{"gene":"KCTD17","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2014,"finding":"KCTD17 functions as a substrate-adaptor for Cullin3-RING E3 ubiquitin ligases (CRL3s) that polyubiquitylates trichoplein, targeting it for proteasomal degradation at mother centrioles, thereby relieving trichoplein-mediated Aurora-A activation and permitting ciliogenesis to initiate at the axoneme extension step.","method":"Two-step global E3 ligase screening, co-immunoprecipitation, proteasome inhibitor treatment, non-ubiquitylatable trichoplein mutant (K50/57R) expression, KCTD17 siRNA knockdown with ciliogenesis readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined cellular phenotype, orthogonal chemical and genetic approaches, replicated mechanistically in subsequent studies","pmids":["25270598"],"is_preprint":false},{"year":2016,"finding":"KCTD17 depletion rescues unscheduled primary cilia formation induced by Ndel1 depletion, placing KCTD17 downstream of Ndel1 in the trichoplein-Aurora A pathway that suppresses ciliogenesis in proliferating cells.","method":"siRNA co-knockdown epistasis experiments; forced trichoplein expression rescue; primary cilia formation readout in cell culture and Ndel1-hypomorphic mouse kidney tubular epithelia","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via co-knockdown, rescue experiments, in vivo corroboration in mouse model, multiple orthogonal approaches","pmids":["26880200"],"is_preprint":false},{"year":2017,"finding":"KCTD17 BTB domain forms a closed pentameric assembly (crystal structure determined), binds Cullin3 to form a 5:5 heterodecamer, and does so without a canonical 3-box motif; Cul3 binding is proposed to stabilize the closed BTB pentamer across BTB-BTB interfaces.","method":"X-ray crystallography of BTB domain, small-angle X-ray scattering (SAXS), size-exclusion chromatography, Cul3 binding assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus SAXS plus in-solution binding assay in a single rigorous study","pmids":["28963344"],"is_preprint":false},{"year":2017,"finding":"KCTD17 mediates glucagon/PKA-dependent degradation of PHLPP2 in the liver. Glucagon-induced PKA phosphorylation of PHLPP2 at Ser1119 and Ser1210 promotes PHLPP2 binding to KCTD17 (a Cul3-RING ubiquitin ligase adaptor), leading to PHLPP2 ubiquitination and proteasomal degradation, which prolongs insulin/Akt signaling and drives hepatic lipogenesis and steatosis.","method":"Mass spectrometry identification of PHLPP2 phosphorylation sites and KCTD17 interaction, Co-IP, shRNA knockdown of KCTD17 in primary hepatocytes and obese mice, CRISPR/Cas9 PHLPP2 knockout hepatoma cells","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction and phospho-sites, reciprocal Co-IP, loss-of-function in vitro and in vivo, multiple orthogonal methods in one study","pmids":["28859855"],"is_preprint":false},{"year":2017,"finding":"KCTD17 (mouse ortholog) is functionally interchangeable with Drosophila Insomniac (Inc) within Cul3 ubiquitin ligase complexes, localizes to synapses in mammalian neurons analogously to Inc in fly neurons, supporting a conserved ubiquitination pathway linking synaptic function and sleep regulation.","method":"Transgenic rescue of Drosophila inc mutant sleep phenotype by mouse KCTD17/KCTD2/KCTD5, biochemical interaction assays with Cul3, neuronal localization imaging","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic rescue plus biochemical Co-IP, single lab study with two orthogonal methods","pmids":["28558011"],"is_preprint":false},{"year":2022,"finding":"In obese mice, hepatocyte Kctd17 expression is increased via Srebp1c-dependent transcription. Kctd17 mediates ubiquitin-proteasomal degradation of O-GlcNAcase (Oga), leading to elevated O-GlcNAcylation and stabilization of ChREBP protein, which drives expression of lipogenic genes and causes glucose intolerance and hepatic steatosis.","method":"AAV-CRISPR hepatocyte-specific Kctd17 knockout mice on HFD, CRISPR/Cas9 Kctd17-KO hepatoma cells, double-knockout (Kctd17/Oga) epistasis, antisense oligonucleotide knockdown in vivo, forced Kctd17 expression in lean mice","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR KO, epistasis double-KO rescue, ASO therapeutic validation, multiple orthogonal approaches, replicated in cell and animal models","pmids":["36402191"],"is_preprint":false},{"year":2023,"finding":"KCTD17 interacts with Gβγ through its C-terminal domain (the C terminus alone is sufficient for Gβγ interaction, unlike KCTD2/KCTD5 which require both BTB and C-terminal regions), and this KCTD-Gβγ interaction blunts Gβγ-mediated sensitization of adenylyl cyclase 5, dampening cAMP signaling downstream of GPCRs.","method":"Live-cell BRET assay, co-immunoprecipitation, C-terminal truncation/domain mapping, adenylyl cyclase 5 cAMP sensitization assay in live cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell BRET and Co-IP with domain mapping, functional cAMP assay, single lab, two orthogonal methods","pmids":["36736897"],"is_preprint":false},{"year":2023,"finding":"Kctd17 binds C/EBP homologous protein (Chop) and targets it for ubiquitin-mediated proteasomal degradation via the Cul3-RING E3 ligase complex, thereby promoting adipogenic differentiation of preadipocytes.","method":"Co-immunoprecipitation of Kctd17 and Chop, gain- and loss-of-function experiments in preadipocytes, adipogenesis readout (lipid accumulation, marker gene expression), ubiquitination assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP plus KO/OE phenotype in single lab, mechanistic follow-up limited to abstract-level detail","pmids":["36868076"],"is_preprint":false},{"year":2023,"finding":"KCTD5 forms hetero-oligomeric complexes with KCTD17, with different regions of KCTD5 contributing uniquely to the interaction with KCTD17 versus other KCTD family members.","method":"Co-immunoprecipitation in cell lysates, live-cell BRET, IP-luminescence domain mapping","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and BRET in single lab; no functional consequence of the KCTD5-KCTD17 heteromer established for KCTD17 specifically","pmids":["37762619"],"is_preprint":false},{"year":2024,"finding":"KCTD17 mediates ubiquitin-proteasomal degradation of LZTR1 (a known Ras destabilizer) via the Cul3 ligase complex, thereby stabilizing Ras protein, activating downstream Ras signaling, and promoting hepatocellular carcinoma cell proliferation, migration, and tumor growth in vivo.","method":"Co-IP identification of LZTR1 as KCTD17-Cul3 substrate, hepatocyte-specific KCTD17-KO mice with DEN-induced HCC, liver cancer xenograft models, KCTD17 antisense oligonucleotide treatment in vivo","journal":"Clinical and molecular hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — substrate identified by Co-IP, loss-of-function in vivo (KO mice + xenograft + ASO), multiple orthogonal approaches in single study with clear mechanistic pathway","pmids":["39098817"],"is_preprint":false},{"year":2024,"finding":"KCTD2, KCTD5, and KCTD17 have partially redundant roles in controlling HEK293 cell growth; triple knockout of all three isoforms has the most pervasive effect on cell growth and gene expression, and these KCTDs regulate cellular levels of Gβ1 (GNB1).","method":"CRISPR/Cas9 progressive knockout of KCTD2, KCTD5, KCTD17 in HEK293 cells, cell growth assays, transcriptome profiling","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function phenotype with gene expression readout, no direct molecular mechanism established for KCTD17 specifically beyond Gβ1 regulation","pmids":["38732215"],"is_preprint":false},{"year":2025,"finding":"KCTD17 facilitates ubiquitin-mediated degradation of the transcription factor Zbtb7b, which reduces Serpina3k (SERPINA3) secretion; decreased SERPINA3 leads to increased Par2/TGFβ-mediated activation of hepatic stellate cells and liver fibrosis in MASH.","method":"KCTD17 depletion in dietary MASH mouse models, mechanistic identification of Zbtb7b as substrate, correlation of SERPINA3 with KCTD17 levels, pharmacological KCTD17 inhibition reversing fibrosis in vivo","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO plus pharmacological inhibition, substrate identification, pathway mechanistic follow-up; single lab","pmids":["40744994"],"is_preprint":false}],"current_model":"KCTD17 is a substrate-adaptor subunit of Cullin3-RING E3 ubiquitin ligase complexes (CRL3-KCTD17) that assembles as a closed BTB-domain pentamer binding Cul3 in a 5:5 heterodecamer; it targets multiple substrates for ubiquitin-mediated proteasomal degradation—including trichoplein (to initiate ciliogenesis by relieving Aurora-A activation), PHLPP2 (promoting hepatic lipogenesis downstream of glucagon/PKA signaling), OGA (stabilizing ChREBP to drive lipogenesis in obesity), LZTR1 (stabilizing Ras to promote hepatocellular carcinoma), Chop (promoting adipogenesis), and Zbtb7b (suppressing SERPINA3 and driving liver fibrosis)—and also interacts with Gβγ via its C-terminal domain to dampen GPCR-mediated cAMP signaling."},"narrative":{"mechanistic_narrative":"KCTD17 is a substrate-recognition adaptor for Cullin3-RING E3 ubiquitin ligase complexes (CRL3-KCTD17) that selects specific protein substrates for polyubiquitylation and proteasomal degradation, thereby controlling processes ranging from ciliogenesis to hepatic metabolism and tumorigenesis [PMID:25270598, PMID:28859855]. Its BTB domain assembles into a closed pentamer that binds Cullin3 to form a 5:5 heterodecamer without a canonical 3-box motif, providing the structural scaffold for ligase assembly [PMID:28963344]. Through this complex KCTD17 ubiquitylates a series of substrates: trichoplein at mother centrioles, whose degradation relieves Aurora-A activation and permits ciliogenesis to initiate downstream of Ndel1 [PMID:25270598, PMID:26880200]; PHLPP2, whose glucagon/PKA-phosphorylation-dependent degradation prolongs Akt signaling to drive hepatic lipogenesis and steatosis [PMID:28859855]; O-GlcNAcase (OGA), whose loss raises O-GlcNAcylation and stabilizes ChREBP to promote lipogenic gene expression in obesity [PMID:36402191]; LZTR1, whose degradation stabilizes Ras and promotes hepatocellular carcinoma growth [PMID:39098817]; Chop, whose degradation promotes adipogenic differentiation [PMID:36868076]; and the transcription factor Zbtb7b, whose degradation lowers SERPINA3 and drives Par2/TGFβ-mediated stellate-cell activation and liver fibrosis [PMID:40744994]. Independently of its adaptor role, KCTD17 also binds Gβγ through its C-terminal domain to blunt Gβγ-mediated sensitization of adenylyl cyclase 5, dampening GPCR-driven cAMP signaling [PMID:36736897].","teleology":[{"year":2014,"claim":"Established KCTD17 as a CRL3 substrate adaptor by showing it polyubiquitylates trichoplein at mother centrioles to license ciliogenesis, defining its core molecular activity.","evidence":"Global E3 ligase screen, reciprocal Co-IP, proteasome inhibition, non-ubiquitylatable trichoplein mutant, and siRNA knockdown with ciliogenesis readout","pmids":["25270598"],"confidence":"High","gaps":["Substrate scope beyond trichoplein unknown at this stage","Structural basis of Cul3 engagement not defined"]},{"year":2016,"claim":"Placed KCTD17 genetically downstream of Ndel1 in the trichoplein-Aurora A axis, resolving where in the ciliogenesis-suppression pathway it acts.","evidence":"siRNA co-knockdown epistasis and trichoplein rescue in cells plus Ndel1-hypomorphic mouse kidney epithelia","pmids":["26880200"],"confidence":"High","gaps":["Does not address non-ciliary substrates","Regulation of KCTD17 activity in cycling cells unclear"]},{"year":2017,"claim":"Defined the structural mechanism of complex assembly, showing the BTB domain forms a closed pentamer binding Cul3 as a 5:5 heterodecamer without a 3-box.","evidence":"X-ray crystallography of the BTB domain, SAXS, size-exclusion chromatography, and Cul3 binding assays","pmids":["28963344"],"confidence":"High","gaps":["Substrate-binding determinants within the assembly not mapped","Full-length complex structure not solved"]},{"year":2017,"claim":"Extended KCTD17 substrate range to metabolism by linking glucagon/PKA-phosphorylated PHLPP2 degradation to hepatic lipogenesis, revealing signal-dependent substrate recognition.","evidence":"MS identification of phospho-sites and interaction, Co-IP, shRNA knockdown in hepatocytes and obese mice, CRISPR PHLPP2-KO hepatoma cells","pmids":["28859855"],"confidence":"High","gaps":["How phosphorylation creates the KCTD17 degron not structurally defined","Tissue specificity of this branch unaddressed"]},{"year":2017,"claim":"Demonstrated functional conservation of the KCTD17-Cul3 module with Drosophila Insomniac, connecting the pathway to synaptic localization and sleep regulation.","evidence":"Transgenic rescue of inc mutant sleep phenotype by mammalian KCTDs, Cul3 interaction assays, neuronal localization imaging","pmids":["28558011"],"confidence":"Medium","gaps":["No mammalian neuronal substrate identified","Redundancy with KCTD2/KCTD5 not separated"]},{"year":2022,"claim":"Identified OGA as a KCTD17 substrate and a transcriptional feedback loop, showing Srebp1c-induced KCTD17 degrades OGA to stabilize ChREBP and drive steatosis.","evidence":"AAV-CRISPR hepatocyte-specific KO mice on HFD, CRISPR KO hepatoma cells, Kctd17/Oga double-KO epistasis, in vivo ASO knockdown, forced expression","pmids":["36402191"],"confidence":"High","gaps":["Direct ubiquitylation sites on OGA not mapped","Crosstalk with the PHLPP2 branch in the same hepatocytes unresolved"]},{"year":2023,"claim":"Revealed a non-adaptor function: the KCTD17 C-terminus binds Gβγ to suppress adenylyl cyclase 5 sensitization, dampening GPCR cAMP signaling distinct from CRL3 activity.","evidence":"Live-cell BRET, Co-IP, C-terminal truncation domain mapping, and AC5 cAMP sensitization assay","pmids":["36736897"],"confidence":"Medium","gaps":["Whether Gβγ binding requires or competes with Cul3 assembly is unknown","Physiological GPCR contexts not defined"]},{"year":2023,"claim":"Added Chop as a KCTD17-Cul3 substrate whose degradation promotes adipogenesis, expanding the metabolic substrate repertoire.","evidence":"Co-IP, gain/loss-of-function in preadipocytes with adipogenesis readouts, and ubiquitination assays","pmids":["36868076"],"confidence":"Medium","gaps":["Mechanistic follow-up limited","Degron on Chop not characterized"]},{"year":2023,"claim":"Showed KCTD17 forms hetero-oligomers with KCTD5, raising the possibility of mixed BTB assemblies.","evidence":"Co-IP, live-cell BRET, and IP-luminescence domain mapping","pmids":["37762619"],"confidence":"Low","gaps":["No functional consequence of the KCTD5-KCTD17 heteromer established for KCTD17","Stoichiometry within the closed pentamer unknown"]},{"year":2024,"claim":"Connected KCTD17 to oncogenesis by showing it degrades LZTR1 to stabilize Ras and promote hepatocellular carcinoma.","evidence":"Co-IP substrate identification, hepatocyte-specific KO mice with DEN-induced HCC, xenografts, and in vivo ASO treatment","pmids":["39098817"],"confidence":"High","gaps":["Selectivity of KCTD17 for LZTR1 versus other Cul3 adaptors unclear","Human tumor genetic validation limited"]},{"year":2024,"claim":"Demonstrated partial redundancy among KCTD2/5/17 in HEK293 growth and GNB1 (Gβ1) regulation, contextualizing KCTD17 within an isoform family.","evidence":"Progressive CRISPR knockouts, cell growth assays, and transcriptome profiling","pmids":["38732215"],"confidence":"Low","gaps":["No KCTD17-specific molecular mechanism beyond Gβ1 regulation established","Whether Gβ1 is a degradation substrate or binding partner not resolved"]},{"year":2025,"claim":"Identified Zbtb7b as a KCTD17 substrate linking it to liver fibrosis via SERPINA3 and Par2/TGFβ signaling, and validated pharmacological inhibition.","evidence":"KCTD17 depletion in dietary MASH mice, substrate identification, SERPINA3 correlation, and pharmacological inhibition reversing fibrosis in vivo","pmids":["40744994"],"confidence":"Medium","gaps":["Direct ubiquitylation of Zbtb7b not biochemically reconstituted","Specificity of the inhibitor for KCTD17 not detailed"]},{"year":null,"claim":"How a single closed BTB pentamer achieves selective recognition of its diverse substrates—and how the adaptor and Gβγ-binding functions are coordinated within a cell—remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of KCTD17 bound to any substrate","Determinants distinguishing substrate degradation from Gβγ sequestration unknown","In vivo balance among competing substrates not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,5,7,9,11]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,5,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,11]}],"complexes":["CRL3-KCTD17 (Cullin3-RING E3 ubiquitin ligase)"],"partners":["CUL3","TRICHOPLEIN","PHLPP2","OGA","LZTR1","CHOP","GNB1","KCTD5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N5Z5","full_name":"BTB/POZ domain-containing protein KCTD17","aliases":[],"length_aa":314,"mass_kda":34.9,"function":"Substrate-adapter for CUL3-RING ubiquitin ligase complexes which mediates the ubiquitination and subsequent proteasomal degradation of TCHP, a protein involved in ciliogenesis down-regulation. Thereby, positively regulates ciliogenesis, playing a crucial role in the initial steps of axoneme extension (PubMed:25270598). May also play a role in endoplasmic reticulum calcium ion homeostasis (PubMed:25983243)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N5Z5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCTD17","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KCTD17","total_profiled":1310},"omim":[{"mim_id":"616398","title":"DYSTONIA 26, MYOCLONIC; DYT26","url":"https://www.omim.org/entry/616398"},{"mim_id":"616386","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 17; KCTD17","url":"https://www.omim.org/entry/616386"},{"mim_id":"612654","title":"TRICHOPLEIN; TCHP","url":"https://www.omim.org/entry/612654"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":147.4}],"url":"https://www.proteinatlas.org/search/KCTD17"},"hgnc":{"alias_symbol":["FLJ12242"],"prev_symbol":[]},"alphafold":{"accession":"Q8N5Z5","domains":[{"cath_id":"3.30.710.10","chopping":"33-137","consensus_level":"high","plddt":91.0751,"start":33,"end":137},{"cath_id":"3.30.70.2000","chopping":"142-177_185-196","consensus_level":"high","plddt":89.6388,"start":142,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N5Z5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N5Z5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N5Z5-F1-predicted_aligned_error_v6.png","plddt_mean":70.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCTD17","jax_strain_url":"https://www.jax.org/strain/search?query=KCTD17"},"sequence":{"accession":"Q8N5Z5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N5Z5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N5Z5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N5Z5"}},"corpus_meta":[{"pmid":"25270598","id":"PMC_25270598","title":"Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25270598","citation_count":117,"is_preprint":false},{"pmid":"25983243","id":"PMC_25983243","title":"A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25983243","citation_count":112,"is_preprint":false},{"pmid":"31197948","id":"PMC_31197948","title":"KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders.","date":"2019","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31197948","citation_count":100,"is_preprint":false},{"pmid":"28963344","id":"PMC_28963344","title":"Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases.","date":"2017","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/28963344","citation_count":85,"is_preprint":false},{"pmid":"26880200","id":"PMC_26880200","title":"Ndel1 suppresses ciliogenesis in proliferating cells by regulating the trichoplein-Aurora A pathway.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26880200","citation_count":62,"is_preprint":false},{"pmid":"26991507","id":"PMC_26991507","title":"Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High-Throughput Sequencing.","date":"2016","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/26991507","citation_count":52,"is_preprint":false},{"pmid":"28859855","id":"PMC_28859855","title":"Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis.","date":"2017","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/28859855","citation_count":34,"is_preprint":false},{"pmid":"28558011","id":"PMC_28558011","title":"Conserved properties of Drosophila Insomniac link sleep regulation and synaptic function.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28558011","citation_count":31,"is_preprint":false},{"pmid":"36736897","id":"PMC_36736897","title":"Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36736897","citation_count":22,"is_preprint":false},{"pmid":"36402191","id":"PMC_36402191","title":"Hepatocyte Kctd17 Inhibition Ameliorates Glucose Intolerance and Hepatic Steatosis Caused by Obesity-induced Chrebp Stabilization.","date":"2022","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/36402191","citation_count":18,"is_preprint":false},{"pmid":"34532296","id":"PMC_34532296","title":"A Co-Expression Network Reveals the Potential Regulatory Mechanism of lncRNAs in Relapsed Hepatocellular Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34532296","citation_count":14,"is_preprint":false},{"pmid":"31097152","id":"PMC_31097152","title":"Associations between single nucleotide polymorphisms and erythrocyte parameters in humans: A systematic literature review.","date":"2019","source":"Mutation research. Reviews in mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/31097152","citation_count":13,"is_preprint":false},{"pmid":"36553572","id":"PMC_36553572","title":"Routine Diagnostics Confirm Novel Neurodevelopmental Disorders.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36553572","citation_count":12,"is_preprint":false},{"pmid":"37762619","id":"PMC_37762619","title":"KCTD5 Forms Hetero-Oligomeric Complexes with Various Members of the KCTD Protein Family.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37762619","citation_count":11,"is_preprint":false},{"pmid":"36868076","id":"PMC_36868076","title":"Kctd17-mediated Chop degradation promotes adipogenic differentiation.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/36868076","citation_count":8,"is_preprint":false},{"pmid":"39098817","id":"PMC_39098817","title":"KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression.","date":"2024","source":"Clinical and molecular hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39098817","citation_count":7,"is_preprint":false},{"pmid":"27678190","id":"PMC_27678190","title":"Proteins involved in sleep homeostasis: Biophysical characterization of INC and its partners.","date":"2016","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/27678190","citation_count":7,"is_preprint":false},{"pmid":"34264428","id":"PMC_34264428","title":"Tremor in Primary Monogenic Dystonia.","date":"2021","source":"Current neurology and neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/34264428","citation_count":4,"is_preprint":false},{"pmid":"33478561","id":"PMC_33478561","title":"Rare functional missense variants in CACNA1H: What can we learn from Writer's cramp?","date":"2021","source":"Molecular brain","url":"https://pubmed.ncbi.nlm.nih.gov/33478561","citation_count":3,"is_preprint":false},{"pmid":"38732215","id":"PMC_38732215","title":"KCTD Proteins Have Redundant Functions in Controlling Cellular Growth.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38732215","citation_count":1,"is_preprint":false},{"pmid":"40744994","id":"PMC_40744994","title":"Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis.","date":"2025","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40744994","citation_count":0,"is_preprint":false},{"pmid":"41969642","id":"PMC_41969642","title":"Childhood-Onset Myoclonus-Dystonia Due to KCTD17 Mutation: A Case Report and Review of Diagnostic Challenges.","date":"2026","source":"Tremor and other hyperkinetic movements (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/41969642","citation_count":0,"is_preprint":false},{"pmid":"41982418","id":"PMC_41982418","title":"Beyond SGCE: expanding the clinical and molecular spectrum of KCTD17- and KCNN2-related myoclonus-dystonia.","date":"2026","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/41982418","citation_count":0,"is_preprint":false},{"pmid":"41373569","id":"PMC_41373569","title":"Genome-Wide Association Studies of Growth and Carcass Traits in Charolais Cattle Based on High-Coverage Whole-Genome Resequencing.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41373569","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14947,"output_tokens":3377,"usd":0.047748,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10874,"output_tokens":4110,"usd":0.07856,"stage2_stop_reason":"end_turn"},"total_usd":0.126308,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"KCTD17 functions as a substrate-adaptor for Cullin3-RING E3 ubiquitin ligases (CRL3s) that polyubiquitylates trichoplein, targeting it for proteasomal degradation at mother centrioles, thereby relieving trichoplein-mediated Aurora-A activation and permitting ciliogenesis to initiate at the axoneme extension step.\",\n      \"method\": \"Two-step global E3 ligase screening, co-immunoprecipitation, proteasome inhibitor treatment, non-ubiquitylatable trichoplein mutant (K50/57R) expression, KCTD17 siRNA knockdown with ciliogenesis readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function with defined cellular phenotype, orthogonal chemical and genetic approaches, replicated mechanistically in subsequent studies\",\n      \"pmids\": [\"25270598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KCTD17 depletion rescues unscheduled primary cilia formation induced by Ndel1 depletion, placing KCTD17 downstream of Ndel1 in the trichoplein-Aurora A pathway that suppresses ciliogenesis in proliferating cells.\",\n      \"method\": \"siRNA co-knockdown epistasis experiments; forced trichoplein expression rescue; primary cilia formation readout in cell culture and Ndel1-hypomorphic mouse kidney tubular epithelia\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via co-knockdown, rescue experiments, in vivo corroboration in mouse model, multiple orthogonal approaches\",\n      \"pmids\": [\"26880200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCTD17 BTB domain forms a closed pentameric assembly (crystal structure determined), binds Cullin3 to form a 5:5 heterodecamer, and does so without a canonical 3-box motif; Cul3 binding is proposed to stabilize the closed BTB pentamer across BTB-BTB interfaces.\",\n      \"method\": \"X-ray crystallography of BTB domain, small-angle X-ray scattering (SAXS), size-exclusion chromatography, Cul3 binding assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus SAXS plus in-solution binding assay in a single rigorous study\",\n      \"pmids\": [\"28963344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCTD17 mediates glucagon/PKA-dependent degradation of PHLPP2 in the liver. Glucagon-induced PKA phosphorylation of PHLPP2 at Ser1119 and Ser1210 promotes PHLPP2 binding to KCTD17 (a Cul3-RING ubiquitin ligase adaptor), leading to PHLPP2 ubiquitination and proteasomal degradation, which prolongs insulin/Akt signaling and drives hepatic lipogenesis and steatosis.\",\n      \"method\": \"Mass spectrometry identification of PHLPP2 phosphorylation sites and KCTD17 interaction, Co-IP, shRNA knockdown of KCTD17 in primary hepatocytes and obese mice, CRISPR/Cas9 PHLPP2 knockout hepatoma cells\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction and phospho-sites, reciprocal Co-IP, loss-of-function in vitro and in vivo, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28859855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KCTD17 (mouse ortholog) is functionally interchangeable with Drosophila Insomniac (Inc) within Cul3 ubiquitin ligase complexes, localizes to synapses in mammalian neurons analogously to Inc in fly neurons, supporting a conserved ubiquitination pathway linking synaptic function and sleep regulation.\",\n      \"method\": \"Transgenic rescue of Drosophila inc mutant sleep phenotype by mouse KCTD17/KCTD2/KCTD5, biochemical interaction assays with Cul3, neuronal localization imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic rescue plus biochemical Co-IP, single lab study with two orthogonal methods\",\n      \"pmids\": [\"28558011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In obese mice, hepatocyte Kctd17 expression is increased via Srebp1c-dependent transcription. Kctd17 mediates ubiquitin-proteasomal degradation of O-GlcNAcase (Oga), leading to elevated O-GlcNAcylation and stabilization of ChREBP protein, which drives expression of lipogenic genes and causes glucose intolerance and hepatic steatosis.\",\n      \"method\": \"AAV-CRISPR hepatocyte-specific Kctd17 knockout mice on HFD, CRISPR/Cas9 Kctd17-KO hepatoma cells, double-knockout (Kctd17/Oga) epistasis, antisense oligonucleotide knockdown in vivo, forced Kctd17 expression in lean mice\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR KO, epistasis double-KO rescue, ASO therapeutic validation, multiple orthogonal approaches, replicated in cell and animal models\",\n      \"pmids\": [\"36402191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KCTD17 interacts with Gβγ through its C-terminal domain (the C terminus alone is sufficient for Gβγ interaction, unlike KCTD2/KCTD5 which require both BTB and C-terminal regions), and this KCTD-Gβγ interaction blunts Gβγ-mediated sensitization of adenylyl cyclase 5, dampening cAMP signaling downstream of GPCRs.\",\n      \"method\": \"Live-cell BRET assay, co-immunoprecipitation, C-terminal truncation/domain mapping, adenylyl cyclase 5 cAMP sensitization assay in live cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell BRET and Co-IP with domain mapping, functional cAMP assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"36736897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kctd17 binds C/EBP homologous protein (Chop) and targets it for ubiquitin-mediated proteasomal degradation via the Cul3-RING E3 ligase complex, thereby promoting adipogenic differentiation of preadipocytes.\",\n      \"method\": \"Co-immunoprecipitation of Kctd17 and Chop, gain- and loss-of-function experiments in preadipocytes, adipogenesis readout (lipid accumulation, marker gene expression), ubiquitination assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP plus KO/OE phenotype in single lab, mechanistic follow-up limited to abstract-level detail\",\n      \"pmids\": [\"36868076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KCTD5 forms hetero-oligomeric complexes with KCTD17, with different regions of KCTD5 contributing uniquely to the interaction with KCTD17 versus other KCTD family members.\",\n      \"method\": \"Co-immunoprecipitation in cell lysates, live-cell BRET, IP-luminescence domain mapping\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and BRET in single lab; no functional consequence of the KCTD5-KCTD17 heteromer established for KCTD17 specifically\",\n      \"pmids\": [\"37762619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KCTD17 mediates ubiquitin-proteasomal degradation of LZTR1 (a known Ras destabilizer) via the Cul3 ligase complex, thereby stabilizing Ras protein, activating downstream Ras signaling, and promoting hepatocellular carcinoma cell proliferation, migration, and tumor growth in vivo.\",\n      \"method\": \"Co-IP identification of LZTR1 as KCTD17-Cul3 substrate, hepatocyte-specific KCTD17-KO mice with DEN-induced HCC, liver cancer xenograft models, KCTD17 antisense oligonucleotide treatment in vivo\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — substrate identified by Co-IP, loss-of-function in vivo (KO mice + xenograft + ASO), multiple orthogonal approaches in single study with clear mechanistic pathway\",\n      \"pmids\": [\"39098817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KCTD2, KCTD5, and KCTD17 have partially redundant roles in controlling HEK293 cell growth; triple knockout of all three isoforms has the most pervasive effect on cell growth and gene expression, and these KCTDs regulate cellular levels of Gβ1 (GNB1).\",\n      \"method\": \"CRISPR/Cas9 progressive knockout of KCTD2, KCTD5, KCTD17 in HEK293 cells, cell growth assays, transcriptome profiling\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function phenotype with gene expression readout, no direct molecular mechanism established for KCTD17 specifically beyond Gβ1 regulation\",\n      \"pmids\": [\"38732215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KCTD17 facilitates ubiquitin-mediated degradation of the transcription factor Zbtb7b, which reduces Serpina3k (SERPINA3) secretion; decreased SERPINA3 leads to increased Par2/TGFβ-mediated activation of hepatic stellate cells and liver fibrosis in MASH.\",\n      \"method\": \"KCTD17 depletion in dietary MASH mouse models, mechanistic identification of Zbtb7b as substrate, correlation of SERPINA3 with KCTD17 levels, pharmacological KCTD17 inhibition reversing fibrosis in vivo\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO plus pharmacological inhibition, substrate identification, pathway mechanistic follow-up; single lab\",\n      \"pmids\": [\"40744994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCTD17 is a substrate-adaptor subunit of Cullin3-RING E3 ubiquitin ligase complexes (CRL3-KCTD17) that assembles as a closed BTB-domain pentamer binding Cul3 in a 5:5 heterodecamer; it targets multiple substrates for ubiquitin-mediated proteasomal degradation—including trichoplein (to initiate ciliogenesis by relieving Aurora-A activation), PHLPP2 (promoting hepatic lipogenesis downstream of glucagon/PKA signaling), OGA (stabilizing ChREBP to drive lipogenesis in obesity), LZTR1 (stabilizing Ras to promote hepatocellular carcinoma), Chop (promoting adipogenesis), and Zbtb7b (suppressing SERPINA3 and driving liver fibrosis)—and also interacts with Gβγ via its C-terminal domain to dampen GPCR-mediated cAMP signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCTD17 is a substrate-recognition adaptor for Cullin3-RING E3 ubiquitin ligase complexes (CRL3-KCTD17) that selects specific protein substrates for polyubiquitylation and proteasomal degradation, thereby controlling processes ranging from ciliogenesis to hepatic metabolism and tumorigenesis [#0, #3]. Its BTB domain assembles into a closed pentamer that binds Cullin3 to form a 5:5 heterodecamer without a canonical 3-box motif, providing the structural scaffold for ligase assembly [#2]. Through this complex KCTD17 ubiquitylates a series of substrates: trichoplein at mother centrioles, whose degradation relieves Aurora-A activation and permits ciliogenesis to initiate downstream of Ndel1 [#0, #1]; PHLPP2, whose glucagon/PKA-phosphorylation-dependent degradation prolongs Akt signaling to drive hepatic lipogenesis and steatosis [#3]; O-GlcNAcase (OGA), whose loss raises O-GlcNAcylation and stabilizes ChREBP to promote lipogenic gene expression in obesity [#5]; LZTR1, whose degradation stabilizes Ras and promotes hepatocellular carcinoma growth [#9]; Chop, whose degradation promotes adipogenic differentiation [#7]; and the transcription factor Zbtb7b, whose degradation lowers SERPINA3 and drives Par2/TGFβ-mediated stellate-cell activation and liver fibrosis [#11]. Independently of its adaptor role, KCTD17 also binds Gβγ through its C-terminal domain to blunt Gβγ-mediated sensitization of adenylyl cyclase 5, dampening GPCR-driven cAMP signaling [#6].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established KCTD17 as a CRL3 substrate adaptor by showing it polyubiquitylates trichoplein at mother centrioles to license ciliogenesis, defining its core molecular activity.\",\n      \"evidence\": \"Global E3 ligase screen, reciprocal Co-IP, proteasome inhibition, non-ubiquitylatable trichoplein mutant, and siRNA knockdown with ciliogenesis readout\",\n      \"pmids\": [\"25270598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate scope beyond trichoplein unknown at this stage\", \"Structural basis of Cul3 engagement not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed KCTD17 genetically downstream of Ndel1 in the trichoplein-Aurora A axis, resolving where in the ciliogenesis-suppression pathway it acts.\",\n      \"evidence\": \"siRNA co-knockdown epistasis and trichoplein rescue in cells plus Ndel1-hypomorphic mouse kidney epithelia\",\n      \"pmids\": [\"26880200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address non-ciliary substrates\", \"Regulation of KCTD17 activity in cycling cells unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the structural mechanism of complex assembly, showing the BTB domain forms a closed pentamer binding Cul3 as a 5:5 heterodecamer without a 3-box.\",\n      \"evidence\": \"X-ray crystallography of the BTB domain, SAXS, size-exclusion chromatography, and Cul3 binding assays\",\n      \"pmids\": [\"28963344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate-binding determinants within the assembly not mapped\", \"Full-length complex structure not solved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KCTD17 substrate range to metabolism by linking glucagon/PKA-phosphorylated PHLPP2 degradation to hepatic lipogenesis, revealing signal-dependent substrate recognition.\",\n      \"evidence\": \"MS identification of phospho-sites and interaction, Co-IP, shRNA knockdown in hepatocytes and obese mice, CRISPR PHLPP2-KO hepatoma cells\",\n      \"pmids\": [\"28859855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation creates the KCTD17 degron not structurally defined\", \"Tissue specificity of this branch unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated functional conservation of the KCTD17-Cul3 module with Drosophila Insomniac, connecting the pathway to synaptic localization and sleep regulation.\",\n      \"evidence\": \"Transgenic rescue of inc mutant sleep phenotype by mammalian KCTDs, Cul3 interaction assays, neuronal localization imaging\",\n      \"pmids\": [\"28558011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mammalian neuronal substrate identified\", \"Redundancy with KCTD2/KCTD5 not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified OGA as a KCTD17 substrate and a transcriptional feedback loop, showing Srebp1c-induced KCTD17 degrades OGA to stabilize ChREBP and drive steatosis.\",\n      \"evidence\": \"AAV-CRISPR hepatocyte-specific KO mice on HFD, CRISPR KO hepatoma cells, Kctd17/Oga double-KO epistasis, in vivo ASO knockdown, forced expression\",\n      \"pmids\": [\"36402191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitylation sites on OGA not mapped\", \"Crosstalk with the PHLPP2 branch in the same hepatocytes unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-adaptor function: the KCTD17 C-terminus binds Gβγ to suppress adenylyl cyclase 5 sensitization, dampening GPCR cAMP signaling distinct from CRL3 activity.\",\n      \"evidence\": \"Live-cell BRET, Co-IP, C-terminal truncation domain mapping, and AC5 cAMP sensitization assay\",\n      \"pmids\": [\"36736897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Gβγ binding requires or competes with Cul3 assembly is unknown\", \"Physiological GPCR contexts not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added Chop as a KCTD17-Cul3 substrate whose degradation promotes adipogenesis, expanding the metabolic substrate repertoire.\",\n      \"evidence\": \"Co-IP, gain/loss-of-function in preadipocytes with adipogenesis readouts, and ubiquitination assays\",\n      \"pmids\": [\"36868076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic follow-up limited\", \"Degron on Chop not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed KCTD17 forms hetero-oligomers with KCTD5, raising the possibility of mixed BTB assemblies.\",\n      \"evidence\": \"Co-IP, live-cell BRET, and IP-luminescence domain mapping\",\n      \"pmids\": [\"37762619\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of the KCTD5-KCTD17 heteromer established for KCTD17\", \"Stoichiometry within the closed pentamer unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected KCTD17 to oncogenesis by showing it degrades LZTR1 to stabilize Ras and promote hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP substrate identification, hepatocyte-specific KO mice with DEN-induced HCC, xenografts, and in vivo ASO treatment\",\n      \"pmids\": [\"39098817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of KCTD17 for LZTR1 versus other Cul3 adaptors unclear\", \"Human tumor genetic validation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated partial redundancy among KCTD2/5/17 in HEK293 growth and GNB1 (Gβ1) regulation, contextualizing KCTD17 within an isoform family.\",\n      \"evidence\": \"Progressive CRISPR knockouts, cell growth assays, and transcriptome profiling\",\n      \"pmids\": [\"38732215\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No KCTD17-specific molecular mechanism beyond Gβ1 regulation established\", \"Whether Gβ1 is a degradation substrate or binding partner not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified Zbtb7b as a KCTD17 substrate linking it to liver fibrosis via SERPINA3 and Par2/TGFβ signaling, and validated pharmacological inhibition.\",\n      \"evidence\": \"KCTD17 depletion in dietary MASH mice, substrate identification, SERPINA3 correlation, and pharmacological inhibition reversing fibrosis in vivo\",\n      \"pmids\": [\"40744994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitylation of Zbtb7b not biochemically reconstituted\", \"Specificity of the inhibitor for KCTD17 not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single closed BTB pentamer achieves selective recognition of its diverse substrates—and how the adaptor and Gβγ-binding functions are coordinated within a cell—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of KCTD17 bound to any substrate\", \"Determinants distinguishing substrate degradation from Gβγ sequestration unknown\", \"In vivo balance among competing substrates not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 5, 7, 9, 11]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [\n      \"CRL3-KCTD17 (Cullin3-RING E3 ubiquitin ligase)\"\n    ],\n    \"partners\": [\n      \"CUL3\",\n      \"trichoplein\",\n      \"PHLPP2\",\n      \"OGA\",\n      \"LZTR1\",\n      \"CHOP\",\n      \"GNB1\",\n      \"KCTD5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}