Affinage

INTU

Protein inturned · UniProt Q9ULD6

Length
942 aa
Mass
105.6 kDa
Annotated
2026-04-28
35 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INTU (Inturned) is a core subunit of the CPLANE complex (with FUZ and WDPCP) that functions as a ciliary assembly factor essential for primary cilia formation, intraflagellar transport A (IFT-A) complex assembly, and cilia-dependent Hedgehog signaling. INTU and FUZ form a heterodimeric tri-longin domain (TLD) RabGEF that activates Rab23 downstream of core planar cell polarity proteins Vangl2 and Prickle, and INTU recruits the small GTPase RSG1 to the mother centriole to enable axonemal extension (PMID:41797376, PMID:29038301, PMID:28459465). Beyond ciliogenesis, INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation, thereby preserving cilia integrity and cell viability during stress such as renal ischemia-reperfusion injury (PMID:29581513). Loss-of-function mutations in INTU cause oral-facial-digital syndrome in humans, and mouse knockouts demonstrate that INTU is required for Hedgehog-dependent processes including neural tube patterning, hair follicle morphogenesis, lung branching, and suppression of basal cell carcinoma (PMID:28289185, PMID:20067783, PMID:22935613, PMID:39029571).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 Medium

    Establishing that INTU belongs to a PCP effector pathway involving membrane trafficking to basal bodies revealed its functional context distinct from core PCP regulators.

    Evidence In vivo imaging of mucociliary epithelium plus genetic mutant analysis and interaction screening in Xenopus

    PMID:19767740

    Open questions at the time
    • Direct molecular function of INTU itself not tested in this study
    • Mechanism by which INTU contributes to membrane trafficking unresolved
  2. 2010 High

    Demonstrating that Intu null mice lose primary cilia and show defective Hedgehog signaling (Gli3 processing, Gli1/Ptch1 expression) established INTU as a bona fide ciliogenesis factor acting cytoplasmically.

    Evidence Mouse gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, GFP-Intu rescue in null fibroblasts

    PMID:20067783

    Open questions at the time
    • Molecular target or binding partner of INTU in ciliogenesis unknown
    • Whether INTU acts on IFT or basal body maturation not distinguished
  3. 2011 Medium

    Genetic epistasis showed INTU does not interact with the core PCP regulator Vangl2 for convergent extension, separating its cilia-dependent function from canonical PCP.

    Evidence Double mutant analysis (Intu;Vangl2 compound mutants) with neural tube phenotyping in mouse

    PMID:21761479

    Open questions at the time
    • Single-lab study; independent replication in other tissues not performed
    • How INTU connects to PCP effector cascade molecularly still undefined
  4. 2012 High

    Tissue-specific deletion in epidermis showed INTU is required for cilia and Hedgehog signaling in keratinocytes but dispensable for stratification, defining its tissue-selective requirement.

    Evidence Conditional knockout in mouse epidermis with immunofluorescence for cilia and Hh pathway analysis

    PMID:22935613

    Open questions at the time
    • Whether INTU loss affects other signaling pathways in keratinocytes not explored
  5. 2015 Medium

    A hypomorphic missense allele (I813N) identified the C-terminal region of INTU as functionally critical for ciliogenesis and Hedgehog signaling, providing the first structure-function insight.

    Evidence Knock-in mouse with hypomorphic allele, cilia quantification, rescue assay in null cells

    PMID:25774014

    Open questions at the time
    • Structural basis for C-terminal requirement not determined
    • Whether I813N disrupts protein folding versus specific interactions unknown
  6. 2017 High

    Three studies collectively established that INTU functions within the CPLANE complex to assemble the IFT-A complex, recruits RSG1 to the mother centriole for axonemal extension, and that INTU mutations cause oral-facial-digital syndrome in humans.

    Evidence Conditional mouse KO in BCC model with IFT-A analysis and Gli2ΔN epistasis (PMID:28459465); RSG1 localization and epistasis with INTU/TTBK2 (PMID:29038301); whole-exome sequencing of OFDS patients (PMID:28289185)

    PMID:28289185 PMID:28459465 PMID:29038301

    Open questions at the time
    • Biochemical mechanism by which INTU promotes IFT-A assembly not defined
    • Whether INTU directly binds IFT-A subunits or acts indirectly through Rab GTPases unknown
  7. 2018 High

    Discovery that INTU interacts with STAT1 at the centriole and promotes its proteasomal degradation revealed a non-canonical, cilia-protective function during cellular stress.

    Evidence Reciprocal co-immunoprecipitation, colocalization by immunofluorescence, proteasome inhibitor assay, conditional kidney-specific KO with ischemia-reperfusion model

    PMID:29581513

    Open questions at the time
    • Whether INTU directly ubiquitinates STAT1 or recruits an E3 ligase not determined
    • Relationship between STAT1 degradation and IFT-A assembly functions unclear
  8. 2020 Low

    Computational analysis predicted that INTU and FUZ form a heterodimeric tri-longin domain RabGEF homologous to HerMon complexes, generating the hypothesis that CPLANE activates Rab GTPases.

    Evidence Coevolution-based contact prediction and sequence conservation analysis (bioinformatic)

    PMID:31562761

    Open questions at the time
    • Purely computational — no biochemical validation of GEF activity in this study
    • Identity of the target Rab GTPase not experimentally determined
  9. 2022 Medium

    Conditional Intu knockout in renal tubules revealed its role in planar cell polarity-mediated tubular repair, linking INTU to centrosome orientation during wound healing.

    Evidence Conditional KO mouse with histology, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis

    PMID:36586478

    Open questions at the time
    • Whether centrosome orientation defect is secondary to cilia loss not resolved
    • Single-lab finding without independent replication
  10. 2024 High

    Double-mutant epistasis (Gli2;Intu) showed that INTU controls lung branching morphogenesis specifically through the Gli2 arm of the Hedgehog pathway, pinpointing the downstream effector.

    Evidence Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant, RNA-seq transcriptomics

    PMID:39029571

    Open questions at the time
    • Whether INTU has Hh-independent roles in lung development not excluded
    • Mechanism by which cilia loss specifically impairs Gli2 activation versus Gli3 processing in lung not detailed
  11. 2026 High

    Crystal structure of the INTU PDZ-like domain revealed a unique fold lacking canonical PDZ-binding capability, and biochemical assays confirmed that INTU/FUZ acts as a TLD RabGEF activating Rab23 downstream of Vangl2/Prickle, unifying the PCP-cilia connection.

    Evidence Crystal structure determination, pulldown/binding assays, structural analysis

    PMID:41797376

    Open questions at the time
    • Kinetic parameters of Rab23 GEF activity not reported
    • Whether INTU/FUZ activates Rabs other than Rab23 not tested
    • Structure of the full INTU-FUZ-WDPCP ternary complex not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for how INTU promotes IFT-A assembly, whether its Rab23 GEF activity is the sole mechanism driving IFT-A recruitment, and how INTU coordinates its STAT1-degradation and ciliogenesis functions remain unresolved.
  • No reconstituted IFT-A assembly assay with purified CPLANE components
  • Relationship between Rab23 activation and IFT-A assembly mechanistically undefined
  • No structure of full-length INTU or the CPLANE ternary complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1266738 Developmental Biology 2
Partners
FUZJBTS17RAB23RSG1STAT1WDPCP
Complex memberships
CPLANE (INTU-FUZ-WDPCP)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 Fuz (a PCP effector like Intu) is essential for membrane trafficking to basal bodies and apical tips of cilia, and interacts with a Rab-related small GTPase required for ciliogenesis and secretion; Intu is identified as a related PCP effector protein in the same pathway. In vivo mucociliary epithelium imaging, genetic mutant analysis, interaction screen Nature cell biology Medium 19767740
2010 Mouse Intu null mutants exhibit loss of primary cilia, defective Hedgehog signaling (reduced Gli1, Ptch1 expression and compromised Gli3 proteolytic processing), and a cytoplasmic GFP-Intu fusion protein rescues ciliogenic defects in Intu mutant cells, demonstrating that Intu acts cytoplasmically to regulate ciliogenesis and Hh signal transduction. Gene targeting/knockout, immunofluorescence, RT-PCR for Hh targets, rescue experiment with GFP-Intu in mutant fibroblasts Developmental biology High 20067783
2011 The functions of both Intu and Fuz in neural tube patterning are dependent on the presence of cilia, and neither Intu nor Fuz genetically interacts with the core PCP regulator Vangl2 in convergent extension; Intu and Fuz are not functionally redundant with each other. Genetic epistasis (double mutants, Vangl2 compound mutants), neural tube phenotype analysis Developmental dynamics Medium 21761479
2012 Tissue-specific disruption of Intu in embryonic epidermis causes almost complete loss of primary cilia in epidermal and follicular keratinocytes and suppression of Hedgehog signaling, arresting hair follicle morphogenesis through failure of follicular keratinocyte differentiation, while epidermal stratification and barrier function are unaffected. Conditional (tissue-specific) knockout, immunofluorescence for cilia, Hh pathway analysis, histology Cell death and differentiation High 22935613
2015 A hypomorphic missense mutation in Intu (I813N, near C-terminus) causes moderate loss of cilia, reduced Hh signaling, and skeletal defects including polydactyly; the Intu(I813N) protein shows compromised ability to rescue ciliogenesis in Intu null cells, establishing the C-terminal region as functionally critical for ciliogenesis. Hypomorphic allele knock-in mouse, cilia quantification, rescue assay in null cells, Hh pathway analysis Developmental dynamics Medium 25774014
2017 RSG1 (a small GTPase) localizes to the mother centriole in a process that depends on the CPLANE protein INTU, and RSG1 is required for final maturation of the mother centriole to allow axonemal extension during cilia initiation. Mouse knockout, localization by immunofluorescence, epistasis with INTU and TTBK2 The Journal of cell biology High 29038301
2017 INTU is essential for IFT-A (intraflagellar transport A) complex assembly during ciliogenesis; loss of INTU blocks primary cilia formation and Hh pathway activation downstream of Smoothened but upstream of Gli2; INTU acts permissively during BCC tumorigenesis. Conditional mouse knockout of Intu in SmoM2-driven BCC model, IFT-A complex analysis, Hh pathway epistasis (Gli2ΔN rescue), MEF ciliogenesis assay Oncogene High 28459465
2017 INTU mutations cause oral-facial-digital syndrome (OFDS) in humans; functional studies place INTU in the CPLANE complex necessary for IFT-A assembly and intraflagellar transport. Whole-exome sequencing, functional characterization of ciliary protein modules Journal of medical genetics Medium 28289185
2018 INTU (CPLANE protein) interacts with STAT1 at the centriole/basal body area and promotes proteasomal degradation of STAT1; Intu expression preserves cilia length and cell viability during stress, effects antagonized by STAT1 expression; kidney proximal tubule-specific ablation of Intu aggravates ischemia-reperfusion injury and causes defective post-injury ciliogenesis. Conditional kidney-specific KO, Co-immunoprecipitation (Intu-STAT1), colocalization by immunofluorescence, proteasomal inhibitor assay, cell viability assay Nature communications High 29581513
2020 Evolutionary analysis identifies INTU and FUZ as forming a heterodimer with homology to HerMon (Hermansky-Pudlak syndrome and MON1-CCZ1) complexes; each protein contains a triplicated Longin domain, suggesting INTU/FUZ acts as a GEF (guanine nucleotide exchange factor) for Rab GTPases during ciliogenesis. Coevolution-based contact prediction, sequence conservation analysis (computational/bioinformatic) Bioinformatics Low 31562761
2022 CPLANE complex is composed of INTU, FUZ, and WDPCP, which bind to JBTS17 and RSG1 for cilia formation; defects in CPLANE components cause defective IFT-A assembly, defective PCP, and defective Hedgehog signaling. Review/synthesis of functional studies (genetic, biochemical, ciliogenesis assays from multiple studies) Biomolecules Medium 35740972
2022 Conditional knockout of Intu in renal tubules delays kidney repair and ameliorates renal fibrosis after ischemic injury; Intu KO kidneys show less senescence but higher cell proliferation and apoptosis; in vitro, Intu knockdown suppresses scratch wound healing with abnormal centrosome orientation, placing Intu in planar cell polarity-mediated tubular repair. Conditional KO mouse, histology/immunohistochemistry, in vitro scratch wound assay with Intu knockdown, centrosome orientation analysis The American journal of pathology Medium 36586478
2024 Loss of Intu severely disrupts lung growth and branching morphogenesis through cilia-dependent Hh signaling; genetic removal of both Gli2 and Intu completely abolishes lung branching, providing epistatic evidence that Intu regulates lung development via the Gli2 arm of the Hh pathway. Mouse knockout, Smo agonist treatment of lung explants, Gli2/Intu double mutant epistasis, transcriptomics (RNA-seq) Developmental biology High 39029571
2026 Inturned contains a unique PDZ-like domain that does not interact with membranes or with the core PCP protein Vangl2; crystal structure of the Intu-PDZ domain reveals a unique fold lacking a canonical interaction site for PDZ-binding motifs; Intu and Fuz are members of the tri-longin domain (TLD) RabGEF family and activate Rab23 downstream of Vangl2 and Prickle. Crystal structure determination, biochemical binding assays (pulldown/interaction assays), structural analysis FEBS letters High 41797376

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The planar cell polarity effector Fuz is essential for targeted membrane trafficking, ciliogenesis and mouse embryonic development. Nature cell biology 193 19767740
2017 Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. Journal of medical genetics 85 28289185
2010 PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals. Developmental biology 85 20067783
2019 Genome-Wide Homozygosity Patterns and Evidence for Selection in a Set of European and Near Eastern Horse Breeds. Genes 43 31261764
2019 Integrated miRNA and mRNA expression profiling identifies novel targets and pathological mechanisms in autoimmune thyroid diseases. EBioMedicine 38 31735554
2017 Single step genome-wide association studies based on genotyping by sequence data reveals novel loci for the litter traits of domestic pigs. Genomics 36 28943389
2011 PCP effector proteins inturned and fuzzy play nonredundant roles in the patterning but not convergent extension of mammalian neural tube. Developmental dynamics : an official publication of the American Association of Anatomists 30 21761479
1980 Hemocyte responses to implanted tissues inDrosophila melanogaster larvae. Wilhelm Roux's archives of developmental biology 30 28305176
2017 The small GTPase RSG1 controls a final step in primary cilia initiation. The Journal of cell biology 29 29038301
2018 The CPLANE protein Intu protects kidneys from ischemia-reperfusion injury by targeting STAT1 for degradation. Nature communications 22 29581513
2018 Chemotherapy-induced peripheral neuropathy: evidence from genome-wide association studies and replication within multiple myeloma patients. BMC cancer 22 30111286
2017 INTU is essential for oncogenic Hh signaling through regulating primary cilia formation in basal cell carcinoma. Oncogene 21 28459465
2012 Planar cell polarity effector gene Intu regulates cell fate-specific differentiation of keratinocytes through the primary cilia. Cell death and differentiation 21 22935613
2015 A hypomorphic allele reveals an important role of inturned in mouse skeletal development. Developmental dynamics : an official publication of the American Association of Anatomists 18 25774014
2022 CPLANE Complex and Ciliopathies. Biomolecules 15 35740972
2020 Hexa-Longin domain scaffolds for inter-Rab signalling. Bioinformatics (Oxford, England) 13 31562761
2022 Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder. Journal of personalized medicine 12 35330412
2022 Estimation of genetic parameters and single-step genome-wide association studies for milk urea nitrogen in Holstein cattle. Journal of dairy science 10 36460511
2018 INTU-related oral-facial-digital syndrome type VI: A confirmatory report. Clinical genetics 9 29451301
2022 Identical IFT140 Variants Cause Variable Skeletal Ciliopathy Phenotypes-Challenges for the Accurate Diagnosis. Frontiers in genetics 8 35873489
2019 A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy. European journal of medical genetics 7 31816441
2021 Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes. Scientific reports 6 33436679
2021 INTU-related oral-facial-digital syndrome XVII: Clinical spectrum of a rare disorder. American journal of medical genetics. Part A 6 34623732
2024 The CPLANE protein Fuzzy regulates ciliogenesis by suppressing actin polymerization at the base of the primary cilium via p190A RhoGAP. Development (Cambridge, England) 5 38546045
2023 Combined genome-wide association study of 136 quantitative ear morphology traits in multiple populations reveal 8 novel loci. PLoS genetics 5 37459304
2023 Molecular investigation in individuals with orofacial clefts and microphthalmia-anophthalmia-coloboma spectrum. European journal of human genetics : EJHG 5 37932364
2021 Exploring the genomic resources of seven domestic Bactrian camel populations in China through restriction site-associated DNA sequencing. PloS one 4 33914766
2024 CPLANE protein INTU regulates growth and patterning of the mouse lungs through cilia-dependent Hh signaling. Developmental biology 3 39029571
2022 Multifaceted investigation underlies diverse mechanisms contributing to the downregulation of Hedgehog pathway-associated genes INTU and IFT88 in lung adenocarcinoma and uterine corpus endometrial carcinoma. Aging 3 36084949
2022 Deficiency of the Planar Cell Polarity Protein Intu Delays Kidney Repair and Suppresses Renal Fibrosis after Acute Kidney Injury. The American journal of pathology 3 36586478
2023 Gene and pathway based burden analyses in familial lymphoid cancer cases: Rare variants in immune pathway genes. PloS one 2 37379307
2023 Reanalysis of Whole-Exome Sequencing Data of an Infant with Suspected Diagnosis of Jeune Syndrome Revealed a Likely Pathogenic Variant in GRK2: A Newly Associated Gene for Jeune Syndrome Phenotype. Molecular syndromology 1 38585547
2026 The planar cell polarity protein Vangl2 interacts with the PDZ-domains of Scribble but not with a unique PDZ-like domain in Inturned. FEBS letters 0 41797376
2025 Wnt5a regulates the expression of developmental genes in the adult retina following optic nerve crush injury. Histology and histopathology 0 40079114
2025 Bi-allelic INTU variants define a ciliopathy disorder characterized by orofacial, digital, and cardiac anomalies. HGG advances 0 40968537