [\"28883095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the acetyldegron logic generalizes to other FBXL17 substrates untested\", \"Structural basis of acetyl-lysine recognition by the LRR not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped the LRR domain as the structural element required for both SCF holoenzyme assembly and ligase activity, and broadened the interactome to include UAP1, linking FBXL17 to O-GlcNAcylation control.\",\n      \"evidence\": \"Yeast two-hybrid screen, Co-IP, LRR truncation constructs, and siRNA knockdown with O-GlcNAcylation measurement in breast cancer cells\",\n      \"pmids\": [\"31560077\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"UAP1 phosphorylation inhibition inferred, not reconstituted\", \"Unclear whether UAP1 is a degradation substrate or a non-degradative binding partner\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed FBXL17 recognizes substrates through BTB-domain binding and operates in a fractionation- and phosphorylation-dependent manner, extending its targeting repertoire to SPAST-M1 with disease relevance.\",\n      \"evidence\": \"Protein chip, Co-IP with BTB domain mapping, fractionation, proteasome inhibitor rescue, CK2 assay, shRNA, and a 3D neuronal differentiation model with disease mutant and chemical inhibitor\",\n      \"pmids\": [\"35869491\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"Why degradation is confined to the nuclear fraction not mechanistically explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a unifying role for SCF-FBXL17 as a dimerization quality-control ligase for BTB-domain proteins acting alongside cotranslational folding control.\",\n      \"evidence\": \"Disome selective profiling, optical tweezers, and ribosome profiling on BTB folding states (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.25.672138\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; direct FBXL17 ubiquitylation assay not described\", \"FBXL17 role inferred in concert with cotranslational mechanism rather than directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FBXL17 substrate selection is partitioned between subcellular compartments and integrated across its diverse PTM-gated degrons remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FBXL17 LRR bound to a substrate degron\", \"Mechanism restricting activity to the nuclear fraction unknown\", \"Relationship between BTB-binding and acetyldegron-reading modes not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"SCF (Skp1-Cul1-Rbx1) E3 ubiquitin ligase\"],\n    \"partners\": [\"SUFU\", \"PRMT1\", \"SPAST\", \"UAP1\", \"SKP1\", \"CUL1\", \"RBX1\", \"KEAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}