Affinage

WASHC1

WASH complex subunit 1 · UniProt A8K0Z3

Length
465 aa
Mass
50.3 kDa
Annotated
2026-06-11
24 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 Medium

    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

    PMID:20923837

    Open questions at the time
    • Single lab; reciprocal Co-IP but no structural model of recruitment
    • Did not identify which transmembrane cargoes depend on this activity
  2. 2014 Medium

    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

    PMID:24998208

    Open questions at the time
    • Morpholino-based depletion without rescue
    • Link to endosomal vs cortical actin pools not dissected
  3. 2015 Low

    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

    PMID:25987849

    Open questions at the time
    • Indirect inhibitor-based evidence without identification of E3 ligase or degron
    • No functional consequence of degradation defined
  4. 2019 High

    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

    PMID:31167970

    Open questions at the time
    • Whether WASHC1 directly contacts these receptors vs. acts through retromer not resolved
    • IDOL pathway link inferred from degradation readouts
  5. 2021 Medium

    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

    PMID:34423835

    Open questions at the time
    • Single lab; E3 ligase for WASHC1 not identified
    • Direct BBS1–WASHC1 contact not demonstrated
  6. 2021 Medium

    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

    PMID:34486665

    Open questions at the time
    • Mechanism of endophilinA–WASHC1 cooperation unresolved
    • Single lab
  7. 2022 Medium

    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

    PMID:35733063

    Open questions at the time
    • How nuclear WASHC1 promotes MCM loading mechanistically is unknown
    • Whether actin nucleation activity is involved nuclear-side unclear
  8. 2023 Medium

    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

    PMID:38086439

    Open questions at the time
    • Specific intestinal cargo receptors not individually mapped
    • Single lab
  9. 2025 Low

    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

    PMID:40868860

    Open questions at the time
    • Correlative ubiquitination without writer/eraser identification
    • Functional consequence of WASHC1 ubiquitination not directly tested
  10. 2026 Medium

    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

    PMID:42233622

    Open questions at the time
    • Single lab
    • In vivo relevance of the WNT2B–WASHC5 competition not established
  11. 2026 Medium

    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

    PMID:41740506

    Open questions at the time
    • Single lab
    • Whether p62 binding is independent of endosomal actin function unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005768 endosome 3 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1430728 Metabolism 2 R-HSA-9612973 Autophagy 2 R-HSA-69306 DNA Replication 1
Partners
BBS1MCM2-7NTRK1SQSTM1VPS35WASHC5WNT2B
Complex memberships
WASH regulatory complexretromer (VPS35/VPS29/VPS26)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Co-immunoprecipitation, identification of retromer-interacting proteins, endosomal localization studies Journal of cell science Medium 20923837
2014 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. Morpholino knockdown, antibody injection, time-lapse microscopy, actin filament quantification Scientific reports Medium 24998208
2017 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. Proteasomal inhibitor treatment, Western blot, strumpellin knockdown in rat cortical neurons Journal of experimental neuroscience Low 25987849
2019 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. Hepatocyte-specific Washc1 knockout mouse, surface receptor quantification, cholesterol metabolism assays, receptor degradation assays JCI insight High 31167970
2021 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. siRNA knockdown, proteasome inhibitor treatment, immunofluorescence, live imaging in T cells Journal of cell science Medium 34423835
2021 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. Knockdown/depletion, live imaging, endosomal tubulation assay in neuronal cultures Journal of cell science Medium 34486665
2022 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. Co-immunoprecipitation, proximity ligation assay, chromatin immunoprecipitation, WASHC1 knockout and rescue, hydroxyurea treatment, chromosomal instability assay Molecular biology reports Medium 35733063
2023 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. Intestine-specific Washc1 knockout mouse, cholesterol absorption assay, fecal neutral sterol measurement, biliary BA analysis, gene expression analysis Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 38086439
2025 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. Immunofluorescence, Western blot with HA-ubiquitin inducible cell line, siRNA depletion, confocal imaging Life (Basel, Switzerland) Low 40868860
2026 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. Co-immunoprecipitation, GST pull-down, proximity ligation assay, FRAP, super-resolution SIM, WASHC1 knockout/rescue, ATG9A trafficking assay Autophagy Medium 42233622
2026 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. CUT&Tag, ChIP-qPCR, co-immunoprecipitation, GST pull-down, RNA sequencing, flow cytometry, genetic manipulation Redox biology Medium 41740506

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. Journal of cell science 204 20923837
2017 Cellular functions of WASP family proteins at a glance. Journal of cell science 163 28646090
2020 SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients. The Journal of general virology 112 32821033
2014 Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome. European journal of human genetics : EJHG 46 24916641
2019 The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance. JCI insight 35 31167970
2014 WASH complex regulates Arp2/3 complex for actin-based polar body extrusion in mouse oocytes. Scientific reports 25 24998208
2019 Investigating the genetic determination of clutch traits in laying hens. Poultry science 24 30101314
2021 The Bardet-Biedl syndrome complex component BBS1 controls T cell polarity during immune synapse assembly. Journal of cell science 14 34423835
2018 Wash exhibits context-dependent phenotypes and, along with the WASH regulatory complex, regulates Drosophila oogenesis. Journal of cell science 11 29549166
2024 The T2T-CHM13 reference assembly uncovers essential WASH1 and GPRIN2 paralogues. Bioinformatics advances 8 38464973
2020 SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected, hospitalized COVID-19 patients. bioRxiv : the preprint server for biology 8 32607507
2020 Genome-scale CRISPR screening for potential targets of ginsenoside compound K. Cell death & disease 7 31959745
2021 Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth disease 2B. Journal of cell science 6 34486665
2018 Homologue-specific chromosome sequencing characterizes translocation junctions and permits allelic assignment. DNA research : an international journal for rapid publication of reports on genes and genomes 6 29518182
2017 Genetic analysis of VCP and WASH complex genes in a German cohort of sporadic ALS-FTD patients. Neurobiology of aging 6 28551275
2024 Deciphering the toxicity of polyhexamethylene guanidine phosphate in lung carcinogenesis: Mutational profiles and molecular mechanisms. Chemosphere 4 39577803
2015 Strumpellin and Spartin, Hereditary Spastic Paraplegia Proteins, are Binding Partners. Journal of experimental neuroscience 3 25987849
2022 WASHC1 interacts with MCM2-7 complex to promote cell survival under replication stress. Molecular biology reports 2 35733063
2026 p300-mediated histone H3K18 lactylation promotes mitochondrial ROS accumulation via mitophagy inhibition to potentiate dopamine agonists efficacy in prolactinomas. Redox biology 1 41740506
2023 Lost in the WASH. The functional human WASH complex 1 gene is on chromosome 20. bioRxiv : the preprint server for biology 1 37398104
2023 Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study. Cancers 1 37444464
2023 Changes in bile acid composition are correlated with reduced intestinal cholesterol uptake in intestine-specific WASH-deficient mice. Biochimica et biophysica acta. Molecular and cell biology of lipids 1 38086439
2026 WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway. Autophagy 0 42233622
2025 Ubiquitination Regulates Reorganization of the Membrane System During Cytomegalovirus Infection. Life (Basel, Switzerland) 0 40868860

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