{"gene":"WASHC1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2010,"finding":"WASH1 (WASHC1) is recruited to endosomal membranes as part of a protein complex (including strumpellin) via interactions with the cargo-selective retromer complex (VPS35/VPS29/VPS26 trimer), where it functions as an actin nucleation-promoting factor to regulate endosomal tubule dynamics.","method":"Co-immunoprecipitation, identification of retromer-interacting proteins, endosomal localization studies","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and endosomal localization with functional tubule phenotype, single lab","pmids":["20923837"],"is_preprint":false},{"year":2014,"finding":"WASH1 (WASHC1) regulates Arp2/3 complex activity to generate actin filaments required for polar body extrusion and asymmetric division during mouse oocyte meiosis; depletion of WASH1 by morpholino injection reduced polar body extrusion, caused symmetric division, and decreased Arp2/3 complex expression.","method":"Morpholino knockdown, antibody injection, time-lapse microscopy, actin filament quantification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (polar body extrusion, spindle migration) and downstream Arp2/3 measurement, single lab","pmids":["24998208"],"is_preprint":false},{"year":2017,"finding":"Proteasomal inhibition stabilizes WASH1 (WASHC1) protein levels, indicating WASH1 is subject to proteasome-dependent degradation; knockdown of strumpellin in cortical neurons reduced endogenous WASH1 protein.","method":"Proteasomal inhibitor treatment, Western blot, strumpellin knockdown in rat cortical neurons","journal":"Journal of experimental neuroscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect evidence from inhibitor treatment and knockdown without direct mechanistic dissection of the degradation pathway","pmids":["25987849"],"is_preprint":false},{"year":2019,"finding":"Hepatic ablation of WASHC1 reduces surface levels of LDLR and LRP1 on hepatocytes, increases LDLR proteolysis by IDOL (inducible degrader of LDLR), and reduces scavenger receptor class B type I surface levels, demonstrating that the WASH complex regulates endosomal recycling of these receptors to the plasma membrane to control LDL and HDL cholesterol clearance.","method":"Hepatocyte-specific Washc1 knockout mouse, surface receptor quantification, cholesterol metabolism assays, receptor degradation assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal receptor trafficking and metabolic readouts, clearly defined molecular mechanism","pmids":["31167970"],"is_preprint":false},{"year":2021,"finding":"BBS1 promotes clearance of WASH1 (WASHC1) and centrosomal F-actin via the proteasome, coupling the 19S proteasome regulatory subunit to dynein for transport to the centrosome; this centrosomal WASH1 clearance is required for centrosome polarization toward the immune synapse in T cells.","method":"siRNA knockdown, proteasome inhibitor treatment, immunofluorescence, live imaging in T cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and mechanistic pathway placement, single lab","pmids":["34423835"],"is_preprint":false},{"year":2021,"finding":"WASH1 (WASHC1), together with endophilinA1/A2/A3, is involved in the formation of tubular microdomains on Rab7-positive late endosomes that retrieve TrkA (NTRK1) receptor, enabling downstream neurotrophin signaling.","method":"Knockdown/depletion, live imaging, endosomal tubulation assay in neuronal cultures","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific tubulation and signaling phenotype, single lab","pmids":["34486665"],"is_preprint":false},{"year":2022,"finding":"Nuclear WASHC1 interacts with multiple subunits of the MCM2-7 replicative helicase complex, associates with DNA replication origins by chromatin immunoprecipitation, and promotes loading of excess MCM complexes at origins; loss of WASHC1 sensitizes cells to hydroxyurea-induced replication stress and increases chromosomal instability, a phenotype rescued by re-expression of nuclear WASHC1.","method":"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, WASHC1 knockout and rescue, hydroxyurea treatment, chromosomal instability assay","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, PLA, ChIP, KO rescue) in a single lab establishing nuclear function","pmids":["35733063"],"is_preprint":false},{"year":2023,"finding":"Intestine-specific ablation of WASHC1 in mice impairs intestinal cholesterol absorption and alters biliary bile acid composition (reduced 12α-/non-12α-hydroxylated BA ratio), demonstrating an in vivo role for intestinal WASH complex in cholesterol uptake via endosomal receptor trafficking.","method":"Intestine-specific Washc1 knockout mouse, cholesterol absorption assay, fecal neutral sterol measurement, biliary BA analysis, gene expression analysis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with multiple metabolic and molecular readouts, single lab","pmids":["38086439"],"is_preprint":false},{"year":2025,"finding":"During murine cytomegalovirus infection, WASHC1 is recruited to the machinery driving expansion of Rab10-positive tubular membranes; WASHC1 undergoes increased ubiquitination during infection, consistent with ubiquitin-dependent rheostatic regulation of membrane tubulation in the viral assembly compartment.","method":"Immunofluorescence, Western blot with HA-ubiquitin inducible cell line, siRNA depletion, confocal imaging","journal":"Life (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative ubiquitination finding without direct mechanistic dissection of writer/eraser or functional consequence of WASHC1 ubiquitination specifically","pmids":["40868860"],"is_preprint":false},{"year":2026,"finding":"WNT2B binds via its conserved middle domain to the spectrin repeat domain of WASHC5, competitively displacing WASHC1 from the WASH complex, thereby disrupting WASHC1-mediated actin polymerization on early endosomes and impairing endosomal cargo trafficking (including ATG9A), leading to autophagy inhibition.","method":"Co-immunoprecipitation, GST pull-down, proximity ligation assay, FRAP, super-resolution SIM, WASHC1 knockout/rescue, ATG9A trafficking assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal binding assays (Co-IP, GST pull-down) and functional trafficking readouts, single lab","pmids":["42233622"],"is_preprint":false},{"year":2026,"finding":"p300-dependent histone H3K18 lactylation promotes transcriptional upregulation of WASHC1 (WASH1); WASH1 protein then binds the ubiquitin-associated domain of p62 (SQSTM1), impairing recognition and clearance of damaged mitochondria, thereby suppressing mitophagy and sustaining mitochondrial ROS accumulation.","method":"CUT&Tag, ChIP-qPCR, co-immunoprecipitation, GST pull-down, RNA sequencing, flow cytometry, genetic manipulation","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, GST pull-down) establishing transcriptional regulation and a protein-protein interaction with functional mitophagy consequence, single lab","pmids":["41740506"],"is_preprint":false}],"current_model":"WASHC1 (WASH1) is a Wiskott-Aldrich syndrome protein family member that functions as a nucleation-promoting factor activating the Arp2/3 complex to generate branched actin networks at early endosomes; it is recruited to endosomes via the cargo-selective retromer complex (VPS35/VPS29/VPS26) and, as part of the WASH regulatory complex, drives endosomal tubule formation to recycle transmembrane receptors (including LDLR, LRP1, SR-BI, TrkA) to the plasma membrane; nuclear WASHC1 additionally associates with the MCM2-7 replicative helicase to facilitate origin licensing and cell survival under replication stress; WASHC1 activity at endosomes is subject to regulation by displacement from the WASH complex (by WNT2B competing for WASHC5 binding) and by proteasome-dependent degradation (regulated by BBS1 at the centrosome), with ubiquitination providing additional rheostatic control in specialized membrane remodeling contexts."},"narrative":{"mechanistic_narrative":"WASHC1 is an actin nucleation-promoting factor that drives branched actin assembly on endosomal membranes to control cargo recycling and membrane tubulation [PMID:20923837]. It is recruited to endosomes as part of a complex including strumpellin through interaction with the cargo-selective retromer trimer VPS35/VPS29/VPS26, where it regulates endosomal tubule dynamics via the Arp2/3 actin machinery [PMID:20923837]. This activity sustains plasma-membrane recycling of lipoprotein and scavenger receptors: hepatic loss of WASHC1 lowers surface LDLR and LRP1, increases IDOL-mediated LDLR degradation, and reduces SR-BI, deranging LDL and HDL cholesterol clearance [PMID:31167970], while intestinal loss impairs cholesterol absorption and shifts biliary bile-acid composition [PMID:38086439]. The same tubulating function operates on Rab7-positive late endosomes with endophilinA proteins to retrieve TrkA and enable neurotrophin signaling [PMID:34486665], and supports Arp2/3-dependent actin generation required for asymmetric division during oocyte meiosis [PMID:24998208]. Beyond the endosome, nuclear WASHC1 binds subunits of the MCM2-7 replicative helicase, associates with replication origins, promotes loading of excess MCM complexes, and protects cells against hydroxyurea-induced replication stress and chromosomal instability [PMID:35733063]. WASHC1 function is further set by its assembly state and abundance: WNT2B competitively displaces WASHC1 from the WASH complex by binding WASHC5, disrupting endosomal actin polymerization and ATG9A trafficking to inhibit autophagy [PMID:42233622], and WASHC1 protein is also tuned by transcriptional induction through p300-dependent H3K18 lactylation, after which it binds the p62 (SQSTM1) UBA domain to suppress mitophagy and sustain mitochondrial ROS [PMID:41740506].","teleology":[{"year":2010,"claim":"Established how WASHC1 reaches endosomes and what it does there, defining it as a retromer-recruited actin nucleation-promoting factor governing endosomal tubule dynamics.","evidence":"Co-IP and endosomal localization with tubule phenotype identifying retromer (VPS35/VPS29/VPS26) and strumpellin association","pmids":["20923837"],"confidence":"Medium","gaps":["Single lab; reciprocal Co-IP but no structural model of recruitment","Did not identify which transmembrane cargoes depend on this activity"]},{"year":2014,"claim":"Extended WASHC1's actin-regulatory role to a developmental context, showing it drives Arp2/3-dependent asymmetric division in meiosis.","evidence":"Morpholino knockdown and antibody injection with time-lapse imaging and actin quantification in mouse oocytes","pmids":["24998208"],"confidence":"Medium","gaps":["Morpholino-based depletion without rescue","Link to endosomal vs cortical actin pools not dissected"]},{"year":2015,"claim":"Indicated that WASHC1 abundance is post-translationally controlled, placing it under proteasomal regulation and dependent on its complex partner strumpellin.","evidence":"Proteasome inhibitor treatment and strumpellin knockdown with Western blot in rat cortical neurons","pmids":["25987849"],"confidence":"Low","gaps":["Indirect inhibitor-based evidence without identification of E3 ligase or degron","No functional consequence of degradation defined"]},{"year":2019,"claim":"Provided in vivo proof that WASH-dependent endosomal recycling controls lipoprotein receptor surface levels and systemic cholesterol handling.","evidence":"Hepatocyte-specific Washc1 knockout mouse with surface receptor, receptor degradation, and cholesterol metabolism assays","pmids":["31167970"],"confidence":"High","gaps":["Whether WASHC1 directly contacts these receptors vs. acts through retromer not resolved","IDOL pathway link inferred from degradation readouts"]},{"year":2021,"claim":"Connected WASHC1 turnover to spatial signaling, showing centrosomal WASHC1/F-actin clearance via the proteasome is needed for immune synapse polarization.","evidence":"siRNA knockdown, proteasome inhibition, and live imaging in T cells implicating BBS1 and dynein","pmids":["34423835"],"confidence":"Medium","gaps":["Single lab; E3 ligase for WASHC1 not identified","Direct BBS1–WASHC1 contact not demonstrated"]},{"year":2021,"claim":"Showed WASHC1 tubulation operates on late endosomes to retrieve a receptor tyrosine kinase, linking it to neurotrophin signaling.","evidence":"Depletion and live imaging with endosomal tubulation assays in neurons defining cooperation with endophilinA1/A2/A3 on Rab7 endosomes","pmids":["34486665"],"confidence":"Medium","gaps":["Mechanism of endophilinA–WASHC1 cooperation unresolved","Single lab"]},{"year":2022,"claim":"Revealed a distinct nuclear function for WASHC1 in DNA replication origin licensing and replication-stress survival, separating it from its endosomal role.","evidence":"Co-IP, PLA, ChIP, knockout/rescue, and hydroxyurea/chromosomal instability assays linking WASHC1 to MCM2-7","pmids":["35733063"],"confidence":"Medium","gaps":["How nuclear WASHC1 promotes MCM loading mechanistically is unknown","Whether actin nucleation activity is involved nuclear-side unclear"]},{"year":2023,"claim":"Confirmed tissue-specific physiological importance of WASH-mediated trafficking by showing intestinal WASHC1 controls cholesterol absorption and bile-acid composition.","evidence":"Intestine-specific Washc1 knockout mouse with cholesterol absorption, fecal sterol, and biliary bile-acid analyses","pmids":["38086439"],"confidence":"Medium","gaps":["Specific intestinal cargo receptors not individually mapped","Single lab"]},{"year":2025,"claim":"Linked WASHC1 to pathogen-driven membrane remodeling and suggested ubiquitination as a rheostatic control on its tubulation activity.","evidence":"Immunofluorescence, HA-ubiquitin Western blot, and siRNA in murine cytomegalovirus infection implicating Rab10 tubules","pmids":["40868860"],"confidence":"Low","gaps":["Correlative ubiquitination without writer/eraser identification","Functional consequence of WASHC1 ubiquitination not directly tested"]},{"year":2026,"claim":"Defined a regulatory switch by which WNT2B displaces WASHC1 from the WASH complex to gate endosomal actin and ATG9A trafficking, coupling WASHC1 to autophagy.","evidence":"Co-IP, GST pull-down, PLA, FRAP, SIM, and knockout/rescue with ATG9A trafficking assays identifying competition at WASHC5","pmids":["42233622"],"confidence":"Medium","gaps":["Single lab","In vivo relevance of the WNT2B–WASHC5 competition not established"]},{"year":2026,"claim":"Showed WASHC1 expression is epigenetically inducible and that WASHC1 protein restrains mitophagy by engaging p62, linking it to mitochondrial redox control.","evidence":"CUT&Tag, ChIP-qPCR, Co-IP, GST pull-down, RNA-seq, and flow cytometry mapping p300/H3K18la induction and p62 (SQSTM1) UBA binding","pmids":["41740506"],"confidence":"Medium","gaps":["Single lab","Whether p62 binding is independent of endosomal actin function unresolved"]},{"year":null,"claim":"The molecular basis coordinating WASHC1's cytoplasmic actin/trafficking role with its nuclear replication-licensing role, and the identity of the E3 ligase(s) controlling its degradation, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No E3 ligase or degron for WASHC1 proteasomal turnover identified","How a single protein partitions between endosomal and nuclear functions is unknown","No structural model of WASHC1 within the WASH regulatory complex in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,9]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,5,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,5,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,7]}],"complexes":["WASH regulatory complex","retromer (VPS35/VPS29/VPS26)"],"partners":["VPS35","WASHC5","WNT2B","SQSTM1","MCM2-7","BBS1","NTRK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A8K0Z3","full_name":"WASH complex subunit 1","aliases":["CXYorf1-like protein on chromosome 9","Protein FAM39E","WAS protein family homolog 1"],"length_aa":465,"mass_kda":50.3,"function":"Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fission of tubules that serve as transport intermediates during endosome sorting (PubMed:19922874, PubMed:19922875, PubMed:20498093, PubMed:23452853). Involved in endocytic trafficking of EGF (By similarity). Involved in transferrin receptor recycling. Regulates the trafficking of endosomal alpha5beta1 integrin to the plasma membrane and involved in invasive cell migration (PubMed:22114305). In T-cells involved in endosome-to-membrane recycling of receptors including T-cell receptor (TCR), CD28 and ITGAL; proposed to be implicated in T cell proliferation and effector function. In dendritic cells involved in endosome-to-membrane recycling of major histocompatibility complex (MHC) class II probably involving retromer and subsequently allowing antigen sampling, loading and presentation during T-cell activation (By similarity). Involved in Arp2/3 complex-dependent actin assembly driving Salmonella typhimurium invasion independent of ruffling. Involved in the exocytosis of MMP14 leading to matrix remodeling during invasive migration and implicating late endosome-to-plasma membrane tubular connections and cooperation with the exocyst complex (PubMed:24344185). Involved in negative regulation of autophagy independently from its role in endosomal sorting by inhibiting BECN1 ubiquitination to inactivate PIK3C3/Vps34 activity (By similarity)","subcellular_location":"Early endosome membrane; Recycling endosome membrane; Late endosome; Cytoplasmic vesicle, autophagosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/A8K0Z3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WASHC1","classification":"Common Essential","n_dependent_lines":5,"n_total_lines":5,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WASHC1","total_profiled":1310},"omim":[{"mim_id":"619925","title":"WASH COMPLEX, SUBUNIT 3; WASHC3","url":"https://www.omim.org/entry/619925"},{"mim_id":"619856","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 50; ANKRD50","url":"https://www.omim.org/entry/619856"},{"mim_id":"615748","title":"WASH COMPLEX, SUBUNIT 4; WASHC4","url":"https://www.omim.org/entry/615748"},{"mim_id":"613632","title":"WASH COMPLEX, SUBUNIT 1; WASHC1","url":"https://www.omim.org/entry/613632"},{"mim_id":"610657","title":"WASH COMPLEX, SUBUNIT 5; WASHC5","url":"https://www.omim.org/entry/610657"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WASHC1"},"hgnc":{"alias_symbol":["FLJ00038"],"prev_symbol":["FAM39E","WASH1"]},"alphafold":{"accession":"A8K0Z3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A8K0Z3","model_url":"https://alphafold.ebi.ac.uk/files/AF-A8K0Z3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A8K0Z3-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WASHC1","jax_strain_url":"https://www.jax.org/strain/search?query=WASHC1"},"sequence":{"accession":"A8K0Z3","fasta_url":"https://rest.uniprot.org/uniprotkb/A8K0Z3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A8K0Z3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A8K0Z3"}},"corpus_meta":[{"pmid":"20923837","id":"PMC_20923837","title":"The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule 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EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24916641","citation_count":46,"is_preprint":false},{"pmid":"31167970","id":"PMC_31167970","title":"The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31167970","citation_count":35,"is_preprint":false},{"pmid":"24998208","id":"PMC_24998208","title":"WASH complex regulates Arp2/3 complex for actin-based polar body extrusion in mouse oocytes.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/24998208","citation_count":25,"is_preprint":false},{"pmid":"30101314","id":"PMC_30101314","title":"Investigating the genetic determination of clutch traits in laying hens.","date":"2019","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/30101314","citation_count":24,"is_preprint":false},{"pmid":"34423835","id":"PMC_34423835","title":"The Bardet-Biedl syndrome complex component BBS1 controls T cell polarity during immune synapse assembly.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34423835","citation_count":14,"is_preprint":false},{"pmid":"29549166","id":"PMC_29549166","title":"Wash exhibits context-dependent phenotypes and, along with the WASH regulatory complex, regulates Drosophila oogenesis.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29549166","citation_count":11,"is_preprint":false},{"pmid":"38464973","id":"PMC_38464973","title":"The T2T-CHM13 reference assembly uncovers essential WASH1 and GPRIN2 paralogues.","date":"2024","source":"Bioinformatics advances","url":"https://pubmed.ncbi.nlm.nih.gov/38464973","citation_count":8,"is_preprint":false},{"pmid":"32607507","id":"PMC_32607507","title":"SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients.","date":"2020","source":"bioRxiv : the preprint 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Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/38086439","citation_count":1,"is_preprint":false},{"pmid":"37398104","id":"PMC_37398104","title":"Lost in the WASH. The functional human WASH complex 1 gene is on chromosome 20.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37398104","citation_count":1,"is_preprint":false},{"pmid":"37444464","id":"PMC_37444464","title":"Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/37444464","citation_count":1,"is_preprint":false},{"pmid":"42233622","id":"PMC_42233622","title":"WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway.","date":"2026","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/42233622","citation_count":0,"is_preprint":false},{"pmid":"40868860","id":"PMC_40868860","title":"Ubiquitination Regulates Reorganization of the Membrane System During Cytomegalovirus Infection.","date":"2025","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40868860","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14918,"output_tokens":2764,"usd":0.043107,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10118,"output_tokens":3922,"usd":0.07432,"stage2_stop_reason":"end_turn"},"total_usd":0.117427,"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\": 2010,\n      \"finding\": \"WASH1 (WASHC1) is recruited to endosomal membranes as part of a protein complex (including strumpellin) via interactions with the cargo-selective retromer complex (VPS35/VPS29/VPS26 trimer), where it functions as an actin nucleation-promoting factor to regulate endosomal tubule dynamics.\",\n      \"method\": \"Co-immunoprecipitation, identification of retromer-interacting proteins, endosomal localization studies\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and endosomal localization with functional tubule phenotype, single lab\",\n      \"pmids\": [\"20923837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WASH1 (WASHC1) regulates Arp2/3 complex activity to generate actin filaments required for polar body extrusion and asymmetric division during mouse oocyte meiosis; depletion of WASH1 by morpholino injection reduced polar body extrusion, caused symmetric division, and decreased Arp2/3 complex expression.\",\n      \"method\": \"Morpholino knockdown, antibody injection, time-lapse microscopy, actin filament quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype (polar body extrusion, spindle migration) and downstream Arp2/3 measurement, single lab\",\n      \"pmids\": [\"24998208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Proteasomal inhibition stabilizes WASH1 (WASHC1) protein levels, indicating WASH1 is subject to proteasome-dependent degradation; knockdown of strumpellin in cortical neurons reduced endogenous WASH1 protein.\",\n      \"method\": \"Proteasomal inhibitor treatment, Western blot, strumpellin knockdown in rat cortical neurons\",\n      \"journal\": \"Journal of experimental neuroscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect evidence from inhibitor treatment and knockdown without direct mechanistic dissection of the degradation pathway\",\n      \"pmids\": [\"25987849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hepatic ablation of WASHC1 reduces surface levels of LDLR and LRP1 on hepatocytes, increases LDLR proteolysis by IDOL (inducible degrader of LDLR), and reduces scavenger receptor class B type I surface levels, demonstrating that the WASH complex regulates endosomal recycling of these receptors to the plasma membrane to control LDL and HDL cholesterol clearance.\",\n      \"method\": \"Hepatocyte-specific Washc1 knockout mouse, surface receptor quantification, cholesterol metabolism assays, receptor degradation assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with multiple orthogonal receptor trafficking and metabolic readouts, clearly defined molecular mechanism\",\n      \"pmids\": [\"31167970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BBS1 promotes clearance of WASH1 (WASHC1) and centrosomal F-actin via the proteasome, coupling the 19S proteasome regulatory subunit to dynein for transport to the centrosome; this centrosomal WASH1 clearance is required for centrosome polarization toward the immune synapse in T cells.\",\n      \"method\": \"siRNA knockdown, proteasome inhibitor treatment, immunofluorescence, live imaging in T cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and mechanistic pathway placement, single lab\",\n      \"pmids\": [\"34423835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WASH1 (WASHC1), together with endophilinA1/A2/A3, is involved in the formation of tubular microdomains on Rab7-positive late endosomes that retrieve TrkA (NTRK1) receptor, enabling downstream neurotrophin signaling.\",\n      \"method\": \"Knockdown/depletion, live imaging, endosomal tubulation assay in neuronal cultures\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific tubulation and signaling phenotype, single lab\",\n      \"pmids\": [\"34486665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nuclear WASHC1 interacts with multiple subunits of the MCM2-7 replicative helicase complex, associates with DNA replication origins by chromatin immunoprecipitation, and promotes loading of excess MCM complexes at origins; loss of WASHC1 sensitizes cells to hydroxyurea-induced replication stress and increases chromosomal instability, a phenotype rescued by re-expression of nuclear WASHC1.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, WASHC1 knockout and rescue, hydroxyurea treatment, chromosomal instability assay\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, PLA, ChIP, KO rescue) in a single lab establishing nuclear function\",\n      \"pmids\": [\"35733063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestine-specific ablation of WASHC1 in mice impairs intestinal cholesterol absorption and alters biliary bile acid composition (reduced 12α-/non-12α-hydroxylated BA ratio), demonstrating an in vivo role for intestinal WASH complex in cholesterol uptake via endosomal receptor trafficking.\",\n      \"method\": \"Intestine-specific Washc1 knockout mouse, cholesterol absorption assay, fecal neutral sterol measurement, biliary BA analysis, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with multiple metabolic and molecular readouts, single lab\",\n      \"pmids\": [\"38086439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During murine cytomegalovirus infection, WASHC1 is recruited to the machinery driving expansion of Rab10-positive tubular membranes; WASHC1 undergoes increased ubiquitination during infection, consistent with ubiquitin-dependent rheostatic regulation of membrane tubulation in the viral assembly compartment.\",\n      \"method\": \"Immunofluorescence, Western blot with HA-ubiquitin inducible cell line, siRNA depletion, confocal imaging\",\n      \"journal\": \"Life (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative ubiquitination finding without direct mechanistic dissection of writer/eraser or functional consequence of WASHC1 ubiquitination specifically\",\n      \"pmids\": [\"40868860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"WNT2B binds via its conserved middle domain to the spectrin repeat domain of WASHC5, competitively displacing WASHC1 from the WASH complex, thereby disrupting WASHC1-mediated actin polymerization on early endosomes and impairing endosomal cargo trafficking (including ATG9A), leading to autophagy inhibition.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, proximity ligation assay, FRAP, super-resolution SIM, WASHC1 knockout/rescue, ATG9A trafficking assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal binding assays (Co-IP, GST pull-down) and functional trafficking readouts, single lab\",\n      \"pmids\": [\"42233622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"p300-dependent histone H3K18 lactylation promotes transcriptional upregulation of WASHC1 (WASH1); WASH1 protein then binds the ubiquitin-associated domain of p62 (SQSTM1), impairing recognition and clearance of damaged mitochondria, thereby suppressing mitophagy and sustaining mitochondrial ROS accumulation.\",\n      \"method\": \"CUT&Tag, ChIP-qPCR, co-immunoprecipitation, GST pull-down, RNA sequencing, flow cytometry, genetic manipulation\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, GST pull-down) establishing transcriptional regulation and a protein-protein interaction with functional mitophagy consequence, single lab\",\n      \"pmids\": [\"41740506\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WASHC1 (WASH1) is a Wiskott-Aldrich syndrome protein family member that functions as a nucleation-promoting factor activating the Arp2/3 complex to generate branched actin networks at early endosomes; it is recruited to endosomes via the cargo-selective retromer complex (VPS35/VPS29/VPS26) and, as part of the WASH regulatory complex, drives endosomal tubule formation to recycle transmembrane receptors (including LDLR, LRP1, SR-BI, TrkA) to the plasma membrane; nuclear WASHC1 additionally associates with the MCM2-7 replicative helicase to facilitate origin licensing and cell survival under replication stress; WASHC1 activity at endosomes is subject to regulation by displacement from the WASH complex (by WNT2B competing for WASHC5 binding) and by proteasome-dependent degradation (regulated by BBS1 at the centrosome), with ubiquitination providing additional rheostatic control in specialized membrane remodeling contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WASHC1 is an actin nucleation-promoting factor that drives branched actin assembly on endosomal membranes to control cargo recycling and membrane tubulation [#0]. It is recruited to endosomes as part of a complex including strumpellin through interaction with the cargo-selective retromer trimer VPS35/VPS29/VPS26, where it regulates endosomal tubule dynamics via the Arp2/3 actin machinery [#0]. This activity sustains plasma-membrane recycling of lipoprotein and scavenger receptors: hepatic loss of WASHC1 lowers surface LDLR and LRP1, increases IDOL-mediated LDLR degradation, and reduces SR-BI, deranging LDL and HDL cholesterol clearance [#3], while intestinal loss impairs cholesterol absorption and shifts biliary bile-acid composition [#7]. The same tubulating function operates on Rab7-positive late endosomes with endophilinA proteins to retrieve TrkA and enable neurotrophin signaling [#5], and supports Arp2/3-dependent actin generation required for asymmetric division during oocyte meiosis [#1]. Beyond the endosome, nuclear WASHC1 binds subunits of the MCM2-7 replicative helicase, associates with replication origins, promotes loading of excess MCM complexes, and protects cells against hydroxyurea-induced replication stress and chromosomal instability [#6]. WASHC1 function is further set by its assembly state and abundance: WNT2B competitively displaces WASHC1 from the WASH complex by binding WASHC5, disrupting endosomal actin polymerization and ATG9A trafficking to inhibit autophagy [#9], and WASHC1 protein is also tuned by transcriptional induction through p300-dependent H3K18 lactylation, after which it binds the p62 (SQSTM1) UBA domain to suppress mitophagy and sustain mitochondrial ROS [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established how WASHC1 reaches endosomes and what it does there, defining it as a retromer-recruited actin nucleation-promoting factor governing endosomal tubule dynamics.\",\n      \"evidence\": \"Co-IP and endosomal localization with tubule phenotype identifying retromer (VPS35/VPS29/VPS26) and strumpellin association\",\n      \"pmids\": [\"20923837\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; reciprocal Co-IP but no structural model of recruitment\", \"Did not identify which transmembrane cargoes depend on this activity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended WASHC1's actin-regulatory role to a developmental context, showing it drives Arp2/3-dependent asymmetric division in meiosis.\",\n      \"evidence\": \"Morpholino knockdown and antibody injection with time-lapse imaging and actin quantification in mouse oocytes\",\n      \"pmids\": [\"24998208\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Morpholino-based depletion without rescue\", \"Link to endosomal vs cortical actin pools not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Indicated that WASHC1 abundance is post-translationally controlled, placing it under proteasomal regulation and dependent on its complex partner strumpellin.\",\n      \"evidence\": \"Proteasome inhibitor treatment and strumpellin knockdown with Western blot in rat cortical neurons\",\n      \"pmids\": [\"25987849\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Indirect inhibitor-based evidence without identification of E3 ligase or degron\", \"No functional consequence of degradation defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided in vivo proof that WASH-dependent endosomal recycling controls lipoprotein receptor surface levels and systemic cholesterol handling.\",\n      \"evidence\": \"Hepatocyte-specific Washc1 knockout mouse with surface receptor, receptor degradation, and cholesterol metabolism assays\",\n      \"pmids\": [\"31167970\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether WASHC1 directly contacts these receptors vs. acts through retromer not resolved\", \"IDOL pathway link inferred from degradation readouts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected WASHC1 turnover to spatial signaling, showing centrosomal WASHC1/F-actin clearance via the proteasome is needed for immune synapse polarization.\",\n      \"evidence\": \"siRNA knockdown, proteasome inhibition, and live imaging in T cells implicating BBS1 and dynein\",\n      \"pmids\": [\"34423835\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab; E3 ligase for WASHC1 not identified\", \"Direct BBS1–WASHC1 contact not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed WASHC1 tubulation operates on late endosomes to retrieve a receptor tyrosine kinase, linking it to neurotrophin signaling.\",\n      \"evidence\": \"Depletion and live imaging with endosomal tubulation assays in neurons defining cooperation with endophilinA1/A2/A3 on Rab7 endosomes\",\n      \"pmids\": [\"34486665\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of endophilinA–WASHC1 cooperation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a distinct nuclear function for WASHC1 in DNA replication origin licensing and replication-stress survival, separating it from its endosomal role.\",\n      \"evidence\": \"Co-IP, PLA, ChIP, knockout/rescue, and hydroxyurea/chromosomal instability assays linking WASHC1 to MCM2-7\",\n      \"pmids\": [\"35733063\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How nuclear WASHC1 promotes MCM loading mechanistically is unknown\", \"Whether actin nucleation activity is involved nuclear-side unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed tissue-specific physiological importance of WASH-mediated trafficking by showing intestinal WASHC1 controls cholesterol absorption and bile-acid composition.\",\n      \"evidence\": \"Intestine-specific Washc1 knockout mouse with cholesterol absorption, fecal sterol, and biliary bile-acid analyses\",\n      \"pmids\": [\"38086439\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Specific intestinal cargo receptors not individually mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked WASHC1 to pathogen-driven membrane remodeling and suggested ubiquitination as a rheostatic control on its tubulation activity.\",\n      \"evidence\": \"Immunofluorescence, HA-ubiquitin Western blot, and siRNA in murine cytomegalovirus infection implicating Rab10 tubules\",\n      \"pmids\": [\"40868860\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Correlative ubiquitination without writer/eraser identification\", \"Functional consequence of WASHC1 ubiquitination not directly tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a regulatory switch by which WNT2B displaces WASHC1 from the WASH complex to gate endosomal actin and ATG9A trafficking, coupling WASHC1 to autophagy.\",\n      \"evidence\": \"Co-IP, GST pull-down, PLA, FRAP, SIM, and knockout/rescue with ATG9A trafficking assays identifying competition at WASHC5\",\n      \"pmids\": [\"42233622\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab\", \"In vivo relevance of the WNT2B–WASHC5 competition not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed WASHC1 expression is epigenetically inducible and that WASHC1 protein restrains mitophagy by engaging p62, linking it to mitochondrial redox control.\",\n      \"evidence\": \"CUT&Tag, ChIP-qPCR, Co-IP, GST pull-down, RNA-seq, and flow cytometry mapping p300/H3K18la induction and p62 (SQSTM1) UBA binding\",\n      \"pmids\": [\"41740506\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab\", \"Whether p62 binding is independent of endosomal actin function unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis coordinating WASHC1's cytoplasmic actin/trafficking role with its nuclear replication-licensing role, and the identity of the E3 ligase(s) controlling its degradation, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No E3 ligase or degron for WASHC1 proteasomal turnover identified\", \"How a single protein partitions between endosomal and nuclear functions is unknown\", \"No structural model of WASHC1 within the WASH regulatory complex in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 5, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"complexes\": [\"WASH regulatory complex\", \"retromer (VPS35/VPS29/VPS26)\"],\n    \"partners\": [\"VPS35\", \"WASHC5\", \"WNT2B\", \"SQSTM1\", \"MCM2-7\", \"BBS1\", \"NTRK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}