Affinage

WDR18

WD repeat-containing protein 18 · UniProt Q9BV38

Length
432 aa
Mass
47.4 kDa
Annotated
2026-06-11
29 papers in source corpus 13 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

WDR18 (human IPI3) is a WD40-repeat scaffolding protein that functions as a core structural subunit of the nucleolar rixosome/Rix1 complex (PELP1–WDR18–TEX10–LAS1L–NOL9), which drives maturation and nucleolar release of the large (60S) ribosomal subunit (PMID:21326211, PMID:22190735, PMID:15528184). Within this complex WDR18 acts as a central bridge: its two TEX10-contact regions tether it to the PELP1–TEX10 core while a C-terminal helix docks the catalytic LAS1L–NOL9 endonuclease/kinase module, coupling scaffold assembly to ITS2 pre-rRNA processing (PMID:40195365). Structural work on the human PELP1 Rix1 domain–WDR18 subcomplex shows an interconnected PELP1₂–WDR18₂ tetramer in which WDR18 association sequesters PELP1's LxxLL motifs away from steroid-receptor-coactivation conformations (PMID:36351913), and orthologous cryo-EM analyses establish that this Rix1–Ipi3–Ipi1 module wedges between the 5S rRNA and L1-stalk to drive 180° rotation of the immature 5S RNP and to position the Las1–Grc3 module for ITS2 cleavage (PMID:32668200, PMID:37921038). Depletion of WDR18 or its complex partners blocks ITS2 processing and triggers p53-dependent G1 arrest (PMID:22190735), and its conserved role in ribosome biogenesis extends to non-autonomous control of germline proliferation in invertebrate orthologs (PMID:16876152). WDR18 is also recruited, via arginine-methylated Chtop, into the 5FMC chromatin complex that modulates SUMO status and transactivation of ZBP-89 (PMID:22872859). Beyond ribosome biogenesis, WDR18 associates with TopBP1 and Chk1 to support ATR-dependent checkpoint signaling (PMID:23333389), promotes MCM chromatin loading and binds replication origins during licensing (PMID:27057756), and serves as a substrate receptor of the CRL4B E3 ubiquitin ligase, where halofuginone acts as a molecular glue to drive integrin β4 degradation (PMID:41874446).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 High

    Established the founding role of the WDR18 ortholog by showing that yeast Ipi3 is a Rix1 complex subunit required for late pre-60S maturation, answering whether this WD-repeat protein acts in ribosome biogenesis.

    Evidence GAL-repressible depletion with Northern pre-rRNA analysis and Rpl25-GFP export assay in yeast

    PMID:15528184

    Open questions at the time
    • Did not define which subunit interfaces Ipi3 contacts
    • Mammalian conservation not addressed
  2. 2006 Medium

    Extended the ribosome-biogenesis function to a metazoan ortholog and linked it to tissue proliferation, showing C. elegans PRO-1 affects rRNA processing and non-autonomously controls germline proliferation.

    Evidence Genetic epistasis with ncl-1/lin-35 suppressors and rRNA processing analysis in C. elegans

    PMID:16876152

    Open questions at the time
    • No biochemical complex definition
    • Mechanism of non-autonomous proliferation control unresolved
  3. 2011 High

    Defined the mammalian complex and its regulation, establishing WDR18 as a SENP3-associated PELP1-TEX10-LAS1L-NOL9 subunit needed for 60S maturation/nucleolar release, with SUMO controlling complex partitioning and depletion triggering p53-dependent G1 arrest.

    Evidence Biochemical purification, Co-IP, sucrose gradient fractionation, siRNA knockdown and pre-rRNA processing assays (two independent labs)

    PMID:21326211 PMID:22190735

    Open questions at the time
    • Did not resolve subunit architecture or contact interfaces
    • Direct enzymatic role of WDR18 not defined
  4. 2012 Medium

    Revealed a chromatin-linked function distinct from ribosome biogenesis, showing WDR18 is part of the 5FMC complex recruited by arginine-methylated Chtop to regulate ZBP-89 sumoylation and transactivation.

    Evidence Biotinylation-proteomics, Co-IP, sumoylation and transcription reporter assays in human cells (single lab)

    PMID:22872859

    Open questions at the time
    • Whether 5FMC and rixosome are the same or distinct assemblies unclear
    • Direct WDR18 contribution to desumoylation activity not isolated
  5. 2013 Medium

    Implicated WDR18 in DNA damage signaling, showing it binds TopBP1 and Chk1 and is required for ATR-dependent Chk1 phosphorylation.

    Evidence Co-IP in vivo and in vitro binding, siRNA knockdown with Chk1 phosphorylation readout (single lab)

    PMID:23333389

    Open questions at the time
    • No reciprocal validation of direct binding
    • Relationship to the nucleolar complex function unestablished
  6. 2016 Medium

    Identified a replication-licensing role, showing WDR18 promotes MCM chromatin loading, hMCM7 nuclear localization, and binds replication origins with cell-cycle-regulated expression.

    Evidence siRNA knockdown, chromatin fractionation, ChIP, Co-IP and immunofluorescence in human cells (single lab)

    PMID:27057756

    Open questions at the time
    • Direct vs. indirect role in origin binding unresolved
    • Mechanistic overlap with checkpoint and rixosome functions not reconciled
  7. 2022 High

    Provided the first near-atomic view of the human PELP1–WDR18 subcomplex, resolving a PELP1₂-WDR18₂ tetramer and showing WDR18 binding directs PELP1 away from steroid-receptor coactivation.

    Evidence Cryo-EM at 2.7 Å with reconstitution and mutagenesis

    PMID:36351913

    Open questions at the time
    • Catalytic module not included in the structure
    • Functional consequence on pre-rRNA processing not directly tested
  8. 2023 High

    Defined the mechanistic action of the Ipi3-containing sphere module on pre-60S particles, showing it lands via Sda1, drives 5S RNP rotation, and positions the Las1-Grc3 module for ITS2 cleavage.

    Evidence Cryo-EM, biochemical complex isolation and mutagenesis in C. thermophilum (ortholog)

    PMID:37921038

    Open questions at the time
    • Human-specific structural confirmation pending
    • Dynamics of rotation step not temporally resolved
  9. 2025 High

    Established WDR18 as the central scaffold of the human rixosome core, mapping two TEX10-contact regions and a C-terminal helix that docks LAS1L, bridging the catalytic module to the PELP1-TEX10 core.

    Evidence Cryo-EM structures with site-directed mutagenesis and binding assays of human subcomplexes

    PMID:40195365

    Open questions at the time
    • Full intact rixosome on the pre-60S not resolved at high resolution
    • Regulation of bridging by SUMO/methylation not structurally captured
  10. 2026 Medium

    Uncovered an E3 ligase function, identifying WDR18 as a CRL4B substrate receptor exploited by halofuginone as a molecular glue to degrade integrin β4.

    Evidence High-throughput screening, in vitro and in vivo degradation assays, ligase complex identification (single lab)

    PMID:41874446

    Open questions at the time
    • Mechanistic validation depth limited
    • Endogenous substrates and relationship to nucleolar role undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WDR18's distinct activities—rixosome scaffolding, replication licensing, checkpoint signaling, transcriptional regulation, and CRL4B substrate-receptor function—are partitioned and regulated within a single protein remains unresolved.
  • No study reconciles nucleolar vs. nuclear/replication functions
  • Whether E3 ligase and rixosome roles use the same WD40 surface is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005730 nucleolus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1
Partners
CHK1LAS1LMCM7NOL9PELP1SENP3TEX10TOPBP1
Complex memberships
5FMC complexCRL4B E3 ubiquitin ligaserixosome/Rix1 complex (PELP1-WDR18-TEX10-LAS1L-NOL9)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 WDR18 is a component of a mammalian SENP3-associated complex (PELP1-TEX10-WDR18), biochemically purified and demonstrated to be involved in maturation and nucleolar release of the large (60S) ribosomal subunit; SUMO conjugation/deconjugation of PELP1 controls the nucleolar partitioning of this complex. Biochemical purification, Co-IP, knockdown with ribosome biogenesis defect readout The EMBO journal High 21326211
2011 WDR18 (mammalian homolog of yeast Rix1/Ipi3 complex subunit) interacts with LAS1L, PELP1, TEX10, NOL9, and SENP3 to form a nucleolar complex that cofractionates with the 60S preribosomal subunit; depletion of complex members causes defects in processing of pre-rRNA ITS2 and triggers p53-dependent G1 arrest. Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown, pre-rRNA processing assay Molecular biology of the cell High 22190735
2012 WDR18 is a core component of the Five Friends of Methylated Chtop (5FMC) nuclear complex, which also includes PELP1, SENP3, TEX10, and LAS1L; the complex is recruited to chromatin only when Chtop is arginine-methylated by PRMT1, and recruitment of 5FMC to the transcription factor ZBP-89 affects its sumoylation status and transactivation potential, linking arginine methylation to desumoylation in transcriptional control. Biotinylation-proteomics pulldown, Co-IP, sumoylation assay, transcription reporter assay Molecular & cellular proteomics : MCP Medium 22872859
2013 WDR18 associates with the C-terminus of TopBP1 in vitro and in vivo (Co-IP and in vitro binding), and also associates with Chk1 in vitro; this association is required for ATR-dependent Chk1 phosphorylation in response to DNA damage, identifying WDR18 as a component of the DNA damage checkpoint signaling pathway. Co-immunoprecipitation, in vitro binding assay, siRNA knockdown, Chk1 phosphorylation assay Biochemical and biophysical research communications Medium 23333389
2016 Human IPI3/WDR18 is required for DNA replication licensing: knockdown of hIPI3 causes defects in chromatin association of the MCM complex, DNA replication, cell cycle progression, and cell proliferation; hIPI3 interacts with other pre-replicative complex proteins, co-localizes with hMCM7 in the nucleus, is required for nuclear localization of hMCM7, and preferentially binds origins of DNA replication (c-Myc, Lamin-B2, β-Globin loci), with mRNA/protein levels peaking from M phase to early G1. siRNA knockdown, chromatin fractionation, co-immunoprecipitation, ChIP, immunofluorescence, cell cycle analysis PloS one Medium 27057756
2011 Zebrafish wdr18 is expressed in dorsal forerunner cells (DFCs) and Kupffer's vesicle (KV); morpholino knockdown of wdr18 results in fewer and shorter immotile KV cilia, disorganized DFC clustering/migration, mis-expression of Nodal-related genes (spaw, pitx2), and laterality defects in visceral organs; genetic interaction with itgb1b was demonstrated by double morpholino injection. Morpholino knockdown, in situ hybridization, cilia motility analysis, genetic epistasis (double morpholino) PloS one Medium 21876750
2022 Cryo-EM structure of the human PELP1 Rix1 domain–WDR18 subcomplex at 2.7 Å resolution reveals an interconnected tetrameric assembly (PELP12-WDR182); the structure shows the architecture of PELP1's eleven LxxLL signaling motifs but demonstrates that none is in a conformation compatible with steroid receptor binding, suggesting that WDR18 association directs PELP1 activity away from steroid receptor coactivation. Cryo-EM structure determination (2.7 Å), complex reconstitution, mutagenesis Nature communications High 36351913
2004 Yeast Ipi3 (ortholog of WDR18) is a component of the Rix1 complex (Rix1-Ipi1-Ipi3); strains depleted of Ipi3 show defects in pre-rRNA processing and late pre-60S ribosome stability (after ITS2 cleavage, before mature 5.8S rRNA generation), and nuclear accumulation of Rpl25-GFP, phenocopying Rea1 depletion. GAL::repressible depletion, pre-rRNA processing analysis (Northern blot), in vivo 60S export assay (Rpl25-GFP) The Journal of biological chemistry High 15528184
2020 Cryo-EM analysis of yeast pre-60S intermediates reveals that the Rix1 complex (including Ipi3/WDR18 ortholog) forms a Rix12-Ipi32 tetramer anchored via Ipi1 to the pre-ribosome, positioned to monitor central protuberance formation and coordinate with the AAA-ATPase Rea1 during two successive structural remodeling steps of 60S maturation. Cryo-EM structural analysis of pre-60S intermediates Molecular cell High 32668200
2023 Cryo-EM and biochemical analysis of the rixosome from Chaetomium thermophilum (ortholog of human complex) shows that the Rix1-Ipi3-Ipi1 sphere sub-module (containing Ipi3/WDR18 ortholog) uses Sda1 as a landing platform on nucleoplasmic pre-60S particles, wedges between the 5S rRNA tip and L1-stalk to facilitate 180° rotation of the immature 5S RNP, and positions the Las1-Grc3 catalytic module for ITS2 cleavage. Cryo-EM structure, biochemical complex isolation, mutagenesis EMBO reports High 37921038
2025 Cryo-EM structures of human PELP1-WDR18-TEX10 and LAS1L-NOL9 complexes, and a lower-resolution model of PELP1-WDR18-LAS1L, reveal the overall organization of the human rixosome core scaffold; WDR18 contacts TEX10 at two regions (mutagenesis of either blocks TEX10 binding) and its C-terminal helix contacts the helical domain of LAS1L (truncation abolishes LAS1L binding), establishing WDR18 as a central scaffold bridging the catalytic LAS1L-NOL9 module to the PELP1-TEX10 core. Cryo-EM structure determination, site-directed mutagenesis, binding assays Nature communications High 40195365
2026 WDR18 is a substrate receptor subunit of the CRL4B E3 ubiquitin ligase complex (CRL4BWDR18); halofuginone acts as a molecular glue degrader that promotes integrin β4 degradation via this CRL4BWDR18 complex. High-throughput screening, degradation assays in vitro and in vivo, E3 ligase complex identification Advanced science Medium 41874446
2006 C. elegans PRO-1, the ortholog of yeast IPI3/WDR18, influences rRNA processing (as shown by suppression of pro-1 germline tumors by mutations in ncl-1 or lin-35/Rb that elevate pre-rRNA levels), establishing a role for this protein in ribosome biogenesis that non-autonomously affects germline proliferation. Genetic epistasis (suppressor mutations), rRNA processing analysis, morphological phenotype scoring Developmental biology Medium 16876152

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro-oncology 397 29106665
2011 The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. The EMBO journal 110 21326211
2011 LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis. Molecular biology of the cell 89 22190735
2004 Rea1, a dynein-related nuclear AAA-ATPase, is involved in late rRNA processing and nuclear export of 60 S subunits. The Journal of biological chemistry 62 15528184
2011 SUMO routes ribosome maturation. Nucleus (Austin, Tex.) 61 22064470
2024 Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial. The Lancet. Oncology 55 38608691
2012 Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation. Molecular & cellular proteomics : MCP 49 22872859
2020 Construction of the Central Protuberance and L1 Stalk during 60S Subunit Biogenesis. Molecular cell 48 32668200
2006 Alterations in ribosome biogenesis cause specific defects in C. elegans hermaphrodite gonadogenesis. Developmental biology 47 16876152
1995 Genetic enhancement of RNA-processing defects by a dominant mutation in B52, the Drosophila gene for an SR protein splicing factor. Molecular and cellular biology 41 7565780
2004 Cloning and expression of the human NMDA receptor subunit NR3B in the adult human hippocampus. Neuroscience letters 29 15722182
2019 A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development. Cellular oncology (Dordrecht, Netherlands) 21 31691159
1994 Suppressor U1 snRNAs in Drosophila. Genetics 18 7828820
2022 Cryo-EM reveals the architecture of the PELP1-WDR18 molecular scaffold. Nature communications 16 36351913
2013 WD40-repeat protein WDR18 collaborates with TopBP1 to facilitate DNA damage checkpoint signaling. Biochemical and biophysical research communications 14 23333389
2011 Wdr18 is required for Kupffer's vesicle formation and regulation of body asymmetry in zebrafish. PloS one 12 21876750
2009 Diffuse large B-cell lymphoma: experience from a tertiary care center in North India. Medical oncology (Northwood, London, England) 12 19350421
2022 Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males. Journal of translational medicine 10 35659704
2023 Granulomatous and Sarcoid-like Immune-Related Adverse Events following CTLA4 and PD1 Blockade Adjuvant Therapy of Melanoma: A Combined Analysis of ECOG-ACRIN E1609 and SWOG S1404 Phase III Trials and a Literature Review. Cancers 8 37174027
2023 Structural insights into coordinating 5S RNP rotation with ITS2 pre-RNA processing during ribosome formation. EMBO reports 6 37921038
2019 The interaction networks of the budding yeast and human DNA replication-initiation proteins. Cell cycle (Georgetown, Tex.) 6 30890025
2016 A Role of hIPI3 in DNA Replication Licensing in Human Cells. PloS one 6 27057756
2024 An atlas of the shared genetic architecture between atopic and gastrointestinal diseases. Communications biology 4 39719505
2025 Molecular insights into the overall architecture of human rixosome. Nature communications 3 40195365
2025 Dramatic Responses to High-Dose Ipilimumab Plus Temozolomide After Progression on Standard- or Low-Dose Ipilimumab in Advanced Melanoma. Current oncology (Toronto, Ont.) 1 40136348
2025 Whole Genome Sequencing of "Mutation-Negative" Individuals With Cornelia de Lange Syndrome. Human mutation 1 40677927
2025 Molecular Mechanism of Body Color Change in the Ecological Seedling Breeding Model of Apostichopus japonicus. Biology 1 40723429
2023 Response to high dose ipilimumab plus temozolomide after progression on standard or low dose ipilimumab in advanced melanoma: a retrospective analysis. Research square 1 37398360
2026 Halofuginone is a Molecular Glue Degrader of Integrin β4. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41874446

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