Affinage

WAC

WW domain-containing adapter protein with coiled-coil · UniProt Q9BTA9

Length
647 aa
Mass
70.7 kDa
Annotated
2026-04-28
44 papers in source corpus 14 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WAC is a WW domain- and coiled-coil-containing adaptor protein that functions as a central scaffold linking chromatin modification, autophagy, cell-cycle progression, and nutrient signaling. Its best-characterized role is promoting histone H2B monoubiquitination by binding the RNF20/RNF40 E3 ligase complex through its coiled-coil domain and recruiting it to RNA polymerase II at active transcription sites via its WW domain, a function critical for transcription-coupled checkpoint activation, plasma cell differentiation, and histone mark crosstalk with H3K27me3 through regulation of KDM6B nuclear entry (PMID:21329877, PMID:37171241, PMID:40893665, PMID:41533567). WAC also regulates starvation-induced autophagy by competing with GM130 for GABARAP binding at the Golgi, thereby enabling delivery of centrosomal GABARAP to the phagophore to activate ULK kinase, and separately promotes mitophagy by protecting PINK1 from ubiquitination-dependent degradation (PMID:26687599, PMID:39555688). Additionally, WAC facilitates timely mitotic entry by serving as a Cdk1-phosphorylated scaffold that bridges Aurora A and Plk1, participates in p97/p47-mediated Golgi membrane fusion by binding and activating the deubiquitinase VCIP135, and associates with mTOR-mLST8/R2TP/TELO2 complexes in a nutrient-responsive manner to modulate mTORC1 activity (PMID:30021153, PMID:21811234, PMID:40653822).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Initial identification of WAC as a novel WW domain-containing adaptor established its domain architecture and suggested a connection to nuclear RNA processing through colocalization with splicing factor SC35.

    Evidence Immunofluorescence and domain analysis in cultured cells

    PMID:11827461

    Open questions at the time
    • Colocalization with SC35 shown by single method without functional consequence demonstrated
    • No interacting partners identified
    • Tyrosine phosphorylation significance unknown
  2. 2011 High

    The discovery that WAC bridges RNF20/RNF40 to RNA polymerase II via distinct domains to promote H2B ubiquitination established WAC's primary molecular function as a transcription-coupled chromatin modification scaffold, and linked this activity to genotoxic stress checkpoint activation.

    Evidence Affinity purification, Co-IP, domain mutagenesis, siRNA knockdown, H2B ubiquitination and checkpoint assays in human cells

    PMID:21329877

    Open questions at the time
    • Structural basis of WAC-RNF20/40 interaction not resolved at atomic level
    • In vivo physiological relevance in organism not tested
  3. 2011 High

    Parallel work revealed a second function for WAC at the Golgi: direct binding and activation of the deubiquitinase VCIP135 for p97/p47-dependent Golgi membrane fusion, establishing WAC as a bifunctional nuclear-Golgi protein.

    Evidence Co-IP, in vitro Golgi reformation assay, DUB activity assay, siRNA knockdown

    PMID:21811234

    Open questions at the time
    • How WAC partitions between nuclear and Golgi functions is unclear
    • Ubiquitin substrates of VCIP135 at the Golgi not identified
  4. 2012 High

    A genome-wide siRNA screen identified WAC as required for starvation-induced autophagosome formation, opening a third functional axis beyond chromatin and Golgi membrane dynamics.

    Evidence Genome-wide siRNA screen with GFP-LC3 reporter validation

    PMID:22354037

    Open questions at the time
    • Molecular mechanism connecting WAC to autophagy not yet defined
    • Potential indirect effects through H2B ubiquitination not excluded
  5. 2015 High

    The autophagy mechanism was resolved: WAC is tethered to the Golgi by GM130 and competes with GM130 for GABARAP binding, enabling starvation-triggered release of centrosomal GABARAP to phagophores where it activates ULK kinase.

    Evidence Co-IP, pulldown, live-cell imaging, subcellular fractionation, ULK kinase activation assay

    PMID:26687599

    Open questions at the time
    • Signal that switches WAC from GM130-bound to GABARAP-releasing state not identified
    • Whether WAC regulation of GABARAP is tissue-specific is unknown
  6. 2018 High

    WAC was shown to promote mitotic entry by acting as a Cdk1-phosphorylated scaffold that recruits Plk1 via its polo-box domain and enhances Plk1 phosphorylation by Aurora A, revealing a cell-cycle regulatory function.

    Evidence In vitro kinase assays, Co-IP, mutagenesis with rescue experiments, mitotic entry assays

    PMID:30021153

    Open questions at the time
    • Whether WAC's mitotic role is coordinated with its chromatin or autophagy functions is unknown
    • Structural details of the WAC-Plk1-AurkA ternary complex not resolved
  7. 2023 High

    Conditional B cell-specific Wac knockout demonstrated that WAC-dependent H2B ubiquitination is essential in vivo for plasma cell differentiation and antibody responses, while germinal center formation is spared.

    Evidence Conditional knockout mouse model, flow cytometry, antibody response assays, ubH2B western blotting

    PMID:37171241

    Open questions at the time
    • Transcriptional targets downstream of WAC-dependent ubH2B in plasma cells not identified
    • Whether other H2B ubiquitination-independent WAC functions contribute to the B cell phenotype is untested
  8. 2023 Medium

    Characterization of WAC protein expression in developing mouse brain showed stage-dependent localization from perinuclear (embryonic) to nuclear (postnatal) in cortical neurons, with a nuclear localization domain identified by deletion analysis.

    Evidence Immunohistochemistry, immunofluorescence, domain deletion constructs in neurons

    PMID:37106788 PMID:37402055

    Open questions at the time
    • Functional consequence of developmental relocalization not demonstrated
    • Domain deletion studies performed only in GABAergic neurons
    • No loss-of-function neuronal phenotype directly shown
  9. 2024 Medium

    WAC was found to protect PINK1 from ubiquitination-dependent degradation by binding its transmembrane domain and blocking K137 ubiquitination, thereby activating mitophagy to promote MSC osteogenesis.

    Evidence Co-IP, ubiquitination assay with K137 mutagenesis, in vitro and in vivo osteogenesis assays

    PMID:39555688

    Open questions at the time
    • Single-lab finding not independently replicated
    • Whether WAC-PINK1 interaction occurs broadly or is specific to MSC context is unclear
    • E3 ligase targeting K137 not identified
  10. 2025 Medium

    Direct binding assays with purified proteins established that WAC interacts with mTOR-mLST8, R2TP, and TELO2 in a nutrient-responsive manner, with associations strengthened during glucose/glutamine deprivation and weakened upon refeeding, linking WAC to mTORC1 regulation.

    Evidence Purified protein binding assays, Co-IP under nutrient stress, proteomics

    PMID:40653822

    Open questions at the time
    • Single study; independent replication needed
    • Functional consequence of WAC on mTORC1 signaling output not directly demonstrated
    • Relationship to WAC's autophagy function via GABARAP/ULK pathway not resolved
  11. 2025 Medium

    Cartilage-specific WAC knockout revealed that WAC-dependent H2BK120ub1 regulates H3K27me3 levels by controlling nuclear entry of the demethylase KDM6B, establishing WAC as a histone mark crosstalk regulator with consequences for inflammatory cartilage degradation.

    Evidence Conditional knockout mice, ChIP, western blotting, KDM6B nuclear entry assays, arthritis mouse models

    PMID:40893665

    Open questions at the time
    • Mechanism by which H2BK120ub1 controls KDM6B nuclear entry not molecularly defined
    • Single-lab finding
    • Whether this crosstalk operates in other tissues unknown
  12. 2026 High

    Crystal structure of the yeast Bre1-Lge1 complex and AlphaFold-predicted structure of human RNF20/RNF40-WAC resolved the interaction interfaces and identified electrostatic contacts critical for binding specificity and H2B ubiquitination, providing the first structural framework for this complex.

    Evidence X-ray crystallography of yeast orthologs, AlphaFold prediction for human complex, structure-guided mutagenesis with in vitro and in vivo validation

    PMID:41533567

    Open questions at the time
    • Human complex structure predicted rather than experimentally determined
    • No structure of WAC WW domain bound to RNA Pol II CTD
    • Structural basis of WAC's non-chromatin functions unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WAC coordinates its multiple scaffold functions—chromatin modification, autophagy, mitotic entry, Golgi membrane fusion, mTORC1 signaling, and mitophagy—in a cell-state-dependent manner remains an open question, as does the upstream regulatory logic that partitions WAC among these pathways.
  • No integrative study examining how WAC's multiple functions are coordinated or mutually exclusive
  • Full post-translational modification map of WAC not established
  • No disease-causative mutations in WAC identified through human genetic studies in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2
Pathway
R-HSA-4839726 Chromatin organization 6 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-9612973 Autophagy 2 R-HSA-162582 Signal Transduction 1 R-HSA-1640170 Cell Cycle 1
Partners
GABARAPGM130PINK1PLK1RNF20RNF40TELO2VCIP135
Complex memberships
RNF20/RNF40/WAC E3 ligase complexmTORC1-R2TP-TTT complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 WAC was identified as a functional partner of RNF20/40 through protein affinity purification. WAC interacts with RNF20/40 via its C-terminal coiled-coil region and promotes RNF20/40's E3 ligase activity for histone H2B ubiquitination. The N-terminal WW domain of WAC recognizes RNA polymerase II, enabling WAC to target RNF20/40 to associate with the RNA polymerase II complex at active transcription sites. Protein affinity purification, Co-IP, domain mutagenesis, siRNA knockdown, H2B ubiquitination assay Molecular cell High 21329877
2011 WAC-dependent H2B ubiquitination and transcription regulation is important for cell-cycle checkpoint activation in response to genotoxic stress, as depletion of WAC abolished H2B ubiquitination and compromised checkpoint activation. siRNA knockdown, genotoxic stress assays, H2B ubiquitination assay Molecular cell High 21329877
2011 WAC localizes to the Golgi and nucleus and was identified as a VCIP135-binding protein. WAC directly binds VCIP135 and increases its deubiquitinating activity, and WAC is required for p97/p47-mediated Golgi membrane fusion (but not p97/p37-mediated reassembly or ER membrane fusion). Co-IP, siRNA knockdown, in vitro Golgi reformation assay, deubiquitinase activity assay The EMBO journal High 21811234
2012 WAC is required for starvation-induced autophagosome formation, identified in a genome-wide siRNA screen; WAC also acts as a potential negative regulator of the ubiquitin-proteasome system. Genome-wide siRNA screen, GFP-LC3 autophagosome marker assay, siRNA knockdown validation The EMBO journal High 22354037
2015 WAC is bound to the Golgi by GM130 (a direct interaction required for autophagy). WAC and GM130 interact with the Atg8 homolog GABARAP and regulate its subcellular localization: GABARAP resides on the pericentriolar matrix, and WAC suppresses GM130 binding to GABARAP, enabling starvation-induced delivery of centrosomal GABARAP to the phagophore to activate ULK kinase. Co-IP, pulldown, siRNA knockdown, live-cell imaging, subcellular fractionation, ULK kinase activation assay Molecular cell High 26687599
2002 WAC was identified as a novel WW domain-containing adaptor protein that colocalizes with splicing factor SC35 (a marker for pre-mRNA splicing machinery) and exists mainly in a tyrosine-phosphorylated form in cells. Immunofluorescence, domain analysis, phosphorylation analysis Genomics Medium 11827461
2018 WAC promotes Polo-like kinase 1 (Plk1) activation for timely mitotic entry: Cdk1 phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. WAC also binds Aurora A kinase (AurkA) and can enhance Plk1 phosphorylation by AurkA in vitro. Knockdown of WAC compromises Plk1 activity and delays mitotic entry, rescued by wild-type but not Plk1-binding-deficient WAC. Co-IP, in vitro kinase assay, mutagenesis, siRNA knockdown with rescue experiment, mitotic entry assay Cell reports High 30021153
2017 WAC functions as part of the RNF20/RNF40/WAC E3 ligase complex for H2B ubiquitination in leukemia cells; knockdown of WAC phenocopied loss of H2B ubiquitination and induced cell death in MLL-rearranged ALL. siRNA knockdown, H2B ubiquitination assay, cell viability assay Leukemia Medium 28690313
2023 B cell-specific Wac knockout mice show severely compromised T cell-dependent and -independent antibody responses, with drastically reduced plasma cell differentiation but intact germinal center B cell responses, linked to significant reduction in global H2B ubiquitination (ubH2B) in Wac-deficient B cells. Conditional B cell-specific knockout mouse model, antibody response assays, ubH2B western blotting, flow cytometry FEBS letters High 37171241
2024 WAC interacts with the transmembrane (TM) domains of PINK1 and prevents ubiquitination at the K137 site of PINK1, protecting PINK1 from ubiquitination-dependent degradation and thereby activating mitophagy to promote MSC osteogenesis. Co-IP, ubiquitination assay, mutagenesis (K137 site), in vitro and in vivo osteogenesis assays Advanced science Medium 39555688
2025 WAC directly binds mTOR-mLST8, R2TP, and TELO2 (but not TTI1 and TTI2) using purified proteins. In cells, WAC is part of complexes containing mTORC1, R2TP, and TTT components, and WAC and TELO2 strongly associate with mTOR under glucose and glutamine deprivation, with these interactions weakened upon nutrient refeeding, correlating with mTORC1 activity changes. Purified protein binding assays, Co-IP in cells under nutrient stress, transcriptomics, proteomics FEBS open bio Medium 40653822
2026 Crystal structure of the yeast Bre1-Lge1 complex and AlphaFold-predicted structure of human RNF20/RNF40-WAC, combined with in vitro and in vivo experiments, revealed extensive interaction interfaces and identified key electrostatic interactions critical for binding specificity and H2B ubiquitination activity. X-ray crystallography (Bre1-Lge1), AlphaFold structure prediction (RNF20/RNF40-WAC), mutagenesis, in vitro ubiquitination assay, in vivo functional assays Nucleic acids research High 41533567
2025 WAC regulates H2BK120ub1 and influences H3K27me3 levels in chondrocytes by regulating nuclear entry of the H3K27 demethylase KDM6B, acting as a key crosstalk factor between H2BK120ub1 and H3K27me3 to control inflammatory mediator secretion and cartilage degradation. Cartilage-specific WAC knockout mice, H2BK120ub1 and H3K27me3 ChIP/western blotting, KDM6B nuclear entry assays, CIA and CIOA mouse models Acta pharmaceutica sinica. B Medium 40893665
2023 WAC protein is expressed in a developmental stage-dependent manner in mouse brain and localizes predominantly to the perinuclear region of cortical neurons embryonically, then becomes enriched in the nucleus after birth; WAC is also present in axons and dendrites of cultured hippocampal neurons in a time-dependent manner. Anti-WAC antibody generation, western blotting, immunohistochemistry, immunofluorescence of primary cultured neurons Medical molecular morphology Medium 37402055
2023 A nuclear localization domain in WAC impacts the cellular distribution of the protein in cortical GABAergic neurons, as shown by deletion analysis of human protein domains. Domain deletion constructs, cellular distribution assay in GABAergic neurons Biology Medium 37106788

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 WAC, a functional partner of RNF20/40, regulates histone H2B ubiquitination and gene transcription. Molecular cell 132 21329877
2015 Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130. Molecular cell 117 26687599
2012 Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. The EMBO journal 101 22354037
2009 Wac: a new Augmin subunit required for chromosome alignment but not for acentrosomal microtubule assembly in female meiosis. The Journal of cell biology 59 19289792
2002 Binding of Acf1 to DNA involves a WAC motif and is important for ACF-mediated chromatin assembly. Molecular and cellular biology 52 12192034
2017 The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. Leukemia 48 28690313
2015 WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome. Journal of medical genetics 48 26264232
1994 Fibritin encoded by bacteriophage T4 gene wac has a parallel triple-stranded alpha-helical coiled-coil structure. Journal of molecular biology 43 7932704
2023 Small extracellular vesicles delivering lncRNA WAC-AS1 aggravate renal allograft ischemia‒reperfusion injury by inducing ferroptosis propagation. Cell death and differentiation 40 37532764
2021 Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma. Frontiers in oncology 39 34527595
2011 VCIP135 deubiquitinase and its binding protein, WAC, in p97ATPase-mediated membrane fusion. The EMBO journal 36 21811234
2016 De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila. European journal of human genetics : EJHG 35 26757981
2002 WAC, a novel WW domain-containing adapter with a coiled-coil region, is colocalized with splicing factor SC35. Genomics 27 11827461
2021 Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript. The Journal of experimental medicine 22 33857290
2002 Transfer of the core region genes of the Yersinia enterocolitica WA-C serotype O:8 high-pathogenicity island to Y. enterocolitica MRS40, a strain with low levels of pathogenicity, confers a yersiniabactin biosynthesis phenotype and enhanced mouse virulence. Infection and immunity 22 11895945
2018 WAC Promotes Polo-like Kinase 1 Activation for Timely Mitotic Entry. Cell reports 20 30021153
2020 A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES). Genes 19 32214004
2012 Coiling up with SCOC and WAC: two new regulators of starvation-induced autophagy. Autophagy 13 22717455
1991 The wac gene product of bacteriophage T4 contains coiled-coil structural patterns. Journal of biomolecular structure & dynamics 13 1878168
2024 WAC Facilitates Mitophagy-mediated MSC Osteogenesis and New Bone Formation via Protecting PINK1 from Ubiquitination-Dependent Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39555688
2013 Synthesis, biological evaluation, WAC and NMR studies of S-galactosides and non-carbohydrate ligands of cholera toxin based on polyhydroxyalkylfuroate moieties. Chemistry (Weinheim an der Bergstrasse, Germany) 12 24264882
2023 LncRNA WAC-AS1 promotes osteosarcoma Metastasis and stemness by sponging miR-5047 to upregulate SOX2. Biology direct 10 37957698
2022 Long non-coding RNA WAC antisense RNA 1 mediates hepatitis B virus replication <em>in vitro</em> by reinforcing miR-192-5p/ATG7-induced autophagy. European journal of histochemistry : EJH 9 36053263
2023 Structure-Function of the Human WAC Protein in GABAergic Neurons: Towards an Understanding of Autosomal Dominant DeSanto-Shinawi Syndrome. Biology 7 37106788
2022 Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant. American journal of medical genetics. Part A 7 35018708
2016 A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders. American journal of medical genetics. Part A 7 27119754
2022 Phenotypic comparison of patients affected with DeSanto-Shinawi syndrome: Point mutations in WAC gene versus a 10p12.1 microdeletion including WAC. Molecular genetics & genomic medicine 6 35266333
2022 Congenital heart defects associated with pathogenic variants in WAC gene: Expanding the phenotypic and genotypic spectrum of DeSanto-Shinawi syndrome. American journal of medical genetics. Part A 4 34997803
2022 Phenotypic and Brain Imaging Findings Associated With a 10p Proximal Deletion Including the WAC Gene: Case Report and Literature Review. Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology 4 35766809
2017 Direct analysis - no sample preparation - of bioavailable cortisol in human plasma by weak affinity chromatography (WAC). Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 3 28820982
2023 The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation. FEBS letters 2 37171241
2023 A novel anticancer quinolone, (R)-WAC-224, has anti-leukemia activities against acute myeloid leukemia. Investigational new drugs 2 37702844
2025 Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome. bioRxiv : the preprint server for biology 1 38826421
2025 (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation. Scientific reports 1 40341200
2025 The WAC-downWAC domain in the yeast ISW2 nucleosome remodeling complex forms a structural module essential for ISW2 function but not cell viability. Epigenetics & chromatin 1 40399979
2025 Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity. FEBS open bio 1 40653822
2025 Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation. Acta pharmaceutica Sinica. B 1 40893665
2024 lncRNA WAC-AS1 promotes the progression of gastric cancer through miR-204-5p/HOXC8 axis. Translational oncology 1 39395273
2023 Expression analyses of WAC, a responsible gene for neurodevelopmental disorders, during mouse brain development. Medical molecular morphology 1 37402055
2021 WAC, a novel GBM tumor suppressor, induces GBM cell apoptosis and promotes autophagy. Medical oncology (Northwood, London, England) 1 34581882
2026 Structural insights into the Bre1-Lge1 and RNF20/RNF40-WAC interactions critical for H2B ubiquitination. Nucleic acids research 0 41533567
2025 Novel WAC gene variant identified in the first documented case of DeSanto-Shinawi Syndrome in India. Molecular and cellular pediatrics 0 40347397
2024 Prenatal diagnosis of a de novo 10p12.1p11.23 microdeletion encompassing the WAC gene in a fetus associated with bilateral hydronephrosis and right clubfoot on prenatal ultrasound. Taiwanese journal of obstetrics & gynecology 0 39004484
2024 Report of DeSanto-Shinawi Syndrome in Three Boys With Two Novel Variants in the WAC Gene and Expansion of the Phenotype. Cureus 0 39493154