INTU (Inturned) is a scaffold protein that functions as a core component of the CPLANE (ciliogenesis and planar polarity effector) complex at basal bodies, where it recruits intraflagellar transport machinery, specifically IFT-A proteins. INTU also serves as an adaptor linking ciliary proteins (NPHP4) to actin-modifying proteins (DAAM1) to control the subapical actin network required for basal body docking and ciliary orientation. Essential for primary cilia assembly and Hedgehog signaling, INTU is mutated in ciliopathies including Oral-Facial-Digital syndrome XVII and Short-Rib Thoracic Dysplasia 20.
Definition: Per PR #760 review feedback: falcon deep research and PMID:35427153 (Langousis 2022) discussion surface a candidate INTU-FUZ GEF activity toward Rab23. Direct biochemical confirmation in human INTU is pending, but the literature signal warrants flagging this molecular function as a candidate NEW annotation (GO:0005085 guanyl-nucleotide exchange factor activity, or a more specific GTPase-family-specific child) once direct evidence is available. Captured here in proposed_new_terms because no GO annotation currently captures this potential molecular function for INTU.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasmic localization is supported by experimental evidence. INTU has cytosolic fractions when not assembled at cilia and likely shuttles between cytosol and ciliary base. The deep research confirms cytosolic localization (GO_REF:0000052). Reason: GO_REF:0000052 provides direct immunofluorescence evidence for cytoplasmic localization, and PMID:27158779 shows INTU can exist in cytosolic pools when not assembled at ciliary structures. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery file:human/INTU/INTU-deep-research.md See deep research file for comprehensive analysis |
| GO:0060271 cilium assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Core function strongly supported by multiple experimental studies. INTU is essential for ciliogenesis through its role in the CPLANE complex recruiting IFT-A machinery to basal bodies (PMID:27158779). Structural and biochemical work confirms INTU as a bona fide CPLANE complex subunit acting at late ciliogenesis stages (PMID:35427153). Mouse knockouts lack primary cilia, and human mutations cause ciliopathies. Reason: PMID:27158779 demonstrated INTU is a core component of the CPLANE complex that recruits IFT-A proteins to basal bodies, with knockout mice showing complete absence of primary cilia and human mutations causing OFD syndrome XVII. PMID:35427153 confirms biochemical CPLANE complex assembly and acts at the ciliary vesicle stage of ciliogenesis. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery PMID:35427153 Dysfunctional cilia cause pleiotropic human diseases termed ciliopathies. These hereditary maladies are often caused by defects in cilia assembly, a complex event that is regulated by the ciliogenesis and planar polarity effector (CPLANE) proteins Wdpcp, Inturned, and Fuzzy. |
| GO:0005929 cilium | IBA GO_REF:0000033 | MODIFY | Summary: While INTU localizes primarily at the basal body/ciliary base rather than within the cilium proper, this broader cellular component term is acceptable as INTU is functionally associated with ciliary structures. More specific localization would be ciliary basal body (GO:0036064). Reason: PMID:26644512 and PMID:27158779 demonstrate that INTU specifically localizes to ciliary basal bodies rather than within the cilium itself. GO:0036064 more accurately captures this specific localization. Proposed replacements: ciliary basal body Supporting Evidence: PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells |
| GO:0007399 nervous system development | IBA GO_REF:0000033 | MODIFY | Summary: While INTU mutations can affect neural development (neural tube defects, developmental delay), this is a consequence of defective ciliogenesis/Hedgehog signaling rather than a direct role in nervous system development. The term is too broad for the specific neural tube patterning defects observed. Proposed replacements: neural tube development |
| GO:0001736 establishment of planar polarity | IEA GO_REF:0000002 | ACCEPT | Summary: INTU is a planar cell polarity effector protein that controls ciliary orientation through its effects on basal body positioning and the subapical actin network. This is well-supported by experimental evidence showing INTU controls rotational polarity of cilia in multiciliated cells (PMID:26644512). Reason: PMID:26644512 demonstrated that INTU is essential for establishing planar cell polarity by linking NPHP4 to DAAM1 to control the subapical actin network required for proper ciliary orientation in multiciliated cells. Supporting Evidence: PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000002 | REMOVE | Summary: No evidence supports a direct role in vesicle-mediated transport. This appears to be an incorrect automated annotation, possibly based on superficial similarity to IFT proteins. INTU functions in intraciliary transport, not vesicle transport. |
| GO:0060271 cilium assembly | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA annotation for cilium assembly. The automated annotation correctly identifies this core function. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of the IBA annotation for cytoplasm. Correctly identifies cytoplasmic localization. |
| GO:0005814 centriole | IEA GO_REF:0000120 | MODIFY | Summary: INTU localizes to the mother centriole/basal body area. While technically correct, the more specific term ciliary basal body (GO:0036064) better captures INTU localization in the context of ciliogenesis. Proposed replacements: ciliary basal body |
| GO:0005856 cytoskeleton | IEA GO_REF:0000043 | REMOVE | Summary: While INTU interacts with actin cytoskeleton components through DAAM1 and controls the subapical actin network, it is not itself a cytoskeletal protein. This term is too broad; INTU specifically regulates actin organization at the apical cortex. |
| GO:0009986 cell surface | IEA GO_REF:0000044 | MODIFY | Summary: Some INTU truncations show enhanced membrane association, and INTU may associate with membrane through predicted phosphatidylinositol binding. However, cell surface is too general; apical plasma membrane would be more accurate given INTU functions at the apical cortex. Proposed replacements: apical plasma membrane |
| GO:0030030 cell projection organization | IEA GO_REF:0000043 | MODIFY | Summary: Cilia are cell projections, and INTU is essential for their organization. However, cilium assembly (GO:0060271) is more specific and informative for INTU function. Proposed replacements: cilium assembly |
| GO:0042995 cell projection | IEA GO_REF:0000043 | MODIFY | Summary: Too vague for a cellular component term. INTU localizes specifically to ciliary basal bodies, not broadly to cell projections. Proposed replacements: ciliary basal body |
| GO:0005515 protein binding | IPI PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to contro... | MODIFY | Summary: This paper shows INTU binds NPHP4 and DAAM1, forming a ternary complex. While protein binding is correct, it is uninformative. INTU functions as a scaffold/adaptor protein linking ciliary and cytoskeletal proteins. A more specific molecular function term would be protein-protein adaptor activity. Reason: PMID:26644512 demonstrated that INTU functions as an adaptor protein that specifically links the ciliary protein NPHP4 to the actin-regulating protein DAAM1, mediating communication between ciliary and cytoskeletal systems. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells |
| GO:0005515 protein binding | IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis... | MODIFY | Summary: Protein interaction study showing INTU interactions. Again, protein binding is too vague. INTU acts as a scaffold in protein complexes. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:27173435 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Another protein interaction network study. The generic protein binding term should be replaced with the more informative scaffold/adaptor function. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0007224 smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU affects Hedgehog signaling indirectly through its essential role in ciliogenesis. Without cilia, Hh signaling is disrupted. This is a valid annotation but represents an indirect effect. |
| GO:0007399 nervous system development | IEA GO_REF:0000107 | MODIFY | Summary: Duplicate of earlier annotation. Too broad; neural tube development is more specific. Proposed replacements: neural tube development |
| GO:0008589 regulation of smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU regulates Hedgehog signaling indirectly through its requirement for ciliogenesis. Valid but represents secondary effect of ciliary dysfunction. |
| GO:0010839 negative regulation of keratinocyte proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Tissue-specific consequence of INTU loss affecting hair follicle development through disrupted Hh signaling. Too specific for a general annotation; represents a downstream developmental effect. |
| GO:0021513 spinal cord dorsal/ventral patterning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neural patterning defects occur in INTU mutants due to disrupted Hedgehog signaling from lack of cilia. This is a downstream developmental consequence, not a core function. |
| GO:0021915 neural tube development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neural tube defects are observed in INTU mutants, supported by experimental evidence in multiple species. Valid developmental consequence of ciliary dysfunction. |
| GO:0030216 keratinocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU affects hair follicle differentiation through its role in ciliogenesis and Hh signaling. Tissue-specific developmental effect. |
| GO:0030278 regulation of ossification | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU mutations cause skeletal defects including delayed ossification through disrupted Indian Hedgehog signaling in growth plates. Valid but represents developmental consequence. |
| GO:0031069 hair follicle morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Experimental evidence shows INTU is required for hair follicle development through cilia-dependent Hh signaling. Tissue-specific developmental effect. |
| GO:0033365 protein localization to organelle | IEA GO_REF:0000107 | MODIFY | Summary: INTU recruits IFT-A proteins to basal bodies as part of the CPLANE complex. This is a core function but could be more specific as intraciliary transport involved in cilium assembly. Per round-2 review of PR #760, the proposed replacement was corrected from GO:0042073 (intraciliary transport, which the same review elsewhere rejects as wrong for INTU) to GO:0035735 (intraciliary transport involved in cilium assembly) to remain internally consistent. Proposed replacements: intraciliary transport involved in cilium assembly |
| GO:0035091 phosphatidylinositol binding | IEA GO_REF:0000107 | MODIFY | Summary: Bioinformatically predicted phosphatidylinositol binding capacity. Now experimentally validated by Langousis et al. 2022 (PMID:35427153), which showed direct PIP-strip binding by recombinant human/mouse CPLANE complexes and by individual MmIntu, with a clear preference for PI(3)P. A more specific replacement term (phosphatidylinositol-3-phosphate binding, GO:0032266) better captures this biochemical specificity. Reason: PMID:35427153 demonstrates that CPLANE proteins, including INTU, bind PI(3)P preferentially over other phosphoinositides, with INTU binding mediated by the N-terminal ~300 residues. The more specific GO:0032266 term captures this validated specificity. Proposed replacements: phosphatidylinositol-3-phosphate binding Supporting Evidence: PMID:35427153 the crescent-shaped CPLANE complex binds phospholipids such as phosphatidylinositol 3-phosphate via multiple modules and a CPLANE ciliopathy mutant exhibits aberrant lipid binding. PMID:35427153 MmIntu uses the N-terminal ~300 amino acids to bind PIPs, with a 47– to 267–amino acid construct being competent for binding |
| GO:0035869 ciliary transition zone | IEA GO_REF:0000107 | MODIFY | Summary: INTU localizes near but not exactly at the transition zone. It is primarily at the basal body with some extension toward the transition zone. Basal body is more accurate. Proposed replacements: ciliary basal body |
| GO:0042733 embryonic digit morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU mutations cause polydactyly in humans and mice. Well-supported developmental consequence of disrupted Hh signaling during limb development. |
| GO:0044458 motile cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: INTU is required for assembly of both motile and primary cilia. Evidence from multiciliated cells shows INTU localizes to basal bodies of motile cilia and controls their polarization. |
| GO:0045880 positive regulation of smoothened signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU enables Hedgehog signaling by building the cilia required for signal transduction. This is an indirect positive effect through ciliogenesis. |
| GO:0051301 cell division | IEA GO_REF:0000107 | REMOVE | Summary: No evidence supports a direct role in cell division. Centrioles are involved in both ciliogenesis and cell division, but INTU functions specifically in the ciliary context. |
| GO:0051782 negative regulation of cell division | IEA GO_REF:0000107 | REMOVE | Summary: No evidence for INTU regulating cell division. This appears to be an incorrect inference. |
| GO:0060173 limb development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: INTU mutations cause limb defects including polydactyly and shortened limbs. Valid developmental process affected by ciliary dysfunction. |
| GO:1905515 non-motile cilium assembly | IEA GO_REF:0000107 | ACCEPT | Summary: INTU is essential for primary (non-motile) cilium assembly. Mouse knockouts lack primary cilia. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct experimental evidence for cytosolic localization by immunofluorescence. INTU has cytosolic fractions when not assembled at cilia. |
| GO:0036064 ciliary basal body | IDA GO_REF:0000052 | ACCEPT | Summary: Direct experimental evidence for basal body localization. This is the primary and most specific localization for INTU, strongly supported by multiple studies. |
| GO:0001736 establishment of planar polarity | NAS PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | ACCEPT | Summary: This paper identifies INTU as part of the CPLANE complex controlling planar polarity through ciliary orientation. Well-supported core function. Supporting Evidence: PMID:27158779 This novel regulatory module is formed by specific protein-protein interactions among Intu, Fuz, and Wdpcp, well-conserved proteins that control planar cell polarity (PCP) in Drosophila and govern ciliogenesis in vertebrates |
| GO:0005929 cilium | NAS PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | MODIFY | Summary: INTU localizes at the ciliary base/basal body rather than within the cilium proper. More specific term would be ciliary basal body. Proposed replacements: ciliary basal body Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0021915 neural tube development | NAS PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | KEEP AS NON CORE | Summary: This paper shows neural tube defects in INTU mutants. Valid developmental consequence of ciliary dysfunction. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0042073 intraciliary transport | NAS PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | MODIFY | Summary: This paper shows INTU recruits IFT-A machinery to basal bodies as part of the CPLANE complex. The newly cited PMID:35427153 shows CPLANE acts at the pre-ciliary vesicle stage with PI(3)P binding and CV-stage arrest, supporting an IFT-A recruitment / particle- assembly role rather than bidirectional axonemal cargo transport. Per PR #760 review feedback, downgraded ACCEPT → MODIFY with proposed replacement GO:0035735 (intraciliary transport particle assembly). Proposed replacements: intraciliary transport involved in cilium assembly Supporting Evidence: PMID:27158779 We show that this module also includes the poorly understood ciliopathy protein Jbts17, which we show recruits CPLANE to basal bodies where it acts specifically by recruiting the IFT-A peripheral proteins PMID:27158779 These data suggest that CPLANE acts by recruiting peripheral IFT-A proteins to the basal body for assembly onto the IFT-A core. |
| GO:1902017 regulation of cilium assembly | NAS PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | MODIFY | Summary: INTU is not just a regulator but is essential for cilium assembly itself. The more specific term cilium assembly (GO:0060271) better captures its essential role. Proposed replacements: cilium assembly Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0035091 phosphatidylinositol binding | ISS GO_REF:0000024 | MODIFY | Summary: Sequence similarity-based prediction for phosphatidylinositol binding. Direct experimental validation now available (PMID:35427153) showing recombinant INTU binds PIPs with PI(3)P preference. Replace with the more specific GO:0032266 (phosphatidylinositol-3-phosphate binding). Proposed replacements: phosphatidylinositol-3-phosphate binding Supporting Evidence: PMID:35427153 CPLANE complexes interacted solely with PIPs having a single inositol phosphate and exhibited a clear preference for PI(3)P, followed by PI(5)P and PI(4)P |
| GO:0042733 embryonic digit morphogenesis | IMP PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | KEEP AS NON CORE | Summary: This paper shows polydactyly in INTU mutant mice. Direct experimental evidence for developmental defect. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0043587 tongue morphogenesis | IMP PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | KEEP AS NON CORE | Summary: This paper shows tongue defects (lobulated tongues, hamartomas) in INTU mutants, consistent with OFD syndrome. Direct experimental evidence. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0060021 roof of mouth development | IMP PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body ... | KEEP AS NON CORE | Summary: This paper shows high-arched palate in INTU mutant mice, characteristic of OFD syndrome. Direct experimental evidence. Supporting Evidence: PMID:27158779 The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. |
| GO:0031514 motile cilium | IDA PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to contro... | MODIFY | Summary: This paper shows INTU localization at basal bodies of motile cilia in multiciliated cells. However, INTU is at the basal body, not in the motile cilium itself. Proposed replacements: ciliary basal body Supporting Evidence: PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells. |
| GO:0036064 ciliary basal body | IDA PMID:26644512 The polarity protein Inturned links NPHP4 to Daam1 to contro... | ACCEPT | Summary: This paper directly shows INTU localization at basal bodies in multiciliated cells. Strong experimental evidence for this core localization. Supporting Evidence: PMID:26644512 NPHP4 was required for Inturned to localize to the basal bodies of motile cilia |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity-based annotation for cytoplasmic localization, consistent with experimental evidence. |
| GO:0007399 nervous system development | ISS GO_REF:0000024 | MODIFY | Summary: Sequence similarity-based annotation. Too broad; neural tube development is more specific. Proposed replacements: neural tube development |
| GO:0008589 regulation of smoothened signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity-based annotation. INTU affects Hh signaling indirectly through ciliogenesis. |
| GO:0060173 limb development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence similarity-based annotation. Supported by polydactyly phenotypes in mutants. |
| GO:0060271 cilium assembly | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence similarity-based annotation for core function. Well-supported by experimental evidence. |
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Download this section (compressed HTML)Q: How does INTU regulate intraflagellar transport and what specific cargo does it help transport within cilia?
Q: What are the molecular mechanisms by which INTU coordinates ciliary assembly with cell cycle progression?
Q: How do mutations in INTU lead to left-right asymmetry defects and what role does it play in nodal cilia function?
Q: What determines the specificity of INTU interactions with different intraflagellar transport complexes?
Experiment: Super-resolution microscopy to track INTU and IFT particle movements along the ciliary axoneme with nanometer precision
Experiment: Biochemical reconstitution of IFT complexes containing INTU to study cargo loading and transport mechanisms in vitro
Experiment: Developmental analysis of left-right patterning in INTU mutant embryos using whole-mount in situ hybridization
Experiment: Proteomics analysis of INTU-associated complexes during different stages of ciliogenesis
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