Affinage

WDR11

WD repeat-containing protein 11 · UniProt Q9BZH6

Length
1224 aa
Mass
136.7 kDa
Annotated
2026-06-11
44 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WDR11 is a WD-repeat β-propeller protein that operates at the interface of trans-Golgi network (TGN) membrane trafficking and Hedgehog-dependent developmental signalling (PMID:29263200, PMID:29426865). At the TGN, WDR11 assembles into a stable complex with FAM91A1 and C17orf75 that is recruited onto AP-1-derived vesicles and tethers them at the TGN via golgin-245 through recruitment of TBC1D23, with loss of WDR11 sharply reducing golgin-245-dependent vesicle capture (PMID:29426865). A cryo-EM structure of the WDR11–FAM91A1 complex shows that WDR11 directly recognizes super-acidic clusters (SACs) on cargo proteins, acting as a sequence-specific cargo receptor required for endosome-to-TGN transport of SAC-containing cargo and for neuronal development (PMID:39013469). In parallel, WDR11 shuttles between the primary cilium and the nucleus in response to Hedgehog signalling, where it regulates proteolytic processing of GLI3 and cooperates with the homeodomain transcription factor EMX1 to drive Hh target gene expression and GnRH neuron development; loss-of-function abolishes ciliogenesis and Hh signalling in mouse and zebrafish (PMID:20887964, PMID:29263200). WDR11 governs both canonical and noncanonical (PTCH2/GAS1) Hedgehog branches and is required for primordial germ cell motility and proliferation, in part through interaction with the ciliary protein IFT20 (PMID:37516749). Disease-associated missense mutations in the WD domains disrupt EMX1 binding and nuclear localization, linking WDR11 loss-of-function to congenital hypogonadotropic hypogonadism/Kallmann syndrome (PMID:20887964, PMID:28453858).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2001 Medium

    Established WDR11 as a ubiquitously expressed WD-repeat gene at a tumor-associated locus, providing the first molecular handle before any function was known.

    Evidence Positional cloning and breakpoint characterization of a t(10;19) translocation in a glioblastoma cell line

    PMID:11536051

    Open questions at the time
    • No functional role for the gene or chimeric transcript demonstrated
    • Causal link to glioma tumorigenesis not established
  2. 2010 Medium

    Identified the first functional partner of WDR11 and tied it to a developmental phenotype, showing WD-domain mutations disrupt the EMX1 interaction relevant to pubertal development.

    Evidence Co-immunoprecipitation with disease-associated missense mutant constructs

    PMID:20887964

    Open questions at the time
    • Mechanism by which WDR11-EMX1 binding controls transcription not defined
    • Single-lab interaction data
  3. 2017 High

    Placed WDR11 within the Hedgehog pathway, defining a cilium-to-nucleus shuttling role that links GLI3 processing and EMX1-dependent transcription to ciliogenesis and GnRH biology.

    Evidence Wdr11 knockout mouse, zebrafish knockdown, cilium-to-nucleus imaging, GLI3 processing assay, Hh reporter and agonist rescue; plus a mutation abolishing EMX1 binding and nuclear localization shown by leptomycin B assay

    PMID:28453858 PMID:29263200

    Open questions at the time
    • Molecular basis of nucleocytoplasmic shuttling not resolved
    • How WDR11 mechanistically alters GLI3 processing unclear
    • Relationship between ciliary and transcriptional functions unmapped
  4. 2018 High

    Defined a distinct membrane-trafficking role, showing WDR11 is a stable complex subunit that tethers AP-1-derived vesicles at the TGN, separating this activity from the ciliary signalling function.

    Evidence Stable complex purification, knockout cells, in vitro vesicle tethering assay, super-resolution microscopy, golgin relocation assay

    PMID:29426865

    Open questions at the time
    • Cargo identity not yet defined
    • Whether trafficking and Hedgehog roles are mechanistically connected unknown
  5. 2023 Medium

    Extended WDR11's Hedgehog role to both canonical and noncanonical branches and to primordial germ cell development, implicating a direct ciliary interaction with IFT20.

    Evidence Wdr11-deficient mouse embryos, SMO localization imaging, PGC motility/proliferation assays, WDR11-IFT20 co-immunoprecipitation

    PMID:37516749

    Open questions at the time
    • WDR11-IFT20 interaction shown by single Co-IP without reciprocal validation
    • Mechanism distinguishing canonical vs noncanonical branch regulation unresolved
  6. 2024 High

    Provided the structural and biochemical basis for cargo selection, identifying WDR11 as a sequence-specific receptor for super-acidic-cluster motifs.

    Evidence Cryo-EM of WDR11-FAM91A1, in vitro binding assays, knockout/rescue, zebrafish neuronal development assay

    PMID:39013469

    Open questions at the time
    • Full repertoire of SAC-containing cargo not catalogued
    • Connection between cargo trafficking defects and Hedgehog/GnRH phenotypes not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WDR11's TGN cargo-receptor activity and its ciliary/Hedgehog signalling functions are integrated into a single coherent mechanism remains unresolved.
  • Whether disease mutations act primarily through trafficking or signalling defects is unknown
  • No unified model linking SAC cargo transport to GLI3 processing and EMX1 transcription

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0038024 cargo receptor activity 2 GO:0140110 transcription regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 2 GO:0005794 Golgi apparatus 2 GO:0005929 cilium 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
C17ORF75EMX1FAM91A1GOLGIN-245IFT20TBC1D23
Complex memberships
WDR11 complex (WDR11-FAM91A1-C17orf75)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 WDR11 protein interacts with EMX1, a homeodomain transcription factor involved in olfactory neuron development. Missense mutations in WD domains (A435T, R448Q, H690Q) reduce or abolish this interaction, implicating WDR11-EMX1 interaction in normal pubertal development. Co-immunoprecipitation / protein-protein interaction assay with missense mutant constructs American journal of human genetics Medium 20887964
2017 WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. WDR11 shuttles from the cilium to the nucleus in response to Hh signalling, regulates proteolytic processing of GLI3, and cooperates with transcription factor EMX1 to induce downstream Hh pathway gene expression and GnRH production. Loss-of-function in mouse and zebrafish causes defective Hh signalling and ciliated tissue dysgenesis. CHH/KS-associated human mutations result in loss of WDR11 function. Wdr11 knockout mouse, zebrafish knockdown, immunofluorescence/live imaging of cilium-to-nucleus shuttling, GLI3 processing assay, luciferase reporter for Hh target gene expression, Hh agonist rescue experiment EMBO reports High 29263200
2017 A WDR11 missense mutation (I436V) causes loss of capacity to bind its functional partner EMX1 and loss of nuclear localization, as demonstrated by Western blotting, co-immunofluorescence, and leptomycin B nuclear export inhibition assays. Western blotting, co-immunofluorescence, leptomycin B treatment with immunofluorescence The Journal of clinical endocrinology and metabolism Medium 28453858
2018 WDR11 forms a stable complex with FAM91A1 and C17orf75 (the WDR11 complex) that localises to the TGN region. The complex is recruited onto AP-1-derived vesicles (not AP-1 itself) and facilitates their tethering at the TGN via golgin-245 by recruiting TBC1D23. Knockout of WDR11 substantially reduces capture of vesicles by golgin-245 in a tethering assay. Stable complex purification, knockout cells, vesicle tethering assay, structured illumination microscopy, golgin relocation assay Nature communications High 29426865
2015 WDR11 is a TGN-resident protein that interacts specifically with HSV virion components (including ICP0) at the trans-Golgi network. During HSV infection, WDR11 undergoes dramatic relocalization from defined perinuclear TGN structures to a dispersed cytoplasmic distribution, dependent on viral late gene expression (not ICP0). Knockdown of WDR11 produces a modest but consistent decrease in yields of both wild-type and ICP0-null viruses without affecting viral gene expression, suggesting a role in viral assembly and/or secondary envelopment. Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, viral yield assay Journal of virology Medium 26178983
2024 Cryo-EM structure of the human WDR11-FAM91A1 complex reveals that WDR11 directly and specifically recognizes a subset of acidic clusters termed super acidic clusters (SACs) on cargo proteins. WDR11 complex assembly and SAC-binding are indispensable for the trafficking of SAC-containing proteins from endosomes to the TGN and for proper neuronal development in zebrafish. Cryo-EM structure determination, in vitro binding assays, WDR11 complex knockout/rescue, zebrafish neuronal development assay Cell High 39013469
2001 WDR11 is a WD-repeat gene disrupted by a balanced t(10;19) reciprocal translocation in the A172 glioblastoma cell line. The translocation deletes exon 5, resulting in a chimeric transcript encoding a WDR11 polypeptide truncated after the second of six WD-repeats, fused to the 3' UTR of ZNF320. WDR11 is ubiquitously expressed and maps to chromosome 10q26, a region with frequent LOH in glial tumors. Positional cloning, RT-PCR, Northern blot, FISH Oncogene Medium 11536051
2023 WDR11 is required for primordial germ cell (PGC) development, regulating both canonical (PTCH1/BOC-cilia-dependent) and noncanonical (PTCH2/GAS1-cilia-independent) Hedgehog signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation. PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside cilia, respectively, and WDR11 loss affects SMO signalling in both contexts. WDR11 also promotes ciliogenesis potentially through interaction with IFT20, and GAS1 is induced by PTCH2-specific HH signalling in a WDR11-dependent manner. Wdr11-deficient mouse embryo analysis, co-immunoprecipitation (WDR11-IFT20), immunofluorescence of SMO localisation, PGC motility and proliferation assays Scientific reports Medium 37516749
2017 WDR11 overexpression in Group 3 medulloblastoma (G3 MB) tumorspheres leads to extended survival in a mouse G3 MB model and downregulates genes in the WNT signalling pathway (including Ccnd1/2/3, Myc, Tcf7l1), consistent with tumor suppressive activity mediated through WNT pathway inhibition. Whole-exome sequencing, overexpression survival experiment, transcriptome analysis of G3 MB tumorspheres Oncotarget Low 29029386

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Melanoma cells present a MAGE-3 epitope to CD4(+) cytotoxic T cells in association with histocompatibility leukocyte antigen DR11. The Journal of experimental medicine 177 10049951
2010 WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. American journal of human genetics 131 20887964
2003 FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26. International journal of oncology 123 12684685
2003 Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. International journal of molecular medicine 68 12684693
2013 A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2. Human molecular genetics 65 24105470
2001 Characterization of novel HLA-DR11-restricted HCV epitopes reveals both qualitative and quantitative differences in HCV-specific CD4+ T cell responses in chronically infected and non-viremic patients. European journal of immunology 53 11465100
2001 A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells. Oncogene 46 11536051
2017 WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. EMBO reports 39 29263200
1999 Association of HLA-DR11 with the anaphylactoid reaction caused by nonsteroidal anti-inflammatory drugs. The Journal of allergy and clinical immunology 39 10200020
2017 Digenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption Syndrome. The Journal of clinical endocrinology and metabolism 38 28453858
2018 The WDR11 complex facilitates the tethering of AP-1-derived vesicles. Nature communications 34 29426865
2003 Significant association of HLA A2-DR11 with CD4 naive decrease in autistic children. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 14568232
2011 The role of CHD7 and the newly identified WDR11 gene in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Molecular and cellular endocrinology 32 21856375
1993 Implication of HLA-DR residues at positions 67, 71, and 86 in interaction between HLA-DR11 and peptide HA306-320. Journal of immunology (Baltimore, Md. : 1950) 28 7504016
2004 HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology (Oxford, England) 27 15572392
1996 Six new DR52-associated DRB1 alleles, three of DR8, two of DR11, and one of DR6, reflect a variety of mechanisms which generate polymorphism in the MHC. Tissue antigens 23 8883301
2020 GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature. Frontiers in endocrinology 22 32982993
2023 LncRNA WDR11-AS1 Promotes Extracellular Matrix Synthesis in Osteoarthritis by Directly Interacting with RNA-Binding Protein PABPC1 to Stabilize SOX9 Expression. International journal of molecular sciences 20 36614257
2024 The WDR11 complex is a receptor for acidic-cluster-containing cargo proteins. Cell 16 39013469
2006 The wild-type sequence (wt) p53(25-35) peptide induces HLA-DR7 and HLA-DR11-restricted CD4+ Th cells capable of enhancing the ex vivo expansion and function of anti-wt p53(264-272) peptide CD8+ T cells. Journal of immunology (Baltimore, Md. : 1950) 16 17082593
2004 Longitudinal mapping of protective CD4+ T cell responses against HCV: analysis of fluctuating dominant and subdominant HLA-DR11 restricted epitopes. Journal of viral hepatitis 16 15230855
2003 HLA-DR11 in addition to donor age, gender, and major blood group incompatibility influence the incidence of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation proceedings 15 12826219
1994 Individual effects of the DR11-variable beta-chain residues 67, 71, and 86 upon DR(alpha,beta 1*1101)-restricted, peptide-specific T cell proliferation. Journal of immunology (Baltimore, Md. : 1950) 14 7989758
1993 DR6 in Koreans. DR11 frequently acts as a recipient gene to create DR13 alleles. Human immunology 14 8300408
2015 Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at the trans-Golgi Network To Promote Virus Replication. Journal of virology 12 26178983
2019 WDR11 is another causative gene for coloboma, cardiac anomaly and growth retardation in 10q26 deletion syndrome. European journal of medical genetics 11 30711679
1994 An HLA-DRB alpha-helix motif shared by DR11 and DR8 alleles is implicated in the pluriallelic restriction of peptide-specific T-cell lines. Human immunology 11 8002376
2021 Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability. European journal of human genetics : EJHG 10 34413497
1995 Differences in peptide binding of DR11 and DR13 microvariants demonstrate the power of minor variation in generating DR functional diversity. Human immunology 10 7591870
2025 WDR11-DT enhances radiosensitivity via promoting PARP1 degradation and homologous recombination deficiency. Cancer letters 9 40320037
2024 An Insulin-Chromogranin A Hybrid Peptide Activates DR11-Restricted T Cells in Human Type 1 Diabetes. Diabetes 9 38295386
2017 Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget 8 29029386
2022 Deciphering the Plasmodium falciparum malaria-specific CD4+ T-cell response: ex vivo detection of high frequencies of PD-1+TIGIT+ EXP1-specific CD4+ T cells using a novel HLA-DR11-restricted MHC class II tetramer. Clinical and experimental immunology 7 35020841
2014 A Human Papillomavirus Type 16 E6 52-62 CD4 T-Cell Epitope Restricted by the HLA-DR11 Molecule Described in an Epitope Hotspot. MOJ immunology 6 25685851
2005 A new small temperate DNA phage BcP15 isolated from Burkholderia cepacia DR11. Archives of virology 6 16052281
1997 Increased frequency of HLA-DR11 in pediatric human immunodeficiency virus-associated parotid gland enlargement. Clinical and diagnostic laboratory immunology 6 9144359
1995 A human hybridoma monoclonal antibody (TrJ11) recognizing a new HLA-DR epitope shared by DR4, DR8, DR11, and DRB1*1303. Human immunology 5 7538497
2023 Coordination of canonical and noncanonical Hedgehog signalling pathways mediated by WDR11 during primordial germ cell development. Scientific reports 4 37516749
2023 Antifungal activity of Klebsiella grimontii DR11 against Fusarium oxysporum causing soybean root rot. Journal of applied microbiology 4 37884449
2000 Sequence analysis of a new HLA-DR11 allele in a Caucasian Italian family: DRB1*11272. Tissue antigens 3 11144300
2022 Delayed Puberty Due to a WDR11 Truncation at Its N-Terminal Domain Leading to a Mild Form of Ciliopathy Presenting With Dissociated Central Hypogonadism: Case Report. Frontiers in pediatrics 1 35722485
2022 Adult-onset reversible idiopathic hypogonadotropic hypogonadism in male adult carrying a WDR11 missense mutation. BMJ case reports 1 36130823
2009 An HLA-DR11/DQ3 haplotype with a DRB1*0301 sequence motif in the third hypervariable region of the HLA-DR beta-1 chain: molecular and serological analysis of its generation in a European Caucasian family. Tissue antigens 1 19624613
2025 Genomic complexity in advanced gastric and esophageal adenocarcinomas: a case report of rare WDR11-AS1-FGFR2 fusions. Frontiers in oncology 0 41357601

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