{"gene":"WDR81","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"WDR81 interacts with the autophagy cargo receptor p62 (SQSTM1) and facilitates recognition of ubiquitinated proteins by p62. WDR81 also interacts with LC3C through canonical LIR (LC3-interacting region) motifs located in the BEACH domain, promoting LC3C recruitment to ubiquitinated protein aggregates. Loss of WDR81 causes accumulation of ubiquitinated proteins and p62 bodies, and WDR81 inactivation in mice causes accumulation of p62 bodies in cortical and striatal neurons.","method":"Co-immunoprecipitation, loss-of-function (KO mice, cell-based), LIR motif mutagenesis, immunofluorescence, mouse brain histology","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis (LIR motifs in BEACH domain), KO mice with defined cellular phenotype, replicated across multiple methods in one study","pmids":["28404643"],"is_preprint":false},{"year":2017,"finding":"WDR81 mutations in patients and Drosophila WDR81 ortholog knockdown both result in increased mitotic index and delayed prometaphase/metaphase transition in neural progenitor/stem cells, indicating a conserved role for WDR81 in mitotic progression.","method":"Patient fibroblast analysis (mitotic index measurement), Drosophila RNAi knockdown of WDR81 ortholog in neural stem cells, whole-exome sequencing of patients","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two independent biological systems (human fibroblasts and Drosophila neural stem cells) with consistent phenotypic readout, single study","pmids":["28969387"],"is_preprint":false},{"year":2016,"finding":"WDR81 functions in a complex with WDR91 to regulate endolysosomal trafficking. Loss of WDR81 results in swollen endolysosomal compartments (enlarged early and late endosomes), reduced delivery of endocytosed cargo to cathepsin-active lysosomes, and impaired degradation of tetherin (BST2) and EGF-stimulated EGFR. The WDR81-WDR91 complex is required for fusion of endolysosomal compartments.","method":"Forward genetic screen (haploid KBM7 cells), KO cell lines, endosomal morphology analysis, receptor degradation assays, dextran trafficking to lysosomes","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen identified WDR81, confirmed by KO with multiple orthogonal functional readouts (receptor degradation, endosomal morphology, lysosomal delivery), complex with WDR91 established","pmids":["27126989"],"is_preprint":false},{"year":2018,"finding":"WDR81 suppresses endosomal PtdIns3P (PI3P) synthesis, likely by inhibiting assembly of the class III PI3K complex. In the absence of WDR81, elevated endosomal PtdIns3P leads to retention of the PtdIns3P-binding protein SARA on endosomes and hyperactivation of SARA-dependent TGFβ signaling, impairing adult hippocampal neurogenesis. Inhibition of PI3K-III or suppression of SARA-dependent TGFβ signaling rescues the neurogenesis defect in WDR81-deficient mice.","method":"WDR81 KO in adult neural progenitor cells (conditional ablation in mice), PtdIns3P measurement, SARA localization analysis, epistasis by PI3K-III inhibitor and TGFβ pathway inhibition, behavioral testing (hippocampus-dependent learning)","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice with defined cellular and behavioral phenotype, PI3P measurement, epistasis rescue experiments with two independent inhibitors, pathway placement established","pmids":["30531936"],"is_preprint":false},{"year":2013,"finding":"A missense mutation L1349P in the predicted major facilitator superfamily (MFS) domain of WDR81 causes Purkinje cell degeneration and photoreceptor cell loss in mice. WDR81 localizes to mitochondria in Purkinje cell neurons (shown by immunoelectron microscopy and mitochondrial-enriched fractionation), and mutant Purkinje cell dendrites display aberrant large spheroid-like mitochondria.","method":"ENU mutant mouse characterization, transgenic rescue, immunoelectron microscopy, subcellular fractionation (mitochondria-enriched fractions), electron microscopy","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic rescue confirms WDR81 causality, immunoelectron microscopy and fractionation for localization, single lab","pmids":["23595742"],"is_preprint":false},{"year":2021,"finding":"WDR81's BEACH and MFS domains are sufficient for its recruitment to Huntingtin polyQ aggregates. The WD40 repeat domain of WDR81 is essential for interaction with the covalently bound ATG5-ATG12 conjugate. WDR81 facilitates recruitment of autophagic proteins onto polyQ aggregates and promotes autophagic clearance. In C. elegans, deletion of the WDR81 homolog SORF-2 causes p62 body accumulation and exacerbates α-synuclein-induced neuron loss; overexpression of SORF-2 or human WDR81 restores neuron viability.","method":"Domain deletion/mutagenesis, Co-immunoprecipitation (WDR81 with ATG5-ATG12), C. elegans loss-of-function and overexpression, fibroblasts from HD patients, primary neuron viability assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — domain mapping by mutagenesis, Co-IP with ATG5-ATG12, C. elegans genetic rescue, human patient fibroblasts, multiple orthogonal methods across species","pmids":["33730050"],"is_preprint":false},{"year":2022,"finding":"WDR81 is required for the endosomal maturation step that allows late-penetrating viruses (reovirus, VSV-EBO GP) to transit through late endosomes. WDR81 KO does not affect viral attachment or uptake into early endosomes, but causes accumulation of viral particles in dead-end compartments and impairs viral gene expression and infectious particle production. Human WDR81 complements mouse WDR81 KO cells, confirming functional conservation.","method":"CRISPR-Cas9 KO screen (>20,000 genes), complementation with human WDR81, viral infection assays (reovirus, VSV, VSV-EBO GP), endosomal trafficking analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen with targeted validation, human WDR81 complementation of KO, multiple viruses tested to map the specific endosomal step, orthogonal readouts","pmids":["35320319"],"is_preprint":false},{"year":2025,"finding":"WDR81 represses IKK complex-mediated activation of NFκB pro-survival gene expression. In WDR81-deficient cells, expression of several pro-survival genes is upregulated via the IKK-NFκB pathway. Blocking IKK signaling in WDR81-deficient cells restores pro-survival gene expression to normal levels and re-sensitizes cells to apoptosis triggers, revealing a link between endosomally localized WDR81 and IKK-NFκB signaling.","method":"WDR81 KO cells, gene expression analysis, IKK inhibitor epistasis, apoptosis assays with multiple agonists","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined transcriptional and apoptosis phenotype, epistasis rescue by IKK inhibition, single lab with multiple agonists tested","pmids":["41042063"],"is_preprint":false},{"year":2021,"finding":"WDR81 gene silencing in U87-MG glioblastoma cells reduces exosome secretion (concentration and protein/RNA content), consistent with WDR81 acting as a negative regulator of class III PI3K activity whose loss normally suppresses autophagy and increases exosome production.","method":"siRNA knockdown, real-time qRT-PCR, exosome isolation and quantification (DLS, protein/RNA content measurement), MTT viability assay","journal":"Journal of molecular neuroscience : MN","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (siRNA KD with exosome quantification), no direct mechanistic dissection of pathway; phenotype consistent with PI3K regulation but not rigorously proven here","pmids":["33954857"],"is_preprint":false},{"year":2025,"finding":"WDR81 contains a conserved TBM (TMEM55B Binding Motif) and co-immunoprecipitates with TMEM55B, a lysosomal membrane protein, in a phospho-Rab-independent manner, placing WDR81 within a lysosomal adaptor complex centered on TMEM55B.","method":"Co-immunoprecipitation, mutational analysis of TBM motif, crystal structure of TMEM55B-RILPL1 complex as reference","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single Co-IP/mutational evidence for WDR81-TMEM55B interaction; WDR81 is one of several proteins listed, no deep functional characterization of WDR81-TMEM55B specifically","pmids":["bio_10.1101_2025.08.19.670962"],"is_preprint":true}],"current_model":"WDR81 is a multi-domain (BEACH, MFS, WD40) endolysosomal protein that: (1) coordinates autophagy receptor p62 and LC3C via its BEACH domain LIR motifs to promote aggrephagy of ubiquitinated proteins; (2) forms a complex with WDR91 to drive endosomal maturation and endolysosomal fusion required for cargo degradation; (3) suppresses class III PI3K-dependent PtdIns3P synthesis on endosomes, thereby restraining SARA-TGFβ signaling; (4) facilitates mitotic progression in neural progenitors; (5) represses IKK-NFκB pro-survival gene expression, linking endosomal function to apoptosis control; and (6) interacts with the lysosomal protein TMEM55B via a conserved TBM motif, placing it in a broader lysosomal adaptor network."},"narrative":{"mechanistic_narrative":"WDR81 is a multi-domain endolysosomal protein that governs the maturation and degradative capacity of the endosome-lysosome system and selective autophagy of aggregated proteins [PMID:27126989, PMID:28404643]. It functions in a complex with WDR91 to drive endolysosomal fusion and cargo delivery to cathepsin-active lysosomes; loss of WDR81 swells early and late endosomes and blocks degradation of cargo such as tetherin and EGF-stimulated EGFR [PMID:27126989]. Mechanistically, WDR81 suppresses endosomal PtdIns3P synthesis by restraining class III PI3K assembly, and its loss elevates PtdIns3P, retains the PtdIns3P-binding effector SARA on endosomes, and hyperactivates SARA-dependent TGFβ signaling, impairing adult hippocampal neurogenesis [PMID:30531936]. In selective autophagy, WDR81 engages the cargo receptor p62/SQSTM1 to recognize ubiquitinated proteins and recruits LC3C through LIR motifs in its BEACH domain, while its WD40 domain binds the ATG5-ATG12 conjugate to deliver autophagic machinery onto protein aggregates; loss of WDR81 causes accumulation of ubiquitinated proteins and p62 bodies in neurons and worsens aggregate-induced neurodegeneration [PMID:28404643, PMID:33730050]. This endosomal maturation function is also exploited by late-penetrating viruses, which require WDR81 to transit through late endosomes [PMID:35320319]. Mutations in WDR81 impair mitotic progression in neural progenitors [PMID:28969387], and an MFS-domain missense mutation causes Purkinje cell and photoreceptor degeneration with aberrant mitochondrial morphology [PMID:23595742].","teleology":[{"year":2013,"claim":"Established WDR81 as a gene whose disruption causes neurodegeneration, providing the first in vivo causal link and a candidate subcellular site of action.","evidence":"ENU mutant mouse with MFS-domain L1349P mutation, transgenic rescue, immunoelectron microscopy and mitochondrial fractionation","pmids":["23595742"],"confidence":"Medium","gaps":["Mitochondrial localization not reconciled with later endolysosomal role","Molecular function of the MFS domain undefined","Mechanism linking mutation to mitochondrial spheroid morphology unknown"]},{"year":2016,"claim":"Defined the core endolysosomal function of WDR81 by showing it acts with WDR91 to drive endosome maturation and fusion required for cargo degradation.","evidence":"Forward genetic screen in haploid KBM7 cells, KO cell lines, endosomal morphology, receptor degradation and dextran-to-lysosome assays","pmids":["27126989"],"confidence":"High","gaps":["Biochemical mechanism of how the WDR81-WDR91 complex promotes fusion not resolved","Direct membrane or lipid targets not identified"]},{"year":2017,"claim":"Connected WDR81 to selective autophagy of ubiquitinated proteins by mapping its interactions with p62 and LC3C and demonstrating neuronal aggregate accumulation on loss.","evidence":"Reciprocal Co-IP, BEACH-domain LIR motif mutagenesis, KO mice, brain histology","pmids":["28404643"],"confidence":"High","gaps":["How endosomal and aggrephagy functions are coordinated unclear","Stoichiometry and order of p62/LC3C engagement not established"]},{"year":2017,"claim":"Revealed a conserved requirement for WDR81 in mitotic progression of neural progenitors, broadening its role beyond trafficking.","evidence":"Patient fibroblast mitotic index, Drosophila neural stem cell RNAi, whole-exome sequencing","pmids":["28969387"],"confidence":"Medium","gaps":["Molecular mechanism linking WDR81 to prometaphase/metaphase transition unknown","Whether mitotic role is downstream of endosomal function untested"]},{"year":2018,"claim":"Placed WDR81 in a defined lipid-signaling pathway by showing it suppresses endosomal PtdIns3P to restrain SARA-TGFβ signaling and support neurogenesis.","evidence":"Conditional KO mice, PtdIns3P measurement, SARA localization, epistasis rescue with PI3K-III and TGFβ inhibitors, behavioral testing","pmids":["30531936"],"confidence":"High","gaps":["Direct mechanism of class III PI3K inhibition by WDR81 not shown","Whether PtdIns3P regulation and WDR91 complex function are the same activity unresolved"]},{"year":2021,"claim":"Refined the aggrephagy mechanism by mapping domain contributions and demonstrating cross-species rescue of aggregate-induced neuron loss.","evidence":"Domain deletion/mutagenesis, Co-IP with ATG5-ATG12, C. elegans loss-of-function and rescue, HD patient fibroblasts, neuron viability assays","pmids":["33730050"],"confidence":"High","gaps":["How WD40-ATG5-ATG12 binding integrates with LIR-mediated LC3C recruitment unclear","Quantitative contribution of aggrephagy to neuroprotection in vivo undefined"]},{"year":2021,"claim":"Linked WDR81 to exosome biogenesis, consistent with its role as a negative regulator of class III PI3K.","evidence":"siRNA knockdown in U87-MG glioblastoma cells, exosome quantification, qRT-PCR, MTT assay","pmids":["33954857"],"confidence":"Low","gaps":["Single-method siRNA study without mechanistic dissection","Causal link between PI3K regulation and exosome output not directly proven"]},{"year":2022,"claim":"Demonstrated that WDR81-dependent endosome maturation is co-opted by late-penetrating viruses requiring late-endosomal transit.","evidence":"Genome-wide CRISPR-Cas9 KO screen, human WDR81 complementation, reovirus/VSV/VSV-EBO GP infection and endosomal trafficking assays","pmids":["35320319"],"confidence":"High","gaps":["Whether viral and physiological cargo use identical WDR81 maturation step not dissected","Specific molecular interactors at the dead-end compartment unidentified"]},{"year":2025,"claim":"Connected endosomal WDR81 to apoptosis control by showing it represses IKK-NFκB pro-survival gene expression.","evidence":"WDR81 KO cells, gene expression analysis, IKK inhibitor epistasis, apoptosis assays with multiple agonists","pmids":["41042063"],"confidence":"Medium","gaps":["Direct molecular link between endosomal WDR81 and the IKK complex not defined","Single-lab study without independent confirmation"]},{"year":2025,"claim":"Began placing WDR81 within a lysosomal adaptor network through a conserved motif-mediated interaction with TMEM55B.","evidence":"Co-IP, TBM motif mutational analysis, reference TMEM55B-RILPL1 crystal structure (preprint)","pmids":["bio_10.1101_2025.08.19.670962"],"confidence":"Low","gaps":["Preprint, single Co-IP/mutational evidence","Functional consequence of WDR81-TMEM55B interaction not characterized","Reciprocal validation absent"]},{"year":null,"claim":"How WDR81's distinct activities — endosome maturation/fusion with WDR91, suppression of class III PI3K/PtdIns3P, aggrephagy, mitotic progression, and IKK-NFκB repression — are mechanistically unified by its BEACH/MFS/WD40 architecture remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length WDR81 or its domain interplay","Whether one biochemical activity underlies all phenotypes is untested","Direct enzymatic substrate or lipid target unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,3,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,9]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7]}],"complexes":["WDR81-WDR91 complex"],"partners":["WDR91","SQSTM1","MAP1LC3C","ATG5","ATG12","TMEM55B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q562E7","full_name":"WD repeat-containing protein 81","aliases":[],"length_aa":1941,"mass_kda":211.7,"function":"Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. By modifying the phosphatidylinositol 3-phosphate/PtdInsP3 content of endosomal membranes may regulate endosome fusion, recycling, sorting and early to late endosome transport (PubMed:26783301). It is for instance, required for the delivery of cargos like BST2/tetherin from early to late endosome and thereby participates indirectly to their degradation by the lysosome (PubMed:27126989). May also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated protein aggregates. In this process, may regulate the interaction of SQSTM1 with ubiquitinated proteins and also recruit MAP1LC3C (PubMed:28404643). May also be involved in maintenance of normal mitochondrial structure and organization (By similarity)","subcellular_location":"Early endosome membrane; Late endosome membrane; Lysosome membrane; Cytoplasmic vesicle, autophagosome membrane; Mitochondrion; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q562E7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR81","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDR81","total_profiled":1310},"omim":[{"mim_id":"617967","title":"HYDROCEPHALUS, CONGENITAL, 3, WITH BRAIN ANOMALIES; HYC3","url":"https://www.omim.org/entry/617967"},{"mim_id":"616303","title":"WD REPEAT-CONTAINING PROTEIN 91; WDR91","url":"https://www.omim.org/entry/616303"},{"mim_id":"614218","title":"WD REPEAT-CONTAINING PROTEIN 81; WDR81","url":"https://www.omim.org/entry/614218"},{"mim_id":"610185","title":"CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 2; CAMRQ2","url":"https://www.omim.org/entry/610185"},{"mim_id":"609427","title":"LHFPL TETRASPAN SUBFAMILY, MEMBER 5; LHFPL5","url":"https://www.omim.org/entry/609427"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR81"},"hgnc":{"alias_symbol":["FLJ33817","PPP1R166","CAMRQ2","SORF-2"],"prev_symbol":[]},"alphafold":{"accession":"Q562E7","domains":[{"cath_id":"1.10.1540.10","chopping":"373-428_435-569","consensus_level":"high","plddt":84.416,"start":373,"end":569},{"cath_id":"1.25.40","chopping":"878-976","consensus_level":"high","plddt":83.7793,"start":878,"end":976},{"cath_id":"1.25.10","chopping":"1238-1268_1275-1442_1457-1522","consensus_level":"medium","plddt":85.3164,"start":1238,"end":1522}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q562E7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q562E7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q562E7-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR81","jax_strain_url":"https://www.jax.org/strain/search?query=WDR81"},"sequence":{"accession":"Q562E7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q562E7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q562E7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q562E7"}},"corpus_meta":[{"pmid":"28404643","id":"PMC_28404643","title":"The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28404643","citation_count":62,"is_preprint":false},{"pmid":"23595742","id":"PMC_23595742","title":"WDR81 is necessary for purkinje and photoreceptor cell survival.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23595742","citation_count":31,"is_preprint":false},{"pmid":"28969387","id":"PMC_28969387","title":"WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28969387","citation_count":30,"is_preprint":false},{"pmid":"30531936","id":"PMC_30531936","title":"WDR81 regulates adult hippocampal neurogenesis through endosomal SARA-TGFβ signaling.","date":"2018","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/30531936","citation_count":24,"is_preprint":false},{"pmid":"27126989","id":"PMC_27126989","title":"A Genetic Screen Identifies a Critical Role for the WDR81-WDR91 Complex in the Trafficking and Degradation of Tetherin.","date":"2016","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/27126989","citation_count":23,"is_preprint":false},{"pmid":"35320319","id":"PMC_35320319","title":"A CRISPR-Cas9 screen reveals a role for WD repeat-containing protein 81 (WDR81) in the entry of late penetrating viruses.","date":"2022","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/35320319","citation_count":12,"is_preprint":false},{"pmid":"33954857","id":"PMC_33954857","title":"WDR81 Gene Silencing Can Reduce Exosome Levels in Human U87-MG Glioblastoma Cells.","date":"2021","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/33954857","citation_count":8,"is_preprint":false},{"pmid":"33724704","id":"PMC_33724704","title":"Novel compound heterozygous frameshift variants in WDR81 associated with congenital hydrocephalus 3 with brain anomalies: First Chinese prenatal case confirms WDR81 involvement.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33724704","citation_count":8,"is_preprint":false},{"pmid":"33996189","id":"PMC_33996189","title":"A Novel Homozygous Frameshift WDR81 Mutation associated with Microlissencephaly, Corpus Callosum Agenesis, and Pontocerebellar Hypoplasia.","date":"2020","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33996189","citation_count":6,"is_preprint":false},{"pmid":"39920811","id":"PMC_39920811","title":"Betaine enhances SCAPs chondrogenic differentiation and promotes cartilage repair in TMJOA through WDR81.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39920811","citation_count":5,"is_preprint":false},{"pmid":"33730050","id":"PMC_33730050","title":"Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33730050","citation_count":4,"is_preprint":false},{"pmid":"27390838","id":"PMC_27390838","title":"Characterization of a novel zebrafish (Danio rerio) gene, wdr81, associated with cerebellar ataxia, mental retardation and dysequilibrium syndrome (CAMRQ).","date":"2015","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27390838","citation_count":4,"is_preprint":false},{"pmid":"41042063","id":"PMC_41042063","title":"WDR81 represses IKK-mediated expression of pro-survival genes to regulate apoptosis.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/41042063","citation_count":1,"is_preprint":false},{"pmid":"39911170","id":"PMC_39911170","title":"Expression of Autophagy-Related Proteins in Microlissencephaly Associated with a Novel Variant in the WDR81 Gene.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/39911170","citation_count":1,"is_preprint":false},{"pmid":"34338917","id":"PMC_34338917","title":"Fetal brain arrest broadens the spectrum of WDR81-related developmental brain malformations.","date":"2021","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/34338917","citation_count":1,"is_preprint":false},{"pmid":"41245233","id":"PMC_41245233","title":"WDR81 Mutation in Two Siblings: A Case Report and Review of Literature.","date":"2025","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/41245233","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.19.670962","title":"Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif","date":"2025-08-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.19.670962","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.27.645662","title":"WDR81 represses IKK mediated expression of pro-survival genes to regulate apoptosis","date":"2025-03-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.27.645662","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11499,"output_tokens":3112,"usd":0.040588,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10471,"output_tokens":3491,"usd":0.069815,"stage2_stop_reason":"end_turn"},"total_usd":0.110403,"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\": 2017,\n      \"finding\": \"WDR81 interacts with the autophagy cargo receptor p62 (SQSTM1) and facilitates recognition of ubiquitinated proteins by p62. WDR81 also interacts with LC3C through canonical LIR (LC3-interacting region) motifs located in the BEACH domain, promoting LC3C recruitment to ubiquitinated protein aggregates. Loss of WDR81 causes accumulation of ubiquitinated proteins and p62 bodies, and WDR81 inactivation in mice causes accumulation of p62 bodies in cortical and striatal neurons.\",\n      \"method\": \"Co-immunoprecipitation, loss-of-function (KO mice, cell-based), LIR motif mutagenesis, immunofluorescence, mouse brain histology\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis (LIR motifs in BEACH domain), KO mice with defined cellular phenotype, replicated across multiple methods in one study\",\n      \"pmids\": [\"28404643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDR81 mutations in patients and Drosophila WDR81 ortholog knockdown both result in increased mitotic index and delayed prometaphase/metaphase transition in neural progenitor/stem cells, indicating a conserved role for WDR81 in mitotic progression.\",\n      \"method\": \"Patient fibroblast analysis (mitotic index measurement), Drosophila RNAi knockdown of WDR81 ortholog in neural stem cells, whole-exome sequencing of patients\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two independent biological systems (human fibroblasts and Drosophila neural stem cells) with consistent phenotypic readout, single study\",\n      \"pmids\": [\"28969387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WDR81 functions in a complex with WDR91 to regulate endolysosomal trafficking. Loss of WDR81 results in swollen endolysosomal compartments (enlarged early and late endosomes), reduced delivery of endocytosed cargo to cathepsin-active lysosomes, and impaired degradation of tetherin (BST2) and EGF-stimulated EGFR. The WDR81-WDR91 complex is required for fusion of endolysosomal compartments.\",\n      \"method\": \"Forward genetic screen (haploid KBM7 cells), KO cell lines, endosomal morphology analysis, receptor degradation assays, dextran trafficking to lysosomes\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen identified WDR81, confirmed by KO with multiple orthogonal functional readouts (receptor degradation, endosomal morphology, lysosomal delivery), complex with WDR91 established\",\n      \"pmids\": [\"27126989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR81 suppresses endosomal PtdIns3P (PI3P) synthesis, likely by inhibiting assembly of the class III PI3K complex. In the absence of WDR81, elevated endosomal PtdIns3P leads to retention of the PtdIns3P-binding protein SARA on endosomes and hyperactivation of SARA-dependent TGFβ signaling, impairing adult hippocampal neurogenesis. Inhibition of PI3K-III or suppression of SARA-dependent TGFβ signaling rescues the neurogenesis defect in WDR81-deficient mice.\",\n      \"method\": \"WDR81 KO in adult neural progenitor cells (conditional ablation in mice), PtdIns3P measurement, SARA localization analysis, epistasis by PI3K-III inhibitor and TGFβ pathway inhibition, behavioral testing (hippocampus-dependent learning)\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice with defined cellular and behavioral phenotype, PI3P measurement, epistasis rescue experiments with two independent inhibitors, pathway placement established\",\n      \"pmids\": [\"30531936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense mutation L1349P in the predicted major facilitator superfamily (MFS) domain of WDR81 causes Purkinje cell degeneration and photoreceptor cell loss in mice. WDR81 localizes to mitochondria in Purkinje cell neurons (shown by immunoelectron microscopy and mitochondrial-enriched fractionation), and mutant Purkinje cell dendrites display aberrant large spheroid-like mitochondria.\",\n      \"method\": \"ENU mutant mouse characterization, transgenic rescue, immunoelectron microscopy, subcellular fractionation (mitochondria-enriched fractions), electron microscopy\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic rescue confirms WDR81 causality, immunoelectron microscopy and fractionation for localization, single lab\",\n      \"pmids\": [\"23595742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR81's BEACH and MFS domains are sufficient for its recruitment to Huntingtin polyQ aggregates. The WD40 repeat domain of WDR81 is essential for interaction with the covalently bound ATG5-ATG12 conjugate. WDR81 facilitates recruitment of autophagic proteins onto polyQ aggregates and promotes autophagic clearance. In C. elegans, deletion of the WDR81 homolog SORF-2 causes p62 body accumulation and exacerbates α-synuclein-induced neuron loss; overexpression of SORF-2 or human WDR81 restores neuron viability.\",\n      \"method\": \"Domain deletion/mutagenesis, Co-immunoprecipitation (WDR81 with ATG5-ATG12), C. elegans loss-of-function and overexpression, fibroblasts from HD patients, primary neuron viability assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — domain mapping by mutagenesis, Co-IP with ATG5-ATG12, C. elegans genetic rescue, human patient fibroblasts, multiple orthogonal methods across species\",\n      \"pmids\": [\"33730050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR81 is required for the endosomal maturation step that allows late-penetrating viruses (reovirus, VSV-EBO GP) to transit through late endosomes. WDR81 KO does not affect viral attachment or uptake into early endosomes, but causes accumulation of viral particles in dead-end compartments and impairs viral gene expression and infectious particle production. Human WDR81 complements mouse WDR81 KO cells, confirming functional conservation.\",\n      \"method\": \"CRISPR-Cas9 KO screen (>20,000 genes), complementation with human WDR81, viral infection assays (reovirus, VSV, VSV-EBO GP), endosomal trafficking analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen with targeted validation, human WDR81 complementation of KO, multiple viruses tested to map the specific endosomal step, orthogonal readouts\",\n      \"pmids\": [\"35320319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR81 represses IKK complex-mediated activation of NFκB pro-survival gene expression. In WDR81-deficient cells, expression of several pro-survival genes is upregulated via the IKK-NFκB pathway. Blocking IKK signaling in WDR81-deficient cells restores pro-survival gene expression to normal levels and re-sensitizes cells to apoptosis triggers, revealing a link between endosomally localized WDR81 and IKK-NFκB signaling.\",\n      \"method\": \"WDR81 KO cells, gene expression analysis, IKK inhibitor epistasis, apoptosis assays with multiple agonists\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined transcriptional and apoptosis phenotype, epistasis rescue by IKK inhibition, single lab with multiple agonists tested\",\n      \"pmids\": [\"41042063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR81 gene silencing in U87-MG glioblastoma cells reduces exosome secretion (concentration and protein/RNA content), consistent with WDR81 acting as a negative regulator of class III PI3K activity whose loss normally suppresses autophagy and increases exosome production.\",\n      \"method\": \"siRNA knockdown, real-time qRT-PCR, exosome isolation and quantification (DLS, protein/RNA content measurement), MTT viability assay\",\n      \"journal\": \"Journal of molecular neuroscience : MN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (siRNA KD with exosome quantification), no direct mechanistic dissection of pathway; phenotype consistent with PI3K regulation but not rigorously proven here\",\n      \"pmids\": [\"33954857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR81 contains a conserved TBM (TMEM55B Binding Motif) and co-immunoprecipitates with TMEM55B, a lysosomal membrane protein, in a phospho-Rab-independent manner, placing WDR81 within a lysosomal adaptor complex centered on TMEM55B.\",\n      \"method\": \"Co-immunoprecipitation, mutational analysis of TBM motif, crystal structure of TMEM55B-RILPL1 complex as reference\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single Co-IP/mutational evidence for WDR81-TMEM55B interaction; WDR81 is one of several proteins listed, no deep functional characterization of WDR81-TMEM55B specifically\",\n      \"pmids\": [\"bio_10.1101_2025.08.19.670962\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"WDR81 is a multi-domain (BEACH, MFS, WD40) endolysosomal protein that: (1) coordinates autophagy receptor p62 and LC3C via its BEACH domain LIR motifs to promote aggrephagy of ubiquitinated proteins; (2) forms a complex with WDR91 to drive endosomal maturation and endolysosomal fusion required for cargo degradation; (3) suppresses class III PI3K-dependent PtdIns3P synthesis on endosomes, thereby restraining SARA-TGFβ signaling; (4) facilitates mitotic progression in neural progenitors; (5) represses IKK-NFκB pro-survival gene expression, linking endosomal function to apoptosis control; and (6) interacts with the lysosomal protein TMEM55B via a conserved TBM motif, placing it in a broader lysosomal adaptor network.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR81 is a multi-domain endolysosomal protein that governs the maturation and degradative capacity of the endosome-lysosome system and selective autophagy of aggregated proteins [#2, #0]. It functions in a complex with WDR91 to drive endolysosomal fusion and cargo delivery to cathepsin-active lysosomes; loss of WDR81 swells early and late endosomes and blocks degradation of cargo such as tetherin and EGF-stimulated EGFR [#2]. Mechanistically, WDR81 suppresses endosomal PtdIns3P synthesis by restraining class III PI3K assembly, and its loss elevates PtdIns3P, retains the PtdIns3P-binding effector SARA on endosomes, and hyperactivates SARA-dependent TGFβ signaling, impairing adult hippocampal neurogenesis [#3]. In selective autophagy, WDR81 engages the cargo receptor p62/SQSTM1 to recognize ubiquitinated proteins and recruits LC3C through LIR motifs in its BEACH domain, while its WD40 domain binds the ATG5-ATG12 conjugate to deliver autophagic machinery onto protein aggregates; loss of WDR81 causes accumulation of ubiquitinated proteins and p62 bodies in neurons and worsens aggregate-induced neurodegeneration [#0, #5]. This endosomal maturation function is also exploited by late-penetrating viruses, which require WDR81 to transit through late endosomes [#6]. Mutations in WDR81 impair mitotic progression in neural progenitors [#1], and an MFS-domain missense mutation causes Purkinje cell and photoreceptor degeneration with aberrant mitochondrial morphology [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established WDR81 as a gene whose disruption causes neurodegeneration, providing the first in vivo causal link and a candidate subcellular site of action.\",\n      \"evidence\": \"ENU mutant mouse with MFS-domain L1349P mutation, transgenic rescue, immunoelectron microscopy and mitochondrial fractionation\",\n      \"pmids\": [\"23595742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial localization not reconciled with later endolysosomal role\", \"Molecular function of the MFS domain undefined\", \"Mechanism linking mutation to mitochondrial spheroid morphology unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the core endolysosomal function of WDR81 by showing it acts with WDR91 to drive endosome maturation and fusion required for cargo degradation.\",\n      \"evidence\": \"Forward genetic screen in haploid KBM7 cells, KO cell lines, endosomal morphology, receptor degradation and dextran-to-lysosome assays\",\n      \"pmids\": [\"27126989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of how the WDR81-WDR91 complex promotes fusion not resolved\", \"Direct membrane or lipid targets not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected WDR81 to selective autophagy of ubiquitinated proteins by mapping its interactions with p62 and LC3C and demonstrating neuronal aggregate accumulation on loss.\",\n      \"evidence\": \"Reciprocal Co-IP, BEACH-domain LIR motif mutagenesis, KO mice, brain histology\",\n      \"pmids\": [\"28404643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How endosomal and aggrephagy functions are coordinated unclear\", \"Stoichiometry and order of p62/LC3C engagement not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a conserved requirement for WDR81 in mitotic progression of neural progenitors, broadening its role beyond trafficking.\",\n      \"evidence\": \"Patient fibroblast mitotic index, Drosophila neural stem cell RNAi, whole-exome sequencing\",\n      \"pmids\": [\"28969387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking WDR81 to prometaphase/metaphase transition unknown\", \"Whether mitotic role is downstream of endosomal function untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed WDR81 in a defined lipid-signaling pathway by showing it suppresses endosomal PtdIns3P to restrain SARA-TGFβ signaling and support neurogenesis.\",\n      \"evidence\": \"Conditional KO mice, PtdIns3P measurement, SARA localization, epistasis rescue with PI3K-III and TGFβ inhibitors, behavioral testing\",\n      \"pmids\": [\"30531936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of class III PI3K inhibition by WDR81 not shown\", \"Whether PtdIns3P regulation and WDR91 complex function are the same activity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the aggrephagy mechanism by mapping domain contributions and demonstrating cross-species rescue of aggregate-induced neuron loss.\",\n      \"evidence\": \"Domain deletion/mutagenesis, Co-IP with ATG5-ATG12, C. elegans loss-of-function and rescue, HD patient fibroblasts, neuron viability assays\",\n      \"pmids\": [\"33730050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WD40-ATG5-ATG12 binding integrates with LIR-mediated LC3C recruitment unclear\", \"Quantitative contribution of aggrephagy to neuroprotection in vivo undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked WDR81 to exosome biogenesis, consistent with its role as a negative regulator of class III PI3K.\",\n      \"evidence\": \"siRNA knockdown in U87-MG glioblastoma cells, exosome quantification, qRT-PCR, MTT assay\",\n      \"pmids\": [\"33954857\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-method siRNA study without mechanistic dissection\", \"Causal link between PI3K regulation and exosome output not directly proven\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that WDR81-dependent endosome maturation is co-opted by late-penetrating viruses requiring late-endosomal transit.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 KO screen, human WDR81 complementation, reovirus/VSV/VSV-EBO GP infection and endosomal trafficking assays\",\n      \"pmids\": [\"35320319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether viral and physiological cargo use identical WDR81 maturation step not dissected\", \"Specific molecular interactors at the dead-end compartment unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected endosomal WDR81 to apoptosis control by showing it represses IKK-NFκB pro-survival gene expression.\",\n      \"evidence\": \"WDR81 KO cells, gene expression analysis, IKK inhibitor epistasis, apoptosis assays with multiple agonists\",\n      \"pmids\": [\"41042063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between endosomal WDR81 and the IKK complex not defined\", \"Single-lab study without independent confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began placing WDR81 within a lysosomal adaptor network through a conserved motif-mediated interaction with TMEM55B.\",\n      \"evidence\": \"Co-IP, TBM motif mutational analysis, reference TMEM55B-RILPL1 crystal structure (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.08.19.670962\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single Co-IP/mutational evidence\", \"Functional consequence of WDR81-TMEM55B interaction not characterized\", \"Reciprocal validation absent\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR81's distinct activities — endosome maturation/fusion with WDR91, suppression of class III PI3K/PtdIns3P, aggrephagy, mitotic progression, and IKK-NFκB repression — are mechanistically unified by its BEACH/MFS/WD40 architecture remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length WDR81 or its domain interplay\", \"Whether one biochemical activity underlies all phenotypes is untested\", \"Direct enzymatic substrate or lipid target unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 3, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"WDR81-WDR91 complex\"],\n    \"partners\": [\"WDR91\", \"SQSTM1\", \"MAP1LC3C\", \"ATG5\", \"ATG12\", \"TMEM55B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}