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Showing WDR36 — UTP21 is a alias.

WDR36

WD repeat-containing protein 36 · UniProt Q8NI36

Length
895 aa
Mass
99.4 kDa
Annotated
2026-06-11
30 papers in source corpus 13 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR36 is a WD40-repeat nucleolar protein that functions in 18S rRNA maturation and ribosome biogenesis as the functional homolog of yeast Utp21, a component of the SSU processome (PMID:18469340). In human cells it localizes to the nucleolus alongside nucleophosmin and PWP2, and its depletion delays processing of the 21S precursor and maturation of 18S rRNA (PMID:21051332). Within the yeast UtpB subcomplex, the WDR36 ortholog Utp21 is engaged through a direct HAT-domain contact from Utp6 that is required for efficient pre-rRNA processing (PMID:18725399). WDR36 is essential for early development: homozygous knockout causes mouse preimplantation lethality, and its loss activates a p53 stress response—inducing BAX, TP53, and CDKN1A and triggering apoptosis—that is reversible by p53 inhibition and governs stem-cell self-renewal (PMID:18469340, PMID:21051332, PMID:35937980). Beyond the nucleolus, WDR36 acts as a plasma-membrane scaffold that binds the thromboxane A2 receptor β (TPβ) and assembles Gαq–PLCβ–receptor complexes, promoting receptor–Gαq coupling, protecting activated Gαq from GRK2 sequestration, and thereby selectively shaping Gq-mediated signalling and calcium responses (PMID:21940795, PMID:32244061). Glaucoma-associated WDR36 variants impair rRNA processing only in sensitizing genetic backgrounds and also alter WDR36's modulation of Gαq signalling, and a deletion variant modeled in transgenic mice produces progressive retinal degeneration with reduced retinal ganglion cell axon outgrowth (PMID:19150991, PMID:21940795, PMID:20631153).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    Established WDR36's core molecular identity by showing it is the functional ortholog of yeast Utp21 and a nucleolar factor required for 18S rRNA processing, placing it in ribosome biogenesis.

    Evidence Sequence alignment, nucleolar localization, and loss-of-function with rRNA processing and nucleolar morphology readouts in zebrafish

    PMID:18469340

    Open questions at the time
    • Did not define the human SSU processome subcomplex composition
    • No direct biochemical assay of WDR36 enzymatic or binding activity in vertebrates
  2. 2008 Medium

    Connected WDR36 loss to the p53 stress-response axis, framing how variant impact could depend on co-inherited p53-pathway status.

    Evidence Zebrafish loss-of-function with p53 pathway readout

    PMID:18469340 PMID:21051332

    Open questions at the time
    • Did not establish whether p53 activation is a direct sensor of disrupted ribosome biogenesis
    • No mechanism linking WDR36 depletion to specific p53 effectors
  3. 2008 High

    Resolved a direct intermolecular contact in the SSU processome by mapping a HAT-domain interaction between Utp6 and the WDR36 ortholog Utp21 and showing it is functionally required.

    Evidence Interaction mapping, mutagenesis, biophysical Kd measurement, and pre-rRNA processing/growth assays in yeast UtpB subcomplex

    PMID:18725399

    Open questions at the time
    • Interaction demonstrated in yeast, not human WDR36
    • Structural basis of the peptide contact not solved
  4. 2010 High

    Demonstrated WDR36 is essential for mammalian development and confirmed its conserved nucleolar rRNA-processing role in human cells, linking depletion to p53-dependent apoptosis.

    Evidence Mouse knockout and siRNA embryo lethality; human HTM-N cell localization, northern blot/metabolic labeling rRNA assays, and apoptosis/mRNA readouts

    PMID:21051332

    Open questions at the time
    • Did not separate the developmental requirement from the general ribosome-biogenesis defect
    • Tissue-specific roles in trabecular meshwork beyond rRNA processing not defined
  5. 2009 Medium

    Showed that POAG-associated WDR36 variants are not intrinsically defective but become functionally consequential for rRNA processing only in a sensitizing genetic background.

    Evidence Yeast UTP21 site-directed mutants with STI1 deletion epistasis and rRNA processing/viability assays

    PMID:19150991

    Open questions at the time
    • Relevance of STI1 modifier to human trabecular meshwork unestablished
    • Did not identify the human equivalent genetic modifier
  6. 2010 Medium

    Provided an in vivo disease-relevant phenotype by showing a WDR36 deletion variant drives retinal degeneration and impaired RGC axon outgrowth independent of intraocular pressure.

    Evidence Transgenic mouse overexpression with retinal histology, RGC axon outgrowth assay, and molecular modeling

    PMID:20631153

    Open questions at the time
    • Molecular modeling of the destabilized β-propeller is computational
    • Mechanism linking the structural change to neuronal phenotype not biochemically resolved
  7. 2011 High

    Revealed a second, non-nucleolar function: WDR36 acts as a plasma-membrane scaffold organizing TPβ–Gαq–PLCβ complexes to potentiate Gq signalling.

    Evidence Yeast two-hybrid, GST pulldown, reciprocal Co-IP, confocal microscopy, and KD/OE signalling assays in cells

    PMID:21940795

    Open questions at the time
    • Structural basis of the WDR40-repeat scaffold engaging Gαq/PLCβ unknown
    • Relationship between the nucleolar and membrane pools of WDR36 not defined
  8. 2011 Medium

    Linked glaucoma-associated WDR36 variants to the scaffold/signalling activity, broadening the disease mechanism beyond rRNA processing.

    Evidence Overexpression of disease-variant constructs with Gαq signalling readout in cells

    PMID:21940795

    Open questions at the time
    • No structural/biochemical mechanism for how variants alter binding
    • Effect sizes not connected to clinical variant penetrance
  9. 2011 Medium

    Reinforced a conserved STI1–WDR36 modifier axis affecting proliferation rather than direct rRNA levels, refining how modifiers act.

    Evidence Yeast double-mutant growth assays, 18S rRNA quantification, and POAG patient variant sequencing

    PMID:21850170

    Open questions at the time
    • Decouples growth from rRNA without identifying the proliferation effector
    • Human STI1/STIP1 modifier role not tested directly
  10. 2014 Medium

    Identified Hsp90/co-chaperone buffering as a mechanism that masks the effects of WDR36 disease-analogous mutations on protein stability.

    Evidence Yeast genetic interaction and protein-level assays under Hsp90 inhibition/mutation

    PMID:24647762

    Open questions at the time
    • Chaperone buffering shown in yeast, not human WDR36
    • Whether Hsp90 directly binds WDR36 in mammalian cells untested
  11. 2020 Medium

    Refined the scaffold model by showing WDR36 differentially tunes Gq output across receptors, consistent with scavenging Gαq and PLCβ into specific signalling complexes.

    Evidence Overexpression in HEK-293 and C2C12 cells with SphK1 translocation imaging, inositol phosphate assays, and calcium imaging

    PMID:32244061

    Open questions at the time
    • Receptor-selectivity mechanism not structurally defined
    • Endogenous physiological consequences of differential Gq tuning untested
  12. 2022 Medium

    Positioned WDR36 upstream of p53 in controlling stem-cell self-renewal versus differentiation, extending the depletion-p53 link to a developmental decision.

    Evidence Inducible knockdown/overexpression in human EPS cells with differentiation assays and p53 inhibitor rescue

    PMID:35937980

    Open questions at the time
    • Did not establish whether the p53 effect is secondary to ribosome-biogenesis stress
    • Direct molecular link from WDR36 to p53 activation not defined
  13. 2024 Medium

    Uncovered a metabolic role by showing WDR36 binds LDHA and promotes glycolysis to drive trophectoderm lineage commitment.

    Evidence Co-IP, siRNA knockdown in blastoids, transcriptomics, and targeted metabolomics

    PMID:39656902

    Open questions at the time
    • Single Co-IP for the WDR36-LDHA interaction without reciprocal/structural validation
    • Mechanism by which WDR36 regulates LDHA activity unknown
  14. 2026 Medium

    Embedded WDR36 in a post-transcriptional protective circuit, showing ELAVL1 promotes WDR36 translation and WDR36 mediates ELAVL1's suppression of p53-driven ischemic retinal cell death.

    Evidence RNA-binding protein assay, siRNA knockdown, overexpression, AAV in vivo delivery, cell death/calcium assays, and p53 markers in retinal precursor cells

    PMID:42046554

    Open questions at the time
    • Whether protection depends on WDR36's ribosome-biogenesis or scaffold function not separated
    • Direct molecular step from WDR36 to p53 inhibition unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WDR36's nucleolar rRNA-processing role, its plasma-membrane Gq scaffold role, and its metabolic/LDHA interaction are integrated within a single cell—and which function underlies its glaucoma association—remains unresolved.
  • No structural model of human WDR36 in either the SSU processome or the Gq complex
  • Mechanism partitioning WDR36 between nucleolar and membrane pools unknown
  • Causal function for glaucoma pathology not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005730 nucleolus 2 GO:0005886 plasma membrane 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2
Partners
ELAVL1GNAQGRK2LDHAPLCBTBXA2RUTP6
Complex memberships
SSU processome (UtpB subcomplex)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 WDR36 (Wdr36) is the functional homolog of yeast Utp21 and localizes to the nucleolus, where it is required for processing of 18S rRNA (ribosome biogenesis). Loss of Wdr36 function in zebrafish causes defects in 18S rRNA processing and abnormal nucleolar morphology. Sequence alignment, subcellular localization (nucleolus), loss-of-function in zebrafish with rRNA processing assay and nucleolar morphology readout Human molecular genetics High 18469340
2008 Loss of Wdr36 function activates the p53 stress-response pathway, suggesting that co-inheritance of defects in p53 pathway genes may influence the impact of WDR36 variants. Loss-of-function in zebrafish with p53 pathway readout Human molecular genetics Medium 18469340 21051332
2010 WDR36 is essential for mammalian preimplantation development: homozygous Wdr36 knockout causes embryonic lethality before the blastocyst stage in mice, and siRNA-mediated depletion replicates this lethality. Targeted gene deletion in mice (knockout); siRNA knockdown in mouse embryos Human molecular genetics High 21051332
2010 WDR36 localizes to the nucleolus in human trabecular meshwork (HTM-N) cells, co-localizing with nucleolar proteins nucleophosmin and PWP2; both endogenous and recombinant/epitope-tagged WDR36 show this nucleolar localization. Immunocytochemistry and recombinant/epitope-tagged protein localization in human cells Human molecular genetics High 21051332
2010 Knockdown of WDR36 in human trabecular meshwork (HTM-N) cells delays maturation of 18S rRNA: northern blot shows decreased 21S rRNA (precursor of 18S rRNA), and metabolic-labeling experiments show delayed 18S rRNA maturation. WDR36 depletion also induces apoptotic cell death with upregulation of BAX, TP53, and CDKN1A mRNAs. siRNA knockdown in human cells; northern blot; metabolic labeling; RT-PCR/mRNA quantification Human molecular genetics High 21051332
2008 In the yeast UtpB subcomplex of the SSU processome, the HAT (half-a-tetratricopeptide repeat) domain of Utp6 directly binds a specific peptide in Utp21 (the yeast ortholog of WDR36) with a Kd of ~10 µM; an intact HAT domain is essential for efficient pre-rRNA processing and cell growth. Comprehensive interaction mapping within UtpB subcomplex; point and deletion mutagenesis of Utp6; biophysical binding assay (Kd measurement); pre-rRNA processing assay; growth assay Molecular and cellular biology High 18725399
2009 POAG-associated WDR36 sequence variants introduced into yeast UTP21 do not produce defects alone, but in combination with disruption of STI1 (a synthetic interactor of UTP21), 5 of 11 tested variants show altered cell viability corresponding to reduced or elevated pre-rRNA levels, demonstrating that WDR36 variants can alter rRNA processing in a specific genetic background. Yeast model system with site-directed mutagenesis of UTP21; genetic epistasis (double mutant with STI1 deletion); rRNA processing assay; growth/viability assay Human molecular genetics Medium 19150991
2011 WDR36 acts as a scaffold protein: it directly interacts with the C-terminus and first intracellular loop of the thromboxane A2 receptor β (TPβ) (confirmed by yeast two-hybrid and GST pulldown), co-immunoprecipitates with Gαq and PLCβ in cells, promotes TPβ–Gαq interaction, increases Gαq–PLCβ interaction, prevents sequestration of activated Gαq by GRK2, and augments the presence of TPβ in PLCβ immunoprecipitates. WDR36 overexpression enhances and siRNA knockdown inhibits TPβ-induced Gαq signalling. The complex translocates from plasma membrane to intracellular vesicles upon receptor stimulation. Yeast two-hybrid; GST pulldown; co-immunoprecipitation; confocal microscopy; siRNA knockdown; overexpression functional assay Journal of cell science High 21940795
2011 Disease-associated WDR36 variants affect WDR36's ability to modulate Gαq-mediated signalling by TPβ, linking glaucoma-associated variants to the scaffold/signalling function. Overexpression of disease-variant WDR36 constructs with Gαq signalling readout in cells Journal of cell science Medium 21940795
2010 Transgenic mice overexpressing mutant mouse Wdr36 Del605-607 (equivalent to human D658G region) develop progressive peripheral retinal degeneration with normal IOP; RGCs and amacrine cell synapses are affected, and axon outgrowth of cultured RGCs from these mice is significantly reduced. Molecular modeling shows the deletion removes a hydrogen bond stabilizing the 6th β-propeller of the second domain. Transgenic mouse overexpression; retinal histology; RGC axon outgrowth assay; molecular modeling Human molecular genetics Medium 20631153
2014 Utp21 (yeast WDR36 ortholog) interacts with Hsp90 and co-chaperones; steady-state levels of Utp21 are reduced upon Hsp90 mutation or inhibition. The utp21-S602F mutation shows severe/lethal growth defects when combined with Hsp90 or co-chaperone mutations. Three Utp21 mutants analogous to glaucoma-associated WDR36 mutations show reduced levels in yeast expressing Hsp90 or co-chaperone mutations, indicating Hsp90 buffers the effects of these mutations. Genetic interaction analysis (double mutant growth assays); Hsp90 inhibition; protein level measurement in yeast PloS one Medium 24647762
2011 STI1 variant K434R combined with specific UTP21 (WDR36 yeast ortholog) variants causes significantly altered culture growth at 37°C, but does not significantly alter 18S rRNA levels, supporting a conserved molecular pathway involving STI1 and WDR36 affecting cell proliferation rather than direct rRNA processing. Yeast model system; double-mutant growth assays; 18S rRNA quantification; gene sequencing in POAG patients Molecular vision Medium 21850170
2020 WDR36 overexpression delays SphK1 (sphingosine kinase-1) translocation to the plasma membrane induced by Gq-coupled M3, B2, and H1 receptors, while augmenting TPβ receptor-induced calcium signalling. WDR36 increases inositol phosphate production by TPβ but attenuates it by M3 and B2 receptors, consistent with WDR36 scavenging Gαq and PLCβ to orchestrate Gq signalling complexes. Overexpression in HEK-293 cells and C2C12 myoblasts; live-cell imaging of SphK1 translocation; inositol phosphate assay; calcium imaging Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 32244061
2022 WDR36 knockdown in human extended pluripotent stem (EPS) cells disrupts self-renewal and promotes mesodermal differentiation; p53 inhibition reverses these effects, placing WDR36 upstream of p53 in the self-renewal regulatory pathway. Inducible knockdown and overexpression in human EPS cells; differentiation assays; p53 inhibitor rescue experiment Frontiers in genetics Medium 35937980
2024 WDR36 interacts with glycolytic metabolic protein LDHA (lactate dehydrogenase A) and positively regulates glycolysis during the late stage of human blastoid formation. WDR36 interference blocks trophectoderm lineage commitment and downregulates glucose metabolism, linking WDR36 to glycolytic regulation of cell fate. Co-immunoprecipitation (WDR36-LDHA interaction); siRNA knockdown in blastoids; transcriptomics; targeted metabolomics Advanced science Medium 39656902
2025 WDR36 overexpression inhibits migration, chemotaxis, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs), while WDR36 depletion promotes these processes and also promotes senescence. Scratch-wound migration assay; transwell chemotaxis assay; ALP activity, Alizarin red staining, calcium content; RT-qPCR; SA-β-galactosidase staining; overexpression and knockdown World journal of stem cells Low 40061266
2026 ELAVL1 binds WDR36 mRNA and promotes its protein translation (post-transcriptional regulation). WDR36 overexpression reduces OGD/R-induced cell death, calcium overload, and p53 pathway activation in retinal precursor cells; WDR36 knockdown abolishes ELAVL1's protective effects, placing WDR36 downstream of ELAVL1 in the p53 inhibition pathway under acute pressure-ischemia stress. RNA-binding protein interaction assay (ELAVL1-WDR36 mRNA); siRNA knockdown; plasmid overexpression; AAV in vivo delivery; cell death assay; calcium measurement; p53 pathway markers Open life sciences Medium 42046554

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma. Investigative ophthalmology & visual science 95 16723468
2008 The primary open-angle glaucoma gene WDR36 functions in ribosomal RNA processing and interacts with the p53 stress-response pathway. Human molecular genetics 90 18469340
2006 A Glaucoma Case-control Study of the WDR36 Gene D658G sequence variant. American journal of ophthalmology 54 16876519
2008 Profiling of WDR36 missense variants in German patients with glaucoma. Investigative ophthalmology & visual science 50 18172102
2010 Lack of WDR36 leads to preimplantation embryonic lethality in mice and delays the formation of small subunit ribosomal RNA in human cells in vitro. Human molecular genetics 47 21051332
2018 Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Scientific reports 42 29540704
2008 A direct interaction between the Utp6 half-a-tetratricopeptide repeat domain and a specific peptide in Utp21 is essential for efficient pre-rRNA processing. Molecular and cellular biology 42 18725399
2009 Glaucoma-associated WDR36 variants encode functional defects in a yeast model system. Human molecular genetics 41 19150991
2007 Association between primary open-angle glaucoma and WDR36 DNA sequence variants in Japanese. Molecular vision 39 17960130
2010 Mutant WDR36 directly affects axon growth of retinal ganglion cells leading to progressive retinal degeneration in mice. Human molecular genetics 35 20631153
2007 Variations in the WDR36 gene in German patients with normal tension glaucoma. Molecular vision 32 17563723
2006 The role of the WDR36 gene on chromosome 5q22.1 in a large family with primary open-angle glaucoma mapped to this region. Archives of ophthalmology (Chicago, Ill. : 1960) 29 16966629
2011 WDR36 and P53 gene variants and susceptibility to primary open-angle glaucoma: analysis of gene-gene interactions. Investigative ophthalmology & visual science 28 21931130
2009 Different WDR36 mutation pattern in Chinese patients with primary open-angle glaucoma. Molecular vision 28 19347049
2011 WDR36 acts as a scaffold protein tethering a G-protein-coupled receptor, Gαq and phospholipase Cβ in a signalling complex. Journal of cell science 22 21940795
2010 Association between primary open-angle glaucoma (POAG) and WDR36 sequence variance in Italian families affected by POAG. The British journal of ophthalmology 17 20813748
2014 Heterozygote Wdr36-deficient mice do not develop glaucoma. Experimental eye research 14 25261604
2011 WDR36 variants in East Indian primary open-angle glaucoma patients. Molecular vision 14 22025897
2017 Association of WDR36 polymorphisms with primary open angle glaucoma: A systematic review and meta-analysis. Medicine 13 28658128
2014 The ribosomal biogenesis protein Utp21 interacts with Hsp90 and has differing requirements for Hsp90-associated proteins. PloS one 8 24647762
2020 The WD40 repeat protein, WDR36, orchestrates sphingosine kinase-1 recruitment and phospholipase C-β activation by Gq-coupled receptors. Biochimica et biophysica acta. Molecular and cell biology of lipids 7 32244061
2021 WDR36-Associated Neurodegeneration: A Case Report Highlights Possible Mechanisms of Normal Tension Glaucoma. Genes 6 34681019
2024 WDR36 Regulates Trophectoderm Differentiation During Human Preimplantation Embryonic Development Through Glycolytic Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 39656902
2011 Co-variation of STI1 and WDR36/UTP21 alters cell proliferation in a glaucoma model. Molecular vision 5 21850170
2009 [Genetic variants of CYP1B1 and WDR36 in the patients with primary congenital glaucoma and primary open angle glaucoma from Saint-Petersburg]. Genetika 5 20198978
2017 An Application of NGS for WDR36 Gene in Taiwanese Patients with Juvenile-Onset Open-Angle Glaucoma. International journal of medical sciences 4 29104481
2008 Effects of timolol on MYOC, OPTN, and WDR36 RNA levels. Archives of ophthalmology (Chicago, Ill. : 1960) 3 18195223
2022 WDR36 Safeguards Self-Renewal and Pluripotency of Human Extended Pluripotent Stem Cells. Frontiers in genetics 2 35937980
2025 WDR36 inhibits the osteogenic differentiation and migration of periodontal ligament stem cells. World journal of stem cells 1 40061266
2026 RNA-binding protein ELAVL1 modulates WDR36 to inhibit p53 pathway and reduce calcium overload in retinal cells under acute pressure elevation. Open life sciences 0 42046554

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