Affinage

WDR6

tRNA (34-2'-O)-methyltransferase regulator WDR6 · UniProt Q9NNW5

Length
1121 aa
Mass
121.7 kDa
Annotated
2026-06-11
27 papers in source corpus 14 papers cited in narrative 13 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

WDR6 is a multidomain WD40-repeat protein that functions principally as an essential auxiliary subunit of the FTSJ1 tRNA methyltransferase, and more broadly as a substrate-recognition module in Cullin-based E3 ubiquitin ligase complexes (PMID:32558197, PMID:36947051, PMID:10903905). As the human ortholog of yeast Trm734, WDR6 partners with FTSJ1 (Trm7) to catalyze 2'-O-methylation at position 34 (Nm34/Gm34) of anticodon-loop residues in specific tRNAs including tRNAPhe, tRNATrp, and tRNALeu, an activity requiring prior m1G37 and biochemically distinct from the FTSJ1-THADA and Trm7-Trm732 complexes that act at position 32 (PMID:32558197, PMID:25404562, PMID:25625329, PMID:40483304). Structural analysis of the yeast complex shows that WDR6/Trm734 is built from three WD40 β-propeller domains: two propellers form a V-shaped cleft that docks onto the FTSJ1 C-terminus, while a third propeller positions the tRNA D-arm to present the anticodon loop to FTSJ1's catalytic pocket, with discrete near-active-site residues contributing to tRNA binding rather than complex assembly (PMID:31586407, PMID:38882062). A patient-derived FTSJ1-p.A26P mutation associated with nonsyndromic X-linked intellectual disability selectively abolishes Gm34, linking this modification activity to neurological development (PMID:26310293). Independently of its tRNA role, WDR6 serves as a recognition subunit of Cullin4-DDB1 and CUL4A-DDB1-ROC1 E3 ubiquitin ligase complexes, binding the SPAK/OSR1 kinases in a phosphorylation-dependent manner to direct OSR1 ubiquitylation and recruiting UVRAG via a WDxR motif for degradation, the latter promoting hepatocellular carcinoma growth and metastasis through an NF-κB/TNFα feedback loop (PMID:31614064, PMID:36947051). WDR6 additionally interacts with LKB1 to synergistically induce p27(Kip1)-dependent G1 arrest (PMID:17216128), promotes hepatic de novo lipogenesis by binding PPP1CB to drive its dephosphorylation during insulin resistance (PMID:37735236), and acts as a cell-intrinsic restriction factor against a vaccinia virus K1L-C7L deletion mutant independently of SAMD9 (PMID:26242627).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 Medium

    Establishing WDR6 as a discrete gene product defined the molecular scaffold whose function would later be dissected — an 1121-residue protein dominated by WD-repeat modules.

    Evidence Molecular cloning, Northern blot, and FISH mapping in human tissues

    PMID:10903905

    Open questions at the time
    • No biochemical activity or binding partner identified at this stage
    • Functional significance of the putative transmembrane domain not resolved
  2. 2007 Medium

    First functional links placed WDR6 in cell-cycle and metabolic signaling, showing it cooperates with LKB1 to enforce G1 arrest and associates with IRS-4 in the hypothalamus.

    Evidence Yeast two-hybrid, co-localization, colony formation and p27 reporter assays in HeLa; subtractive hybridization and Co-IP in rat hypothalamus

    PMID:17216128 PMID:17720279

    Open questions at the time
    • Mechanism by which WDR6 amplifies LKB1 signaling not defined
    • IRS-4 interaction rests on a single Co-IP with mostly expression-level readouts
    • No connection yet to WDR6's later-defined enzymatic or ubiquitin ligase roles
  3. 2014 High

    Yeast genetics identified the WDR6 ortholog Trm734 as the position-34-specific partner of Trm7, distinguishing it from the position-32 Trm732 complex and defining its core conserved function.

    Evidence Genetic complementation and tRNA modification analysis in S. cerevisiae and S. pombe deletion mutants

    PMID:25404562 PMID:25625329

    Open questions at the time
    • Direct demonstration of catalysis required reconstitution
    • Human ortholog activity not yet shown
  4. 2015 High

    Coupling tRNA modification to disease, a patient FTSJ1-A26P mutation was shown to selectively abolish Gm34 without affecting Cm32, tying the Trm7-Trm734 activity to X-linked intellectual disability.

    Evidence LC-MS/MS of patient cell lines and yeast trm7-A26P mutant with complementation and binding assays

    PMID:26310293

    Open questions at the time
    • How loss of Gm34 mechanistically impairs neuronal function not established
    • Effect of human WDR6 mutations on disease not tested
  5. 2015 Medium

    A genome-wide screen revealed an unrelated antiviral role, identifying WDR6 as a SAMD9-independent restriction factor against a vaccinia K1L-C7L deletion mutant.

    Evidence Genome-wide siRNA screen confirmed by CRISPR/Cas9 knockout and viral replication assays in HeLa, with negative interaction tests

    PMID:26242627

    Open questions at the time
    • Molecular mechanism of viral restriction unknown
    • Whether restriction relates to WDR6's enzymatic or ubiquitin-ligase activities untested
  6. 2019 High

    Crystallography defined the structural logic of the complex, showing WDR6/Trm734's three β-propellers both dock FTSJ1 and orient the tRNA substrate for catalysis.

    Evidence X-ray crystallography (apo and SAM-bound), SAXS, and in vitro methylation with tRNA/protein mutants in yeast

    PMID:31586407

    Open questions at the time
    • Human FTSJ1-WDR6 structure not solved at this time
    • Catalytic contribution of WDR6 residues not yet mapped
  7. 2019 Medium

    WDR6 was shown to function as a substrate-recognition subunit of a Cullin4-DDB1 E3 ligase, binding SPAK/OSR1 phospho-dependently to direct OSR1 ubiquitylation regulated by osmotic stress.

    Evidence Affinity pull-down, mass spectrometry, and proteasome/neddylation inhibitor and osmotic stress experiments

    PMID:31614064

    Open questions at the time
    • In vivo physiological consequence of OSR1 ubiquitylation not established
    • Whether the same complex degrades other substrates not addressed here
  8. 2020 High

    Reconstitution proved the human ortholog is enzymatically functional, with FTSJ1-WDR6 catalyzing 2'-O-methylation at position 34 in vitro contingent on m1G37.

    Evidence Co-IP, in vitro reconstitution of methyltransferase activity, and ftsj1 knockout validation

    PMID:32558197

    Open questions at the time
    • Full substrate repertoire of the human complex not exhaustively defined
    • Regulation of human complex assembly in cells unresolved
  9. 2023 Medium

    Two studies expanded WDR6's E3-ligase and metabolic functions, showing it recruits UVRAG to CUL4A-DDB1-ROC1 for degradation to drive an immunosuppressive HCC program, and binds PPP1CB to promote hepatic lipogenesis during insulin resistance.

    Evidence CRISPR knockout, Co-IP, orthotopic mouse tumor models, flow cytometry, and transcription assays; plus Co-IP, mouse insulin-resistance models, and molecular dynamics

    PMID:36947051 PMID:37735236

    Open questions at the time
    • Structural basis of UVRAG and PPP1CB recognition not solved
    • How WDR6 partitions between tRNA-methylation and ubiquitin-ligase roles in vivo unclear
  10. 2024 Medium

    Mutagenesis refined the catalytic model, distinguishing WDR6/Trm734 residues required for tRNA binding near the active site from those mediating complex assembly.

    Evidence Site-directed mutagenesis, yeast complementation, and Co-IP with structural mapping

    PMID:38882062

    Open questions at the time
    • Residue assignments inferred from yeast onto human complex
    • Direct tRNA-binding affinity of variants not measured
  11. 2025 Medium

    Comparative structural work established that WDR6 and THADA occupy distinct functional niches as alternative auxiliary subunits of FTSJ1, with WDR6 specifically supporting Nm34.

    Evidence Cryo-EM of FTSJ1-THADA complex with biochemical comparison to the FTSJ1-WDR6 complex

    PMID:40483304

    Open questions at the time
    • WDR6-specific conclusions inferred indirectly from comparison
    • What selects between WDR6 and THADA partnering in cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how WDR6 coordinates its parallel roles as a tRNA-methyltransferase subunit, an E3 ligase substrate adaptor, and a metabolic/antiviral factor within a single cell.
  • No study integrates the tRNA-modification and ubiquitin-ligase functions
  • Mechanism of antiviral restriction undefined
  • No human structural model of WDR6 in its E3 ligase complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 3 GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 2
Partners
DDB1FTSJ1IRS4LKB1OSR1PPP1CBSPAKUVRAG
Complex memberships
CUL4A-DDB1-ROC1 E3 ubiquitin ligaseCullin4-DDB1-WDR6 E3 ubiquitin ligaseFTSJ1-WDR6 tRNA methyltransferase complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 WDR6 is an interacting protein of FTSJ1 (human TRM7 ortholog), and the FTSJ1-WDR6 complex reconstituted in vitro catalyzes 2'-O-methylation at position 34 of specific tRNAs, with m1G37 as a prerequisite for this activity. Co-immunoprecipitation to identify interaction; in vitro reconstitution of methyltransferase activity; genetic knockout of ftsj1 to assess modification loss EMBO reports High 32558197
2014 Yeast Trm734 (WDR6 ortholog) forms a complex with Trm7 to specifically 2'-O-methylate position 34 (N34) of tRNA anticodon loop substrates including tRNAPhe, tRNATrp, and tRNALeu; this is distinct from the Trm7-Trm732 complex which methylates position 32. Genetic complementation assays in S. cerevisiae and S. pombe deletion mutants; tRNA modification analysis; growth phenotype rescue experiments RNA (New York, N.Y.) High 25404562 25625329
2015 Defects in the Trm7-Trm734 (WDR6 ortholog) complex result in loss of Gm34 on tRNAPhe, and a FTSJ1-p.A26P missense mutation (corresponding to nonsyndromic X-linked intellectual disability) specifically abolishes Gm34 without affecting Cm32; the reduced Gm34 is not due to weaker Trm734 binding to Trm7. LC-MS/MS tRNA modification analysis from patient cell lines and yeast trm7-A26P mutant; yeast complementation assays; binding assays Human mutation High 26310293
2019 Crystal structure of the yeast Trm7-Trm734 (WDR6 ortholog) complex reveals Trm734 consists of three WD40 β-propeller domains (BPA, BPB, BPC); BPA and BPC form a V-shaped cleft that docks to Trm7; the C-terminal region of Trm7 is required for Trm734 binding; Trm734's BPB domain positions tRNA D-arm, placing the anticodon loop near Trm7's catalytic pocket; the complex is a heterodimer in solution. X-ray crystallography (apo and SAM-bound forms); SAXS; in vitro methylation assays with tRNA variants; mutagenesis of Trm7 and tRNA substrates Nucleic acids research High 31586407
2025 The human FTSJ1-WDR6 complex (distinct from FTSJ1-THADA) mediates Nm34 modification; cryo-EM structure of the FTSJ1-THADA complex reveals FTSJ1 binds THADA via its C-terminal region with an interaction mode distinct from the FTSJ1-WDR6 complex, confirming that WDR6 and THADA occupy distinct functional niches as auxiliary subunits of FTSJ1. Cryo-electron microscopy structure determination; biochemical interaction analyses; comparison with previously solved FTSJ1-WDR6 structure Communications biology Medium 40483304
2024 Specific amino acids in Trm734 (WDR6 ortholog) located near the active site of Trm7 (not at the Trm7-Trm734 protein-protein interface) are required for tRNA modification activity; a nonfunctional but stable Trm734 variant was identified, suggesting these residues may be important for tRNA binding rather than protein complex assembly. Site-directed mutagenesis of Trm734; yeast functional complementation assays; immunoprecipitation to verify Trm7-Trm734 binding; structural mapping onto published crystal structure ACS omega Medium 38882062
2007 WDR6 interacts with LKB1 (STK11) and is localized in the cytoplasm co-incident with LKB1; co-expression of WDR6 with LKB1 enhances LKB1-mediated inhibition of HeLa cell proliferation, synergizes to induce G1 cell cycle arrest, and elevates p27(Kip1) protein and promoter activity beyond the effect of LKB1 alone. Yeast two-hybrid screening; immunofluorescence co-localization; colony formation assay; cell cycle analysis; p27(Kip1) promoter-reporter assay; co-expression in HeLa cells Molecular and cellular biochemistry Medium 17216128
2007 WDR6 interacts with insulin receptor substrate 4 (IRS-4) in rat brain hypothalamus; WDR6 mRNA is abundantly expressed in the hypothalamus and is decreased by caloric restriction and in GH-antisense transgenic rats (both associated with increased lifespan); IGF-I and insulin treatment increase WDR6 gene expression in hypothalamic GT1-7 cells. Suppression subtractive hybridization; co-immunoprecipitation/interaction assay from rat brain; in vitro stimulation of GT1-7 cells with IGF-I/insulin Neurobiology of aging Low 17720279
2019 WDR6 is a component of a Cullin4-DDB1-WDR6 E3 ubiquitin ligase complex that binds SPAK and OSR1 kinases in a phosphorylation-dependent manner (dependent on S-motif phosphorylation); this binding is reduced under osmotic stress when the S-motif is phosphorylated, and OSR1 ubiquitylation is abolished under osmotic stress. Affinity pull-down; mass spectrometry; proteasomal and neddylation inhibitor treatment; osmotic stress experiments Chembiochem Medium 31614064
2023 WDR6 promotes hepatic de novo lipogenesis during insulin resistance by interacting with PPP1CB (PP1β catalytic subunit) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthase transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Co-immunoprecipitation; molecular dynamics simulation; in vivo mouse models of insulin resistance; siRNA knockdown and overexpression; transcription reporter assays Nature metabolism Medium 37735236
2023 WDR6 promotes UVRAG degradation by recruiting it to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a WDxR motif; WDR6 deficiency in HCC cells reduces tumor growth and lung metastasis in immunocompetent mice but not in vitro, linked to blocking autophagic degradation of p65, elevating TNFα, increasing MDSCs, and reducing CD8+ T cell infiltration; TNFα activates NF-κB to transcribe WDR6, establishing a feedback loop. CRISPR/Cas9 knockout; co-immunoprecipitation; in vivo orthotopic tumor implantation in C57BL/6J mice; chromatin accessibility assays; flow cytometry for immune cell analysis; TNFα blockade experiments; peptide disruption assay EMBO molecular medicine Medium 36947051
2015 WDR6 was identified as a restriction factor that inhibits replication of vaccinia virus K1L-C7L double deletion mutant in human cells; CRISPR/Cas9 knockout of WDR6 in HeLa cells permitted enhanced replication of the mutant virus; WDR6 acts independently of SAMD9 (interactions of WDR6 with SAMD9, C7, and K1 proteins were not detected), and WDR6 knockout did not reduce SAMD9 levels. Genome-wide siRNA screen; CRISPR/Cas9 knockout of WDR6 in HeLa cells; viral replication assays; immunoprecipitation (negative for WDR6-SAMD9/C7/K1 interactions) mBio Medium 26242627
2000 Human WDR6 encodes a protein of 1121 amino acids containing 11 WD-repeat units clustered in two groups separated by a putative transmembrane domain; the gene maps to chromosome 15q21 and is ubiquitously expressed in human adult and fetal tissues. Molecular cloning; Northern blot analysis; fluorescence in situ hybridization (FISH) Biochemical and biophysical research communications Medium 10903905

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets. JAMA neurology 155 33523105
2015 Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1. Human mutation 117 26310293
2014 Two-subunit enzymes involved in eukaryotic post-transcriptional tRNA modification. RNA biology 92 25625329
2014 Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes. RNA (New York, N.Y.) 65 25404562
2015 Identification of Restriction Factors by Human Genome-Wide RNA Interference Screening of Viral Host Range Mutants Exemplified by Discovery of SAMD9 and WDR6 as Inhibitors of the Vaccinia Virus K1L-C7L- Mutant. mBio 63 26242627
2020 Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs. EMBO reports 48 32558197
2009 Integrative analysis of the human cis-antisense gene pairs, miRNAs and their transcription regulation patterns. Nucleic acids research 46 19906709
2025 Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. Nature genetics 37 40360802
2007 Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction. Molecular and cellular biochemistry 33 17216128
2023 Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice. Nature metabolism 31 37735236
2018 Human Host Range Restriction of the Vaccinia Virus C7/K1 Double Deletion Mutant Is Mediated by an Atypical Mode of Translation Inhibition. Journal of virology 23 30209174
2019 Structure of tRNA methyltransferase complex of Trm7 and Trm734 reveals a novel binding interface for tRNA recognition. Nucleic acids research 21 31586407
2023 Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression. EMBO molecular medicine 20 36947051
2013 Global DNA methylation screening of liver in piperonyl butoxide-treated mice in a two-stage hepatocarcinogenesis model. Toxicology letters 20 23968726
2007 Identification and characterization of an insulin receptor substrate 4-interacting protein in rat brain: implications for longevity. Neurobiology of aging 20 17720279
2025 Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. medRxiv : the preprint server for health sciences 17 38712091
2023 Multiomic prioritisation of risk genes for anorexia nervosa. Psychological medicine 16 36803885
2016 Whole-exome sequencing analysis in twin sibling males with an anterior cruciate ligament rupture. Injury 14 27692106
2000 Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene. Biochemical and biophysical research communications 13 10903905
2017 Suppression subtractive hybridization identified differentially expressed genes in colorectal cancer: microRNA-451a as a novel colorectal cancer-related gene. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 28468585
2019 The Cul4-DDB1-WDR3/WDR6 Complex Binds SPAK and OSR1 Kinases in a Phosphorylation-Dependent Manner. Chembiochem : a European journal of chemical biology 11 31614064
2022 Identification of a Trm732 Motif Required for 2'-O-methylation of the tRNA Anticodon Loop by Trm7. ACS omega 7 35559166
2023 PABPN1 functions as a predictive biomarker in colorectal carcinoma. Molecular biology reports 2 38158471
2025 Structural insights into tRNA recognition of the human FTSJ1-THADA complex. Communications biology 1 40483304
2026 [WD40 repeat-containing protein 6 aggravates diabetic kidney disease by promoting lipid accumulation in renal tubular cells]. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 0 42252270
2025 Machine Learning Reveals Common Regulatory Mechanisms Mediated by Autophagy-Related Genes in the Development of Inflammatory Bowel Disease and Major Depressive Disorder. Genes 0 41595424
2024 Identification of Amino Acids in Trm734 Required for 2'-O-Methylation of the tRNAPhe Wobble Residue. ACS omega 0 38882062

Missed literature

Know a paper Affinage missed for WDR6? Flag it for the maintainers and the community.

No submissions yet.