{"gene":"WDR26","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2004,"finding":"WDR26 is a novel WD40 repeat, Gβ-like protein that, when overexpressed, suppresses MAPK signaling by inhibiting ELK-1 and c-fos SRE transcriptional activities mediated by MEKK1, acting as a negative regulator of the MAPK pathway.","method":"Overexpression in cells with transcriptional reporter assays (ELK-1 and SRE-driven luciferase) downstream of MEKK1","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, reporter assay overexpression, consistent with Gβ-like domain architecture but no mutagenesis or in vitro reconstitution","pmids":["15378603"],"is_preprint":false},{"year":2011,"finding":"WDR26 directly binds free Gβγ in vitro and forms a complex with endogenous Gβγ in SDF1α-stimulated Jurkat T cells; WDR26 is required for Gβγ-dependent PLCβ and PI3K activation and for leukocyte chemotaxis. WDR26 also controls RACK1 (a negative regulator) binding to Gβγ.","method":"In vitro direct binding assay, co-immunoprecipitation with endogenous Gβγ, siRNA knockdown with functional readouts (PLCβ/PI3K activation, chemotaxis, in vivo homing in SCID mice), WDR26 deletion mutant expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct in vitro binding, deletion mutant epistasis, multiple functional readouts, replicated in two cell lines and in vivo","pmids":["22065575"],"is_preprint":false},{"year":2013,"finding":"WDR26 functions as a scaffolding protein that directly binds both Gβγ and PLCβ2 (with overlapping but non-identical binding sites on Gβ1γ2), forms higher-order oligomers through its LisH-CTLH and WD40 domains, and promotes PLCβ2 membrane translocation and interaction with Gβγ, thereby enhancing PLCβ2 activation in leukocytes.","method":"Direct binding assays, co-immunoprecipitation, domain-mapping with deletion mutants, fluorescence imaging of PLCβ2 translocation, functional PLCβ2 activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (direct binding, Co-IP, mutant analysis, imaging, activity assay) in a single rigorous study","pmids":["23625927"],"is_preprint":false},{"year":2016,"finding":"WDR26 serves as a scaffold downstream of GPCR stimulation to assemble a specific signaling complex consisting of Gβγ, PI3Kβ, and AKT2, selectively promoting GPCR- (but not EGF receptor-) stimulated PI3K/AKT signaling in breast cancer cells. Disrupting this complex via WDR26 mutants abrogated PI3K/AKT activation and tumor growth/metastasis in an orthotopic xenograft model.","method":"siRNA knockdown, overexpression of WDR26 mutants disrupting complex assembly, signaling assays (pAKT, pPI3K), orthotopic xenograft mouse model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, mutant epistasis, in vivo xenograft validation, isoform selectivity established","pmids":["26895380"],"is_preprint":false},{"year":2016,"finding":"WDR26 binds Axin1 and acts as a negative regulator of canonical Wnt signaling by promoting ubiquitination and degradation of β-catenin; WDR26/Axin interaction is required for this effect.","method":"Co-immunoprecipitation (WDR26–Axin1 interaction), β-catenin ubiquitination assay, Wnt reporter assay, WDR26 overexpression/knockdown","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, reporter assay, and ubiquitination assay, single lab, no in vitro reconstitution","pmids":["27098453"],"is_preprint":false},{"year":2016,"finding":"WDR26 promotes hypoxia-induced mitophagy in cardiomyocytes (H9c2 cells) by increasing mitochondrial membrane potential and facilitating Parkin translocation to mitochondria, leading to increased mitochondrial protein ubiquitination.","method":"WDR26 overexpression/knockdown in H9c2 cells under hypoxia, Parkin translocation imaging, mitochondrial membrane potential measurement, ubiquitination assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional imaging and biochemical assays, single lab, mechanism of membrane potential increase not resolved","pmids":["27797717"],"is_preprint":false},{"year":2020,"finding":"Wdr26, as part of the GID/CTLH E3 ubiquitin ligase complex, regulates ubiquitination and proteasomal degradation of nuclear proteins including lamin B during terminal erythropoiesis; loss of Wdr26 impairs lamin B degradation, blocks nuclear opening formation, and causes defective nuclear condensation and enucleation.","method":"Wdr26 knockout in mouse erythroblasts (enucleation defects), zebrafish knockdown (anemia), ubiquitination assays for lamin B, lamin B protein level measurement, CTLH/GID complex co-immunoprecipitation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — two organism models (mouse KO, zebrafish KD), specific substrate (lamin B) identified with ubiquitination assay, mechanistic pathway from complex to substrate to nuclear phenotype","pmids":["31945154"],"is_preprint":false},{"year":2009,"finding":"WDR26 overexpression suppresses H2O2-induced cell death in SH-SY5Y neuroblastoma cells and downregulates AP-1 transcriptional activity during oxidative stress; conversely, antisense ODN knockdown of WDR26 enhances H2O2-induced cell death.","method":"Overexpression and antisense ODN knockdown, cell viability assay, AP-1 luciferase reporter assay","journal":"Neuroscience letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, reporter assay without mechanistic resolution of how WDR26 suppresses AP-1","pmids":["19446606"],"is_preprint":false},{"year":2012,"finding":"WDR26 localizes to mitochondria and inhibits cytochrome c release from mitochondria, thereby suppressing apoptosis in H9c2 cardiomyocytes under oxidative stress.","method":"Subcellular fractionation/localization assay, cytochrome c release assay, WDR26 overexpression with H2O2 treatment, apoptosis readout","journal":"Free radical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single cell line, fractionation-based localization, no mechanistic detail on how mitochondrial WDR26 blocks cytochrome c release","pmids":["22448652"],"is_preprint":false},{"year":2024,"finding":"WDR26 acts as a non-canonical substrate receptor within the CTLH E3 complex to bind NMNAT1 via an internal basic degron motif and mediate its ubiquitylation and cellular degradation independently of canonical GID/CTLH substrate receptors. YPEL5 inhibits this process by N-terminal degron mimicry of NMNAT1. Cryo-EM structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes were determined.","method":"Cryo-EM structure determination, in vitro ubiquitylation assay, co-immunoprecipitation, degron mutagenesis, cellular degradation assays, YPEL5 knockout/overexpression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional mutagenesis of degron, in vitro reconstitution of ubiquitylation, cellular validation, mechanism of YPEL5 inhibition structurally resolved","pmids":["38759627"],"is_preprint":false},{"year":2024,"finding":"SKDEAS-associated WDR26 mutations impair CTLH E3 complex assembly and function; WDR26 homodimers bridge two core-CTLH E3 complexes to form supramolecular oval-shaped assemblies, mediates CTLH E3 binding to YPEL5, and functions as substrate receptor for transcriptional repressor HBP1. 15 of 16 patient-derived mutants impaired at least one of these functions.","method":"Structural modeling of WDR26, complementation assays in WDR26-KO cells engineered to lack CTLH supramolecular assemblies, functional assays for complex assembly, YPEL5 binding, and HBP1 substrate receptor activity","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetically engineered cell lines, multiple mutants tested across multiple orthogonal functions, structural model used to map mutations, consistent with independent cryo-EM data","pmids":["38575527"],"is_preprint":false},{"year":2024,"finding":"WDR26 and muskelin β-propeller proteins compete for binding to the CTLH complex scaffold in an interchangeable manner, forming separate WDR26- or muskelin-containing complexes with distinct proteomes. CTLH E3 ligase activity in HeLa cells is dictated by the interplay between WDR26 and muskelin; muskelin protein turnover is a major ubiquitin-dependent degradation event dependent on the CTLH complex.","method":"Proteomic experiments (mass spectrometry), WDR26 and muskelin knockout cell lines, co-immunoprecipitation, ubiquitin assays, mTOR inhibition experiments","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal KO cell lines, quantitative proteomics, multiple substrates tested, functional consequence of WDR26/muskelin interplay mechanistically resolved","pmids":["39702571"],"is_preprint":false},{"year":2025,"finding":"The CTLH-WDR26 E3 complex mediates ubiquitin-dependent degradation of UCK2 (rate-limiting enzyme of pyrimidine salvage pathway) during mTORC1 inhibition; UCK1, an isoform of UCK2, affects UCK2 turnover by influencing its subcellular localization.","method":"mTORC1 inhibition (rapamycin) with WDR26/CTLH knockdown/knockout, UCK2 half-life/degradation assays, ubiquitination assays, cellular localization experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — specific substrate (UCK2) identified with degradation assays, mTORC1 pathway placement, UCK1-mediated localization mechanism, functional consequence on pyrimidine salvage established","pmids":["39808525"],"is_preprint":false},{"year":2026,"finding":"Wdr26 haploinsufficiency in mice stabilizes RUNX1T1 (a transcriptional coactivator) by impairing its ubiquitination and proteasomal degradation via the CTLH complex, leading to elevated MAP2 and disrupted dendritic/synaptic architecture. AAV-shRNA knockdown of Runx1t1 in neonatal Wdr26+/- mice reversed MAP2 overexpression and behavioral deficits.","method":"Wdr26 heterozygous KO mouse model, RUNX1T1 ubiquitination assay, MAP2 protein level measurement, AAV-shRNA rescue experiment, behavioral tests","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model, specific substrate identified with ubiquitination assay, pathway confirmed by in vivo rescue (AAV-shRNA), behavioral phenotype correlated with molecular mechanism","pmids":["42138082"],"is_preprint":false},{"year":2025,"finding":"Missense variants in WDR26 associated with Skraban-Deardorff syndrome markedly reduce WDR26 protein levels through accelerated proteasomal degradation (reversed by proteasome inhibitor), while a frameshift variant reduces WDR26 mRNA via nonsense-mediated decay; both mechanisms result in loss of function and impaired cell proliferation.","method":"Cycloheximide chase, proteasome inhibitor treatment, mRNA stability assays, lymphoblastoid cell proliferation assay with patient-derived variants","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal protein/mRNA stability methods, patient-derived variants, single lab","pmids":["40826479"],"is_preprint":false}],"current_model":"WDR26 is a WD40 repeat protein that functions primarily as a subunit and substrate receptor of the CTLH E3 ubiquitin ligase complex, where it forms homodimers bridging two core-CTLH complexes into supramolecular assemblies, recruits substrates (including NMNAT1, UCK2, RUNX1T1, lamin B, and HBP1) via degron recognition for ubiquitylation and proteasomal degradation, and also acts as a scaffolding protein that binds Gβγ and PLCβ2 to enhance GPCR-dependent PI3K/AKT and PLCβ signaling in leukocytes and cancer cells; WDR26 competes with muskelin for CTLH complex scaffold binding to regulate substrate selectivity, and its haploinsufficiency disrupts CTLH-dependent protein homeostasis, leading to the neurodevelopmental features of Skraban-Deardorff syndrome."},"narrative":{"mechanistic_narrative":"WDR26 is a WD40-repeat, Gβ-like protein that operates in two convergent regulatory modes: as a substrate-receptor and architectural subunit of the CTLH/GID E3 ubiquitin ligase complex, and as a signaling scaffold downstream of G-protein-coupled receptors [PMID:22065575, PMID:38759627]. Through its LisH-CTLH and WD40 domains, WDR26 homodimerizes to bridge two core-CTLH complexes into supramolecular oval-shaped assemblies, and it functions as a non-canonical substrate receptor that recognizes degron motifs on target proteins to direct their ubiquitylation and proteasomal degradation [PMID:38759627, PMID:38575527]. Identified substrates span diverse processes — NMNAT1 (with the recognition controlled by YPEL5 degron mimicry), the pyrimidine-salvage enzyme UCK2 during mTORC1 inhibition, the transcriptional repressor HBP1, lamin B during terminal erythropoiesis, and the transcriptional coactivator RUNX1T1 [PMID:38759627, PMID:39808525, PMID:38575527, PMID:31945154, PMID:42138082]. WDR26 and muskelin β-propeller proteins compete interchangeably for the CTLH scaffold, forming distinct complexes with separate proteomes and thereby dictating substrate selectivity and overall CTLH ligase output [PMID:39702571]. In its scaffolding role, WDR26 directly binds free Gβγ and PLCβ2 and assembles a Gβγ–PI3Kβ–AKT2 complex that selectively amplifies GPCR-stimulated PLCβ and PI3K/AKT signaling, supporting leukocyte chemotaxis and, in breast cancer, tumor growth and metastasis [PMID:22065575, PMID:23625927, PMID:26895380]. WDR26 loss-of-function causes the neurodevelopmental disorder Skraban-Deardorff syndrome: haploinsufficiency stabilizes RUNX1T1, elevating MAP2 and disrupting dendritic and synaptic architecture, and patient variants impair CTLH assembly or destabilize WDR26 itself through accelerated proteasomal degradation or nonsense-mediated decay [PMID:42138082, PMID:38575527, PMID:40826479].","teleology":[{"year":2004,"claim":"Established WDR26 as a Gβ-like WD40 protein with a regulatory role in signaling, first framed as a negative regulator of the MEKK1-driven MAPK pathway.","evidence":"Overexpression with ELK-1/SRE luciferase reporter assays downstream of MEKK1","pmids":["15378603"],"confidence":"Medium","gaps":["Effect shown only by overexpression reporter assays","No direct binding partner or biochemical mechanism for MAPK suppression identified"]},{"year":2011,"claim":"Defined WDR26's first concrete molecular function — direct Gβγ binding required for downstream PLCβ/PI3K activation and leukocyte chemotaxis — moving it from a phenotypic regulator to a defined signaling effector.","evidence":"In vitro direct binding, reciprocal Co-IP of endogenous Gβγ, siRNA knockdown with chemotaxis/in vivo homing readouts in Jurkat T cells and SCID mice","pmids":["22065575"],"confidence":"High","gaps":["Structural basis of Gβγ binding not resolved","Relationship to its later-described CTLH role not addressed"]},{"year":2013,"claim":"Refined the scaffolding mechanism, showing WDR26 simultaneously binds Gβγ and PLCβ2 and oligomerizes via LisH-CTLH and WD40 domains to promote PLCβ2 membrane translocation and activation.","evidence":"Direct binding, Co-IP, deletion-mutant domain mapping, fluorescence imaging of PLCβ2 translocation, PLCβ2 activity assays","pmids":["23625927"],"confidence":"High","gaps":["Did not connect oligomerization domains to E3 ligase scaffolding function later attributed to the same domains","Stoichiometry of the higher-order assembly not defined"]},{"year":2016,"claim":"Showed the WDR26 scaffold has receptor-selective output, assembling a Gβγ–PI3Kβ–AKT2 complex that drives GPCR- but not EGFR-stimulated PI3K/AKT signaling and promotes tumor growth and metastasis.","evidence":"siRNA knockdown, complex-disrupting WDR26 mutants, pAKT/pPI3K assays, orthotopic xenograft mouse model","pmids":["26895380"],"confidence":"High","gaps":["Did not address whether CTLH-associated WDR26 contributes to or is separate from this signaling pool"]},{"year":2016,"claim":"Linked WDR26 to ubiquitin-dependent degradation in additional pathways — Axin1-dependent β-catenin turnover and Parkin-mediated mitophagy — early hints of a broader proteostatic role.","evidence":"Co-IP, β-catenin ubiquitination and Wnt reporter assays; Parkin translocation imaging and mitochondrial ubiquitination assays in H9c2 cells","pmids":["27098453","27797717"],"confidence":"Medium","gaps":["No in vitro reconstitution of the ubiquitination events","Mechanistic relationship to CTLH complex not established at the time"]},{"year":2020,"claim":"Placed WDR26 firmly within the GID/CTLH E3 ligase and identified its first physiological substrate, lamin B, establishing a complex→substrate→phenotype axis in erythropoiesis.","evidence":"Mouse Wdr26 knockout erythroblasts and zebrafish knockdown, lamin B ubiquitination/level assays, CTLH/GID Co-IP","pmids":["31945154"],"confidence":"High","gaps":["Did not define how WDR26 recognizes lamin B as a degron-bearing substrate","Generality of receptor function across substrates untested"]},{"year":2024,"claim":"Resolved the structural and mechanistic basis of WDR26 substrate receptor activity, showing it reads an internal basic degron on NMNAT1 and is competitively inhibited by YPEL5 N-terminal degron mimicry.","evidence":"Cryo-EM of NMNAT1- and YPEL5-bound WDR26-CTLH complexes, in vitro ubiquitylation, degron mutagenesis, cellular degradation and YPEL5 perturbation assays","pmids":["38759627"],"confidence":"High","gaps":["Whether all WDR26 substrates use a common degron architecture unknown","Physiological triggers gating NMNAT1 degradation not defined"]},{"year":2024,"claim":"Defined WDR26's architectural role and its substrate-selection logic: homodimers bridge two core-CTLH complexes into supramolecular assemblies, and WDR26 competes interchangeably with muskelin to set distinct CTLH proteomes.","evidence":"Structural modeling and complementation in WDR26-KO cells; reciprocal WDR26/muskelin KO cell lines with quantitative proteomics, Co-IP, and ubiquitin assays","pmids":["38575527","39702571"],"confidence":"High","gaps":["Signals controlling the WDR26-versus-muskelin choice not identified","Function of the supramolecular oval assembly beyond scaffold bridging unclear"]},{"year":2025,"claim":"Connected WDR26-CTLH activity to nutrient/growth signaling by showing it degrades the pyrimidine-salvage enzyme UCK2 during mTORC1 inhibition, with UCK1 modulating UCK2 localization.","evidence":"Rapamycin-induced mTORC1 inhibition with WDR26/CTLH knockdown, UCK2 half-life, ubiquitination, and localization assays","pmids":["39808525"],"confidence":"High","gaps":["How mTORC1 status is transduced to WDR26-CTLH activity unresolved","Degron on UCK2 not mapped"]},{"year":2024,"claim":"Established the disease mechanism of Skraban-Deardorff syndrome: in vivo, Wdr26 haploinsufficiency stabilizes RUNX1T1, elevating MAP2 and disrupting neuronal architecture, with knockdown of Runx1t1 rescuing the phenotype.","evidence":"Wdr26 heterozygous KO mice, RUNX1T1 ubiquitination assays, MAP2 measurement, AAV-shRNA Runx1t1 rescue, behavioral testing","pmids":["42138082"],"confidence":"High","gaps":["Other CTLH substrates contributing to neurodevelopmental phenotype not fully cataloged"]},{"year":2025,"claim":"Explained how patient variants cause loss of function — missense variants accelerate WDR26 proteasomal degradation while a frameshift triggers NMD — unifying the genetic findings at the protein-stability level.","evidence":"Cycloheximide chase, proteasome inhibitor rescue, mRNA stability and proliferation assays in patient-derived lymphoblastoid cells","pmids":["40826479"],"confidence":"Medium","gaps":["Single lab","Direct link between reduced WDR26 levels and specific CTLH substrate dysregulation in patient cells not shown"]},{"year":null,"claim":"How WDR26's signaling-scaffold role (Gβγ/PLCβ2/PI3K-AKT) and its CTLH E3 substrate-receptor role are integrated within a single cell, and what governs the choice between WDR26- and muskelin-defined CTLH proteomes, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No study reconciles the GPCR-scaffold and E3-ligase functions mechanistically","Upstream signals selecting WDR26 substrate panels are undefined","Full WDR26-specific substrate repertoire incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,6,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,6,12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,13,14]}],"complexes":["CTLH/GID E3 ubiquitin ligase complex"],"partners":["GNB1","PLCB2","PIK3CB","AKT2","YPEL5","AXIN1","MKLN1","NMNAT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7D7","full_name":"WD repeat-containing protein 26","aliases":["CUL4- and DDB1-associated WDR protein 2","Myocardial ischemic preconditioning up-regulated protein 2"],"length_aa":661,"mass_kda":72.1,"function":"G-beta-like protein involved in cell signal transduction (PubMed:15378603, PubMed:19446606, PubMed:22065575, PubMed:23625927, PubMed:26895380, PubMed:27098453). Acts as a negative regulator in MAPK signaling pathway (PubMed:15378603). Functions as a scaffolding protein to promote G beta:gamma-mediated PLCB2 plasma membrane translocation and subsequent activation in leukocytes (PubMed:22065575, PubMed:23625927). Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Acts as a negative regulator of the canonical Wnt signaling pathway through preventing ubiquitination of beta-catenin CTNNB1 by the beta-catenin destruction complex, thus negatively regulating CTNNB1 degradation (PubMed:27098453). Serves as a scaffold to coordinate PI3K/AKT pathway-driven cell growth and migration (PubMed:26895380). Protects cells from oxidative stress-induced apoptosis via the down-regulation of AP-1 transcriptional activity as well as by inhibiting cytochrome c release from mitochondria (PubMed:19446606). Also protects cells by promoting hypoxia-mediated autophagy and mitophagy (By similarity)","subcellular_location":"Cytoplasm; Nucleus; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9H7D7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR26","classification":"Not Classified","n_dependent_lines":631,"n_total_lines":1208,"dependency_fraction":0.5223509933774835},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RANBP10","stoichiometry":10.0},{"gene":"RANBP9","stoichiometry":10.0},{"gene":"GYG1","stoichiometry":0.2},{"gene":"HMGB2","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR26","total_profiled":1310},"omim":[{"mim_id":"617616","title":"SKRABAN-DEARDORFF SYNDROME; SKDEAS","url":"https://www.omim.org/entry/617616"},{"mim_id":"617424","title":"WD REPEAT-CONTAINING PROTEIN 26; WDR26","url":"https://www.omim.org/entry/617424"},{"mim_id":"612530","title":"CHROMOSOME 1q41-q42 DELETION SYNDROME","url":"https://www.omim.org/entry/612530"},{"mim_id":"604114","title":"PHOSPHOLIPASE C, BETA-2; PLCB2","url":"https://www.omim.org/entry/604114"},{"mim_id":"603816","title":"AXIS INHIBITOR 1; AXIN1","url":"https://www.omim.org/entry/603816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR26"},"hgnc":{"alias_symbol":["FLJ21016","GID7"],"prev_symbol":[]},"alphafold":{"accession":"Q9H7D7","domains":[{"cath_id":"2.130.10.10","chopping":"341-360_528-645","consensus_level":"medium","plddt":95.9376,"start":341,"end":645},{"cath_id":"2.130.10.10","chopping":"406-524","consensus_level":"medium","plddt":93.997,"start":406,"end":524},{"cath_id":"1.25.40","chopping":"156-191_201-298","consensus_level":"high","plddt":84.931,"start":156,"end":298}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7D7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7D7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7D7-F1-predicted_aligned_error_v6.png","plddt_mean":79.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR26","jax_strain_url":"https://www.jax.org/strain/search?query=WDR26"},"sequence":{"accession":"Q9H7D7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7D7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7D7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7D7"}},"corpus_meta":[{"pmid":"26895380","id":"PMC_26895380","title":"Upregulated WDR26 serves as a scaffold to coordinate PI3K/ AKT pathway-driven breast cancer cell growth, migration, and invasion.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26895380","citation_count":58,"is_preprint":false},{"pmid":"31945154","id":"PMC_31945154","title":"Wdr26 regulates nuclear condensation in developing erythroblasts.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/31945154","citation_count":55,"is_preprint":false},{"pmid":"15378603","id":"PMC_15378603","title":"WDR26: a novel Gbeta-like protein, suppresses MAPK signaling pathway.","date":"2004","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15378603","citation_count":52,"is_preprint":false},{"pmid":"28686853","id":"PMC_28686853","title":"WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28686853","citation_count":51,"is_preprint":false},{"pmid":"27098453","id":"PMC_27098453","title":"WDR26 is a new partner of Axin1 in the canonical Wnt signaling pathway.","date":"2016","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/27098453","citation_count":35,"is_preprint":false},{"pmid":"22065575","id":"PMC_22065575","title":"The WD40 repeat protein WDR26 binds Gβγ and promotes Gβγ-dependent signal transduction and leukocyte migration.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22065575","citation_count":31,"is_preprint":false},{"pmid":"27797717","id":"PMC_27797717","title":"WDR26 promotes mitophagy of cardiomyocytes induced by hypoxia through Parkin translocation.","date":"2016","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/27797717","citation_count":31,"is_preprint":false},{"pmid":"38759627","id":"PMC_38759627","title":"Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38759627","citation_count":29,"is_preprint":false},{"pmid":"19446606","id":"PMC_19446606","title":"A novel WD-40 repeat protein WDR26 suppresses H2O2-induced cell death in neural cells.","date":"2009","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/19446606","citation_count":29,"is_preprint":false},{"pmid":"23625927","id":"PMC_23625927","title":"WDR26 functions as a scaffolding protein to promote Gβγ-mediated phospholipase C β2 (PLCβ2) activation in leukocytes.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23625927","citation_count":22,"is_preprint":false},{"pmid":"22448652","id":"PMC_22448652","title":"A novel WD-repeat protein, WDR26, inhibits apoptosis of cardiomyocytes induced by oxidative stress.","date":"2012","source":"Free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/22448652","citation_count":19,"is_preprint":false},{"pmid":"39808525","id":"PMC_39808525","title":"mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39808525","citation_count":13,"is_preprint":false},{"pmid":"38575527","id":"PMC_38575527","title":"Skraban-Deardorff intellectual disability syndrome-associated mutations in WDR26 impair CTLH E3 complex assembly.","date":"2024","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/38575527","citation_count":13,"is_preprint":false},{"pmid":"33675273","id":"PMC_33675273","title":"Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33675273","citation_count":13,"is_preprint":false},{"pmid":"33506510","id":"PMC_33506510","title":"Skraban-Deardorff syndrome: Six new cases of WDR26-related disease and expansion of the clinical phenotype.","date":"2021","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33506510","citation_count":11,"is_preprint":false},{"pmid":"39702571","id":"PMC_39702571","title":"Interplay between β-propeller subunits WDR26 and muskelin regulates the CTLH E3 ligase supramolecular complex.","date":"2024","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/39702571","citation_count":10,"is_preprint":false},{"pmid":"34876184","id":"PMC_34876184","title":"WDR26 and MTF2 are therapeutic targets in multiple myeloma.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34876184","citation_count":9,"is_preprint":false},{"pmid":"35627197","id":"PMC_35627197","title":"Two Novel Variants of WDR26 in Chinese Patients with Intellectual Disability.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35627197","citation_count":7,"is_preprint":false},{"pmid":"39363971","id":"PMC_39363971","title":"Novel loss-of-function variants in WDR26 cause Skraban-Deardorff syndrome in two Chinese patients.","date":"2024","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/39363971","citation_count":2,"is_preprint":false},{"pmid":"40826479","id":"PMC_40826479","title":"WDR26-related Skraban-Deardorff syndrome: clinical, genetic and pathomechanistic insights.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/40826479","citation_count":0,"is_preprint":false},{"pmid":"42138082","id":"PMC_42138082","title":"Wdr26 insufficiency causes Skraban-Deardorff syndrome-like neurodevelopmental deficits in mice.","date":"2026","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/42138082","citation_count":0,"is_preprint":false},{"pmid":"41994129","id":"PMC_41994129","title":"miR-34 regulates stress-induced depression-like state through the WDR26 ortholog melancholy in Drosophila.","date":"2026","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/41994129","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12489,"output_tokens":4121,"usd":0.049641,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11953,"output_tokens":4279,"usd":0.08337,"stage2_stop_reason":"end_turn"},"total_usd":0.133011,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"WDR26 is a novel WD40 repeat, Gβ-like protein that, when overexpressed, suppresses MAPK signaling by inhibiting ELK-1 and c-fos SRE transcriptional activities mediated by MEKK1, acting as a negative regulator of the MAPK pathway.\",\n      \"method\": \"Overexpression in cells with transcriptional reporter assays (ELK-1 and SRE-driven luciferase) downstream of MEKK1\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, reporter assay overexpression, consistent with Gβ-like domain architecture but no mutagenesis or in vitro reconstitution\",\n      \"pmids\": [\"15378603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR26 directly binds free Gβγ in vitro and forms a complex with endogenous Gβγ in SDF1α-stimulated Jurkat T cells; WDR26 is required for Gβγ-dependent PLCβ and PI3K activation and for leukocyte chemotaxis. WDR26 also controls RACK1 (a negative regulator) binding to Gβγ.\",\n      \"method\": \"In vitro direct binding assay, co-immunoprecipitation with endogenous Gβγ, siRNA knockdown with functional readouts (PLCβ/PI3K activation, chemotaxis, in vivo homing in SCID mice), WDR26 deletion mutant expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct in vitro binding, deletion mutant epistasis, multiple functional readouts, replicated in two cell lines and in vivo\",\n      \"pmids\": [\"22065575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR26 functions as a scaffolding protein that directly binds both Gβγ and PLCβ2 (with overlapping but non-identical binding sites on Gβ1γ2), forms higher-order oligomers through its LisH-CTLH and WD40 domains, and promotes PLCβ2 membrane translocation and interaction with Gβγ, thereby enhancing PLCβ2 activation in leukocytes.\",\n      \"method\": \"Direct binding assays, co-immunoprecipitation, domain-mapping with deletion mutants, fluorescence imaging of PLCβ2 translocation, functional PLCβ2 activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (direct binding, Co-IP, mutant analysis, imaging, activity assay) in a single rigorous study\",\n      \"pmids\": [\"23625927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR26 serves as a scaffold downstream of GPCR stimulation to assemble a specific signaling complex consisting of Gβγ, PI3Kβ, and AKT2, selectively promoting GPCR- (but not EGF receptor-) stimulated PI3K/AKT signaling in breast cancer cells. Disrupting this complex via WDR26 mutants abrogated PI3K/AKT activation and tumor growth/metastasis in an orthotopic xenograft model.\",\n      \"method\": \"siRNA knockdown, overexpression of WDR26 mutants disrupting complex assembly, signaling assays (pAKT, pPI3K), orthotopic xenograft mouse model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, mutant epistasis, in vivo xenograft validation, isoform selectivity established\",\n      \"pmids\": [\"26895380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR26 binds Axin1 and acts as a negative regulator of canonical Wnt signaling by promoting ubiquitination and degradation of β-catenin; WDR26/Axin interaction is required for this effect.\",\n      \"method\": \"Co-immunoprecipitation (WDR26–Axin1 interaction), β-catenin ubiquitination assay, Wnt reporter assay, WDR26 overexpression/knockdown\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, reporter assay, and ubiquitination assay, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"27098453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR26 promotes hypoxia-induced mitophagy in cardiomyocytes (H9c2 cells) by increasing mitochondrial membrane potential and facilitating Parkin translocation to mitochondria, leading to increased mitochondrial protein ubiquitination.\",\n      \"method\": \"WDR26 overexpression/knockdown in H9c2 cells under hypoxia, Parkin translocation imaging, mitochondrial membrane potential measurement, ubiquitination assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional imaging and biochemical assays, single lab, mechanism of membrane potential increase not resolved\",\n      \"pmids\": [\"27797717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wdr26, as part of the GID/CTLH E3 ubiquitin ligase complex, regulates ubiquitination and proteasomal degradation of nuclear proteins including lamin B during terminal erythropoiesis; loss of Wdr26 impairs lamin B degradation, blocks nuclear opening formation, and causes defective nuclear condensation and enucleation.\",\n      \"method\": \"Wdr26 knockout in mouse erythroblasts (enucleation defects), zebrafish knockdown (anemia), ubiquitination assays for lamin B, lamin B protein level measurement, CTLH/GID complex co-immunoprecipitation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two organism models (mouse KO, zebrafish KD), specific substrate (lamin B) identified with ubiquitination assay, mechanistic pathway from complex to substrate to nuclear phenotype\",\n      \"pmids\": [\"31945154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WDR26 overexpression suppresses H2O2-induced cell death in SH-SY5Y neuroblastoma cells and downregulates AP-1 transcriptional activity during oxidative stress; conversely, antisense ODN knockdown of WDR26 enhances H2O2-induced cell death.\",\n      \"method\": \"Overexpression and antisense ODN knockdown, cell viability assay, AP-1 luciferase reporter assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, reporter assay without mechanistic resolution of how WDR26 suppresses AP-1\",\n      \"pmids\": [\"19446606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDR26 localizes to mitochondria and inhibits cytochrome c release from mitochondria, thereby suppressing apoptosis in H9c2 cardiomyocytes under oxidative stress.\",\n      \"method\": \"Subcellular fractionation/localization assay, cytochrome c release assay, WDR26 overexpression with H2O2 treatment, apoptosis readout\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single cell line, fractionation-based localization, no mechanistic detail on how mitochondrial WDR26 blocks cytochrome c release\",\n      \"pmids\": [\"22448652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR26 acts as a non-canonical substrate receptor within the CTLH E3 complex to bind NMNAT1 via an internal basic degron motif and mediate its ubiquitylation and cellular degradation independently of canonical GID/CTLH substrate receptors. YPEL5 inhibits this process by N-terminal degron mimicry of NMNAT1. Cryo-EM structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes were determined.\",\n      \"method\": \"Cryo-EM structure determination, in vitro ubiquitylation assay, co-immunoprecipitation, degron mutagenesis, cellular degradation assays, YPEL5 knockout/overexpression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional mutagenesis of degron, in vitro reconstitution of ubiquitylation, cellular validation, mechanism of YPEL5 inhibition structurally resolved\",\n      \"pmids\": [\"38759627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SKDEAS-associated WDR26 mutations impair CTLH E3 complex assembly and function; WDR26 homodimers bridge two core-CTLH E3 complexes to form supramolecular oval-shaped assemblies, mediates CTLH E3 binding to YPEL5, and functions as substrate receptor for transcriptional repressor HBP1. 15 of 16 patient-derived mutants impaired at least one of these functions.\",\n      \"method\": \"Structural modeling of WDR26, complementation assays in WDR26-KO cells engineered to lack CTLH supramolecular assemblies, functional assays for complex assembly, YPEL5 binding, and HBP1 substrate receptor activity\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetically engineered cell lines, multiple mutants tested across multiple orthogonal functions, structural model used to map mutations, consistent with independent cryo-EM data\",\n      \"pmids\": [\"38575527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR26 and muskelin β-propeller proteins compete for binding to the CTLH complex scaffold in an interchangeable manner, forming separate WDR26- or muskelin-containing complexes with distinct proteomes. CTLH E3 ligase activity in HeLa cells is dictated by the interplay between WDR26 and muskelin; muskelin protein turnover is a major ubiquitin-dependent degradation event dependent on the CTLH complex.\",\n      \"method\": \"Proteomic experiments (mass spectrometry), WDR26 and muskelin knockout cell lines, co-immunoprecipitation, ubiquitin assays, mTOR inhibition experiments\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal KO cell lines, quantitative proteomics, multiple substrates tested, functional consequence of WDR26/muskelin interplay mechanistically resolved\",\n      \"pmids\": [\"39702571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CTLH-WDR26 E3 complex mediates ubiquitin-dependent degradation of UCK2 (rate-limiting enzyme of pyrimidine salvage pathway) during mTORC1 inhibition; UCK1, an isoform of UCK2, affects UCK2 turnover by influencing its subcellular localization.\",\n      \"method\": \"mTORC1 inhibition (rapamycin) with WDR26/CTLH knockdown/knockout, UCK2 half-life/degradation assays, ubiquitination assays, cellular localization experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — specific substrate (UCK2) identified with degradation assays, mTORC1 pathway placement, UCK1-mediated localization mechanism, functional consequence on pyrimidine salvage established\",\n      \"pmids\": [\"39808525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Wdr26 haploinsufficiency in mice stabilizes RUNX1T1 (a transcriptional coactivator) by impairing its ubiquitination and proteasomal degradation via the CTLH complex, leading to elevated MAP2 and disrupted dendritic/synaptic architecture. AAV-shRNA knockdown of Runx1t1 in neonatal Wdr26+/- mice reversed MAP2 overexpression and behavioral deficits.\",\n      \"method\": \"Wdr26 heterozygous KO mouse model, RUNX1T1 ubiquitination assay, MAP2 protein level measurement, AAV-shRNA rescue experiment, behavioral tests\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model, specific substrate identified with ubiquitination assay, pathway confirmed by in vivo rescue (AAV-shRNA), behavioral phenotype correlated with molecular mechanism\",\n      \"pmids\": [\"42138082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Missense variants in WDR26 associated with Skraban-Deardorff syndrome markedly reduce WDR26 protein levels through accelerated proteasomal degradation (reversed by proteasome inhibitor), while a frameshift variant reduces WDR26 mRNA via nonsense-mediated decay; both mechanisms result in loss of function and impaired cell proliferation.\",\n      \"method\": \"Cycloheximide chase, proteasome inhibitor treatment, mRNA stability assays, lymphoblastoid cell proliferation assay with patient-derived variants\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal protein/mRNA stability methods, patient-derived variants, single lab\",\n      \"pmids\": [\"40826479\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR26 is a WD40 repeat protein that functions primarily as a subunit and substrate receptor of the CTLH E3 ubiquitin ligase complex, where it forms homodimers bridging two core-CTLH complexes into supramolecular assemblies, recruits substrates (including NMNAT1, UCK2, RUNX1T1, lamin B, and HBP1) via degron recognition for ubiquitylation and proteasomal degradation, and also acts as a scaffolding protein that binds Gβγ and PLCβ2 to enhance GPCR-dependent PI3K/AKT and PLCβ signaling in leukocytes and cancer cells; WDR26 competes with muskelin for CTLH complex scaffold binding to regulate substrate selectivity, and its haploinsufficiency disrupts CTLH-dependent protein homeostasis, leading to the neurodevelopmental features of Skraban-Deardorff syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR26 is a WD40-repeat, Gβ-like protein that operates in two convergent regulatory modes: as a substrate-receptor and architectural subunit of the CTLH/GID E3 ubiquitin ligase complex, and as a signaling scaffold downstream of G-protein-coupled receptors [#1, #9]. Through its LisH-CTLH and WD40 domains, WDR26 homodimerizes to bridge two core-CTLH complexes into supramolecular oval-shaped assemblies, and it functions as a non-canonical substrate receptor that recognizes degron motifs on target proteins to direct their ubiquitylation and proteasomal degradation [#9, #10]. Identified substrates span diverse processes — NMNAT1 (with the recognition controlled by YPEL5 degron mimicry), the pyrimidine-salvage enzyme UCK2 during mTORC1 inhibition, the transcriptional repressor HBP1, lamin B during terminal erythropoiesis, and the transcriptional coactivator RUNX1T1 [#9, #12, #10, #6, #13]. WDR26 and muskelin β-propeller proteins compete interchangeably for the CTLH scaffold, forming distinct complexes with separate proteomes and thereby dictating substrate selectivity and overall CTLH ligase output [#11]. In its scaffolding role, WDR26 directly binds free Gβγ and PLCβ2 and assembles a Gβγ–PI3Kβ–AKT2 complex that selectively amplifies GPCR-stimulated PLCβ and PI3K/AKT signaling, supporting leukocyte chemotaxis and, in breast cancer, tumor growth and metastasis [#1, #2, #3]. WDR26 loss-of-function causes the neurodevelopmental disorder Skraban-Deardorff syndrome: haploinsufficiency stabilizes RUNX1T1, elevating MAP2 and disrupting dendritic and synaptic architecture, and patient variants impair CTLH assembly or destabilize WDR26 itself through accelerated proteasomal degradation or nonsense-mediated decay [#13, #10, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established WDR26 as a Gβ-like WD40 protein with a regulatory role in signaling, first framed as a negative regulator of the MEKK1-driven MAPK pathway.\",\n      \"evidence\": \"Overexpression with ELK-1/SRE luciferase reporter assays downstream of MEKK1\",\n      \"pmids\": [\"15378603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect shown only by overexpression reporter assays\", \"No direct binding partner or biochemical mechanism for MAPK suppression identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined WDR26's first concrete molecular function — direct Gβγ binding required for downstream PLCβ/PI3K activation and leukocyte chemotaxis — moving it from a phenotypic regulator to a defined signaling effector.\",\n      \"evidence\": \"In vitro direct binding, reciprocal Co-IP of endogenous Gβγ, siRNA knockdown with chemotaxis/in vivo homing readouts in Jurkat T cells and SCID mice\",\n      \"pmids\": [\"22065575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Gβγ binding not resolved\", \"Relationship to its later-described CTLH role not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Refined the scaffolding mechanism, showing WDR26 simultaneously binds Gβγ and PLCβ2 and oligomerizes via LisH-CTLH and WD40 domains to promote PLCβ2 membrane translocation and activation.\",\n      \"evidence\": \"Direct binding, Co-IP, deletion-mutant domain mapping, fluorescence imaging of PLCβ2 translocation, PLCβ2 activity assays\",\n      \"pmids\": [\"23625927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect oligomerization domains to E3 ligase scaffolding function later attributed to the same domains\", \"Stoichiometry of the higher-order assembly not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the WDR26 scaffold has receptor-selective output, assembling a Gβγ–PI3Kβ–AKT2 complex that drives GPCR- but not EGFR-stimulated PI3K/AKT signaling and promotes tumor growth and metastasis.\",\n      \"evidence\": \"siRNA knockdown, complex-disrupting WDR26 mutants, pAKT/pPI3K assays, orthotopic xenograft mouse model\",\n      \"pmids\": [\"26895380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether CTLH-associated WDR26 contributes to or is separate from this signaling pool\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked WDR26 to ubiquitin-dependent degradation in additional pathways — Axin1-dependent β-catenin turnover and Parkin-mediated mitophagy — early hints of a broader proteostatic role.\",\n      \"evidence\": \"Co-IP, β-catenin ubiquitination and Wnt reporter assays; Parkin translocation imaging and mitochondrial ubiquitination assays in H9c2 cells\",\n      \"pmids\": [\"27098453\", \"27797717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the ubiquitination events\", \"Mechanistic relationship to CTLH complex not established at the time\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed WDR26 firmly within the GID/CTLH E3 ligase and identified its first physiological substrate, lamin B, establishing a complex→substrate→phenotype axis in erythropoiesis.\",\n      \"evidence\": \"Mouse Wdr26 knockout erythroblasts and zebrafish knockdown, lamin B ubiquitination/level assays, CTLH/GID Co-IP\",\n      \"pmids\": [\"31945154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how WDR26 recognizes lamin B as a degron-bearing substrate\", \"Generality of receptor function across substrates untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the structural and mechanistic basis of WDR26 substrate receptor activity, showing it reads an internal basic degron on NMNAT1 and is competitively inhibited by YPEL5 N-terminal degron mimicry.\",\n      \"evidence\": \"Cryo-EM of NMNAT1- and YPEL5-bound WDR26-CTLH complexes, in vitro ubiquitylation, degron mutagenesis, cellular degradation and YPEL5 perturbation assays\",\n      \"pmids\": [\"38759627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all WDR26 substrates use a common degron architecture unknown\", \"Physiological triggers gating NMNAT1 degradation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined WDR26's architectural role and its substrate-selection logic: homodimers bridge two core-CTLH complexes into supramolecular assemblies, and WDR26 competes interchangeably with muskelin to set distinct CTLH proteomes.\",\n      \"evidence\": \"Structural modeling and complementation in WDR26-KO cells; reciprocal WDR26/muskelin KO cell lines with quantitative proteomics, Co-IP, and ubiquitin assays\",\n      \"pmids\": [\"38575527\", \"39702571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling the WDR26-versus-muskelin choice not identified\", \"Function of the supramolecular oval assembly beyond scaffold bridging unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected WDR26-CTLH activity to nutrient/growth signaling by showing it degrades the pyrimidine-salvage enzyme UCK2 during mTORC1 inhibition, with UCK1 modulating UCK2 localization.\",\n      \"evidence\": \"Rapamycin-induced mTORC1 inhibition with WDR26/CTLH knockdown, UCK2 half-life, ubiquitination, and localization assays\",\n      \"pmids\": [\"39808525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mTORC1 status is transduced to WDR26-CTLH activity unresolved\", \"Degron on UCK2 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the disease mechanism of Skraban-Deardorff syndrome: in vivo, Wdr26 haploinsufficiency stabilizes RUNX1T1, elevating MAP2 and disrupting neuronal architecture, with knockdown of Runx1t1 rescuing the phenotype.\",\n      \"evidence\": \"Wdr26 heterozygous KO mice, RUNX1T1 ubiquitination assays, MAP2 measurement, AAV-shRNA Runx1t1 rescue, behavioral testing\",\n      \"pmids\": [\"42138082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other CTLH substrates contributing to neurodevelopmental phenotype not fully cataloged\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Explained how patient variants cause loss of function — missense variants accelerate WDR26 proteasomal degradation while a frameshift triggers NMD — unifying the genetic findings at the protein-stability level.\",\n      \"evidence\": \"Cycloheximide chase, proteasome inhibitor rescue, mRNA stability and proliferation assays in patient-derived lymphoblastoid cells\",\n      \"pmids\": [\"40826479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct link between reduced WDR26 levels and specific CTLH substrate dysregulation in patient cells not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR26's signaling-scaffold role (Gβγ/PLCβ2/PI3K-AKT) and its CTLH E3 substrate-receptor role are integrated within a single cell, and what governs the choice between WDR26- and muskelin-defined CTLH proteomes, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No study reconciles the GPCR-scaffold and E3-ligase functions mechanistically\", \"Upstream signals selecting WDR26 substrate panels are undefined\", \"Full WDR26-specific substrate repertoire incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 6, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 6, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 13, 14]}\n    ],\n    \"complexes\": [\"CTLH/GID E3 ubiquitin ligase complex\"],\n    \"partners\": [\"GNB1\", \"PLCB2\", \"PIK3CB\", \"AKT2\", \"YPEL5\", \"AXIN1\", \"MKLN1\", \"NMNAT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}