Affinage

WDR18

WD repeat-containing protein 18 · UniProt Q9BV38

Round 2 corrected
Length
432 aa
Mass
47.4 kDa
Annotated
2026-04-28
59 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR18 is a WD-repeat scaffold protein that functions as a core subunit of the mammalian rixosome (PELP1–WDR18–TEX10–LAS1L–NOL9–SENP3), the complex responsible for 60S ribosomal subunit maturation and ITS2 pre-rRNA processing. Within this complex, WDR18 forms a heterotetrameric assembly with PELP1, bridges TEX10 via two distinct contact sites, and recruits LAS1L through its C-terminal helix, thereby coupling the Rix1 sphere sub-module to the Las1–Grc3/NOL9 endonuclease–kinase sub-module that executes ITS2 cleavage during 5S RNP rotation on pre-60S particles (PMID:36351913, PMID:40195365, PMID:37921038). Beyond ribosome biogenesis, WDR18 participates in DNA damage checkpoint signaling by associating with TopBP1 and Chk1 to facilitate ATR-dependent Chk1 phosphorylation (PMID:23333389), contributes to DNA replication licensing by promoting MCM complex chromatin loading at replication origins (PMID:27057756), and can serve as a substrate receptor in the CRL4B E3 ubiquitin ligase complex, where the molecular glue halofuginone redirects it to recruit integrin β4 for proteasomal degradation (PMID:41874446).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Identification of WDR18 as a subunit of the mammalian Rix1-equivalent complex (PELP1–TEX10–WDR18–LAS1L–NOL9–SENP3) established its primary role in 60S ribosomal subunit biogenesis and ITS2 pre-rRNA processing, answering what the human ortholog of yeast Ipi3 does and how SUMO-dependent nucleolar partitioning regulates complex activity.

    Evidence Biochemical purification, reciprocal Co-IP, sucrose gradient fractionation, siRNA knockdown with pre-rRNA processing and G1-arrest phenotypes, SUMO modification assays across two independent labs

    PMID:21326211 PMID:22064470 PMID:22190735

    Open questions at the time
    • Structural basis of how WDR18 contacts other rixosome subunits was unknown
    • Whether WDR18 has functions outside ribosome biogenesis was not addressed
    • Direct role of WDR18 versus other subunits in ITS2 cleavage was unresolved
  2. 2012 Medium

    Discovery that the same PELP1–WDR18–TEX10–LAS1L–SENP3 module is recruited to arginine-methylated Chtop as the '5FMC' complex revealed a second context—transcriptional regulation via desumoylation of the transcription factor ZBP-89—linking ribosome biogenesis components to chromatin-associated signaling.

    Evidence Biotinylation-proteomics, Co-IP, luciferase reporter assays for transactivation

    PMID:22872859

    Open questions at the time
    • Whether WDR18 has a specific role in 5FMC beyond structural scaffolding is unknown
    • Functional significance of 5FMC-mediated desumoylation for endogenous gene regulation was not tested genome-wide
  3. 2013 Medium

    Demonstration that WDR18 binds TopBP1 and Chk1 and is required for ATR-dependent Chk1 phosphorylation established a ribosome-biogenesis-independent role in the DNA damage checkpoint, answering whether WDR18 participates in genome integrity pathways.

    Evidence In vitro and in vivo Co-IP with TopBP1 and Chk1, siRNA knockdown with Chk1 phosphorylation readout after AT70-induced damage

    PMID:23333389

    Open questions at the time
    • Single-lab finding; independent replication is lacking
    • Mechanism of bridging between TopBP1 and Chk1 (direct or complex-mediated) is undefined
    • Whether rixosome subunits co-participate in checkpoint signaling was not tested
  4. 2016 Medium

    Evidence that WDR18 promotes MCM complex chromatin loading at replication origins and that its depletion impairs DNA replication licensing broadened its nuclear functions to the initiation of DNA replication.

    Evidence siRNA knockdown, BrdU incorporation, ChIP at c-Myc/Lamin-B2/β-Globin origins, Co-IP with replication-initiation proteins, immunofluorescence co-localization with MCM7

    PMID:27057756

    Open questions at the time
    • Single-lab study; replication licensing role not independently confirmed
    • Whether WDR18 acts at origins as part of the rixosome or independently is unknown
    • Biochemical mechanism linking a WD-repeat protein to pre-RC assembly is not defined
  5. 2020 High

    Cryo-EM of yeast pre-60S intermediates revealed that the Rix1 complex (Ipi3/WDR18 ortholog included) forms a Rix1²–Ipi3² tetramer positioned near the central protuberance to monitor L1-stalk maturation in concert with Rea1, establishing the structural logic of WDR18's role in ribosome remodeling.

    Evidence Cryo-EM of multiple pre-60S states in S. cerevisiae

    PMID:32668200

    Open questions at the time
    • Human-specific structural features of WDR18 in pre-60S context were not resolved
    • Functional contribution of WDR18/Ipi3 versus Rix1/PELP1 within the tetramer was not dissected
  6. 2022 High

    Determination of the 2.7 Å cryo-EM structure of the human PELP1–WDR18 heterotetramer revealed the atomic architecture of the core rixosome scaffold and showed that WDR18 association occludes PELP1's LxxLL motifs, structurally explaining how rixosome assembly diverts PELP1 from steroid receptor coactivation.

    Evidence Cryo-EM at 2.7 Å, complex reconstitution, biochemical subcomplex mapping

    PMID:36351913

    Open questions at the time
    • How TEX10 and LAS1L attach to the PELP1–WDR18 core was not structurally resolved
    • Whether PELP1 switches between SR-coactivation and rixosome pools in vivo was not tested
  7. 2023 High

    Cryo-EM of the Chaetomium thermophilum rixosome on pre-60S particles showed how the Rix1 sub-module (including WDR18 ortholog) wedges between 5S rRNA and the L1 stalk to enable the 180° 5S RNP rotation required for ITS2 cleavage by Las1, providing the mechanistic basis for rixosome-coupled pre-rRNA processing.

    Evidence Cryo-EM of isolated rixosome and pre-60S-bound states from C. thermophilum

    PMID:37921038

    Open questions at the time
    • Whether the human rixosome engages the pre-60S in an identical geometry was not confirmed
    • Regulatory inputs controlling rixosome docking timing are unresolved
  8. 2025 High

    High-resolution structures of human PELP1–WDR18–TEX10 and PELP1–WDR18–LAS1L defined the precise interfaces by which WDR18 bridges the sphere and butterfly sub-modules: two WDR18 regions contact TEX10 and a C-terminal helix contacts LAS1L, answering how the full rixosome is assembled.

    Evidence Cryo-EM of human subcomplexes, site-directed mutagenesis disrupting each contact, biochemical binding assays

    PMID:40195365

    Open questions at the time
    • Complete structure of the fully assembled human rixosome on a pre-60S particle is still lacking
    • Conformational change of TEX10 upon ribosome engagement needs mechanistic explanation
  9. 2026 Medium

    Discovery that WDR18 functions as a substrate receptor in the CRL4B E3 ubiquitin ligase complex and that halofuginone acts as a molecular glue to recruit integrin β4 for degradation revealed an unexpected ubiquitin-ligase adaptor function for WDR18 outside ribosome biogenesis.

    Evidence High-throughput screening, Co-IP, ubiquitination assay, in vitro and in vivo degradation assays

    PMID:41874446

    Open questions at the time
    • Endogenous substrates of CRL4B-WDR18 in the absence of molecular glue are unknown
    • Whether CRL4B-WDR18 activity intersects with ribosome biogenesis or checkpoint functions is unexplored
    • Single-lab finding; independent replication is awaited

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of physiological CRL4B-WDR18 substrates, a complete cryo-EM structure of the human rixosome on the pre-60S particle, and whether WDR18's checkpoint and replication-licensing functions operate through the rixosome or represent independent moonlighting activities.
  • No endogenous CRL4B-WDR18 substrates identified
  • Full human rixosome-on-pre-60S structure not yet determined
  • Mechanistic relationship between ribosome biogenesis and DNA replication/checkpoint roles is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005730 nucleolus 3 GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-392499 Metabolism of proteins 1 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1
Partners
CHEK1LAS1LMCM7NOL9PELP1SENP3TEX10TOPBP1
Complex memberships
5FMC (Five Friends of Methylated Chtop)CRL4B-WDR18 E3 ubiquitin ligaseRix1/rixosome (PELP1-WDR18-TEX10-LAS1L-NOL9-SENP3)

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 PELP1-TEX10-WDR18 complex (homologous to the yeast Rix1 complex) that is involved in maturation and nucleolar release of the large (60S) ribosomal subunit. Biochemical purification showed this complex associates with SENP3, and SUMO conjugation/deconjugation of PELP1 controls the nucleolar partitioning of the complex, thereby regulating ribosome biogenesis. Biochemical purification (SENP3-associated complex isolation), co-immunoprecipitation, functional depletion assays The EMBO journal High 21326211
2011 WDR18 (as part of the PELP1-TEX10-WDR18-LAS1L-NOL9-SENP3 complex) co-fractionates with the 60S preribosomal subunit. Depletion of complex members including WDR18-associated proteins causes a p53-dependent G1 arrest and defects in processing of the pre-rRNA ITS2 region. Nucleolar localization of the complex requires active RNA Pol I transcription and SENP3. Co-immunoprecipitation, sucrose gradient fractionation, siRNA knockdown with phenotypic readout (G1 arrest, pre-rRNA processing defects), fluorescence microscopy Molecular biology of the cell High 22190735
2011 SUMO-dependent subnuclear trafficking controls the PELP1-TEX10-WDR18 complex. PELP1 is a SENP3-sensitive SUMO target; lack of SENP3-mediated desumoylation prevents nucleolar partitioning of the PELP1-WDR18-TEX10 complex, restricting premature loading onto 60S particles and limiting ribosome maturation rate. SUMO modification assays, SENP3 depletion/overexpression, subcellular fractionation, imaging Nucleus (Austin, Tex.) Medium 22064470
2012 WDR18 is a member of the 'Five Friends of Methylated Chtop' (5FMC) nuclear complex, recruited to the chromatin-associated protein Chtop only when Chtop is arginine-methylated by PRMT1. The 5FMC complex (PELP1, SENP3, WDR18, TEX10, LAS1L) affects the sumoylation status and transactivation potential of the transcription factor ZBP-89, linking arginine methylation to desumoylation in transcriptional control. PELP1 functions as the core scaffold; other components including WDR18 become unstable in its absence. Biotinylation-proteomics (BioID-like), co-immunoprecipitation, luciferase reporter assays, western blotting Molecular & cellular proteomics : MCP Medium 22872859
2013 WDR18 associates with the C-terminus of TopBP1 (in vitro and in vivo) and with Chk1 in vitro. This association is required for ATR-dependent Chk1 phosphorylation in response to DNA damage (AT70-induced). WDR18 depletion abolishes Chk1 activation, identifying WDR18 as a DNA damage checkpoint protein that facilitates ATR-Chk1 signaling by bridging TopBP1 and Chk1. Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown with Chk1 phosphorylation readout Biochemical and biophysical research communications Medium 23333389
2011 Zebrafish wdr18 is expressed in dorsal forerunner cells (DFCs) and Kupffer's vesicle (KV). Morpholino knockdown of wdr18 causes laterality defects (mis-expression of Nodal-related genes spaw and pitx2), KV with fewer, shorter, immotile cilia and smaller cavity, and disorganized DFC clustering and migration. Genetic interaction with itgb1b was demonstrated by double morpholino injection, placing wdr18 in a pathway controlling DFC migration and left-right asymmetry determination. Morpholino knockdown, in situ hybridization, cilia motility analysis, genetic epistasis (double morpholino), fluorescence imaging with cell-lineage markers PloS one Medium 21876750
2016 Human WDR18 (hIPI3) is required for DNA replication licensing. Knockdown causes defects in chromatin association of the MCM complex, DNA replication, and cell cycle progression without affecting global protein synthesis. hIPI3 protein and mRNA levels peak from M phase to early G1, similar to pre-RC proteins. hIPI3 interacts with replication-initiation proteins, co-localizes with hMCM7 in the nucleus, is important for nuclear localization of hMCM7, and preferentially binds origins of replication at c-Myc, Lamin-B2, and β-Globin loci. siRNA knockdown, DNA replication assay (BrdU incorporation), ChIP at replication origins, co-immunoprecipitation, immunofluorescence co-localization, cell cycle analysis PloS one Medium 27057756
2019 In systematic pairwise yeast two-hybrid and co-immunoprecipitation analyses of human replication-initiation proteins, WDR18 (hIPI3) was found to interact with several pre-RC and pre-IC proteins, including novel interactions not previously reported, consistent with its role in replication licensing. Yeast two-hybrid (systematic pairwise), co-immunoprecipitation validation of novel interactions Cell cycle (Georgetown, Tex.) Low 30890025
2022 Cryo-EM structure of the human PELP1-WDR18 subcomplex was determined at 2.7 Å, revealing an interconnected tetrameric assembly (PELP1-WDR18 heterotetramer). The structure shows the architecture of PELP1's eleven LxxLL motifs previously implicated in steroid receptor (SR) signaling; none is in a conformation compatible with SR binding, suggesting that WDR18 association directs PELP1 activity away from SR coactivation toward Rix1 complex functions. PELP1 was confirmed as the central scaffold of the human Rix1 complex (PELP1, WDR18, TEX10, SENP3) by reconstitution. Cryo-EM (2.7 Å structure), complex reconstitution, biochemical subcomplex mapping Nature communications High 36351913
2020 The yeast Rix1 complex (Rix1-Ipi1-Ipi3, orthologs of human PELP1-TEX10-WDR18) forms a Rix1²-Ipi3² tetramer anchored to the pre-60S ribosome via Ipi1. Cryo-EM analysis of nuclear pre-60S intermediates shows this complex is strategically positioned near the central protuberance to monitor and assist large-scale structural remodeling events including L1 stalk maturation, working in concert with the AAA-ATPase Rea1. Cryo-EM of pre-60S intermediates (multiple states), structural modeling Molecular cell High 32668200
2023 Cryo-EM structures of the conserved rixosome from Chaetomium thermophilum (Rix1-Ipi3-Ipi1 sphere sub-module plus Las1-Grc3 butterfly sub-module) reveal how the Rix1 complex (WDR18 ortholog Ipi3 included) wedges between the 5S rRNA tip and L1-stalk on nucleoplasmic pre-60S particles to facilitate 180° rotation of the immature 5S RNP, enabling ITS2 pre-rRNA cleavage by Las1 endonuclease and phosphorylation by Grc3 kinase. Cryo-EM structural analysis of isolated rixosome and pre-60S-bound states, biochemical isolation EMBO reports High 37921038
2025 Cryo-EM structures of the human PELP1-WDR18-TEX10 complex and the LAS1L-NOL9 complex were determined, plus a lower-resolution model of PELP1-WDR18-LAS1L. WDR18 contacts TEX10 at two distinct regions and its C-terminal helix contacts the helical domain of LAS1L. Mutagenesis confirmed that disrupting either WDR18-TEX10 contact blocks TEX10 binding, and truncation of the WDR18 C-terminal helix abolishes LAS1L recruitment. TEX10 undergoes substantial conformational changes between the PELP1-WDR18-TEX10 complex alone and when bound to the pre-ribosome. Cryo-EM structure determination, site-directed mutagenesis, biochemical binding assays Nature communications High 40195365
2026 WDR18 functions as a substrate receptor within the CRL4B^WDR18 E3 ubiquitin ligase complex. The natural product halofuginone acts as a molecular glue that promotes recruitment of integrin β4 to this CRL4B-WDR18 complex, leading to integrin β4 polyubiquitination and proteasomal degradation. High-throughput screening, co-immunoprecipitation, ubiquitination assay, in vitro and in vivo degradation assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41874446

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Nucleolar proteome dynamics. Nature 934 15635413
2002 Directed proteomic analysis of the human nucleolus. Current biology : CB 780 11790298
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2018 Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro-oncology 392 29106665
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2004 The DNA sequence and biology of human chromosome 19. Nature 271 15057824
2016 The cell proliferation antigen Ki-67 organises heterochromatin. eLife 265 26949251
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2013 The protein interaction landscape of the human CMGC kinase group. Cell reports 174 23602568
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2020 Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer. Molecular cell 159 32416067
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2020 AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Signal Transduction System. Molecular cell 152 31995728
2011 Maintenance of silent chromatin through replication requires SWI/SNF-like chromatin remodeler SMARCAD1. Molecular cell 148 21549307
2011 The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex. The EMBO journal 109 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
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
2006 Alterations in ribosome biogenesis cause specific defects in C. elegans hermaphrodite gonadogenesis. Developmental biology 47 16876152
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 46 38608691
2020 Construction of the Central Protuberance and L1 Stalk during 60S Subunit Biogenesis. Molecular cell 46 32668200
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 7 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