Affinage

IFT38

Annotated
2026-06-10
28 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT38 (CLUAP1) is an integral peripheral subunit of the intraflagellar transport IFT-B complex that is essential for axoneme elongation and ciliary signaling (PMID:26980730, PMID:23742838). Within IFT-B it forms a connecting tetramer with IFT52, IFT57, and IFT88 that bridges the IFT-B1 and IFT-B2 subcomplexes, and mutual stability of these subcomplexes depends on this tetramer (PMID:36411782); the same tetramer directly engages heterotrimeric kinesin-II through KIF3B to couple the IFT train to its anterograde motor, an interaction required for ciliogenesis (PMID:29903877). IFT38 itself moves bidirectionally along cilia with kinetics matching other IFT-B proteins, confirming it as a bona fide IFT cargo (PMID:24970261). Functional integration into IFT-B is obligatory: a binding-deficient mutant fails to rescue ciliogenesis in Cluap1-deficient cells, and in knockout mice the basal body docks normally but the axoneme fails to grow and Hedgehog/Shh signaling is lost (PMID:26980730, PMID:23742838, PMID:23351563). Beyond train assembly, IFT38 directly binds BBSome subunits BBS1, BBS2, and BBS9, and this IFT-B–BBSome link is specifically required to export GPR161 from cilia upon Hedgehog stimulation (PMID:31471295). During ciliogenesis IFT38 localizes to the mother-centriole distal appendage in proliferating cells and accumulates with other IFT-B proteins in a transient cytoplasmic IFT spot that depends on the ciliogenesis machinery (PMID:31554018). Hypomorphic and compound-heterozygous CLUAP1 variants that reduce protein level or IFT velocity impair ciliary function and cause photoreceptor degeneration and ciliopathy (PMID:26820066, PMID:28679688). Additional roles in actin cytoskeletal organization and in GPCR/serum-driven YAP/Hippo activation have been reported (PMID:29615496, PMID:37783116).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2004 Medium

    Before any ciliary role was known, CLUAP1 was first characterized as a cell-cycle-regulated protein, raising the question of its cellular function.

    Evidence Yeast two-hybrid with nuclear Clusterin, cell-cycle protein-level measurement, and siRNA knockdown proliferation assay

    PMID:15480429

    Open questions at the time
    • Clusterin interaction not validated by reciprocal or in-cell methods
    • no link to cilia established at this stage
    • mechanism of growth retardation unresolved
  2. 2012 High

    Establishing the gene's physiological role, knockout showed Cluap1 is required for cilia formation and acts upstream of Sonic hedgehog signaling in mammals.

    Evidence Cluap1 knockout mouse with cilia immunofluorescence, qRT-PCR of Shh targets, and beta-galactosidase pathway reporter

    PMID:23351563

    Open questions at the time
    • molecular step within ciliogenesis not pinpointed
    • biochemical interactions undefined
  3. 2013 High

    Refining the ciliary defect, Cluap1 was shown to be needed for axoneme elongation rather than basal body docking, and to behave as a transported IFT-B cargo.

    Evidence Knockout mouse phenotyping with tissue-specific rescue plus high-speed in vivo imaging of tagged Cluap1 in Xenopus multiciliated cells compared to IFT20

    PMID:23742838 PMID:24970261

    Open questions at the time
    • direct biochemical placement within IFT-B not yet defined
    • motor coupling unknown
  4. 2016 High

    Biochemical mapping placed IFT38 in the IFT-B peripheral subcomplex and showed that integration into IFT-B is required for its function, while patient genetics linked CLUAP1 to retinal disease.

    Evidence VIP interaction mapping with binding-deficient rescue in Cluap1-deficient MEFs; whole-exome sequencing with cluap1-knockout zebrafish mRNA rescue

    PMID:26820066 PMID:26980730

    Open questions at the time
    • partners bridging IFT-B subcomplexes not yet identified
    • motor connection unmapped
  5. 2018 High

    Resolving how IFT-B engages its anterograde motor and tethers accessory subunits, IFT38 was shown to form a connecting tetramer that binds kinesin-II via KIF3B, with IFT80 tethered through IFT38.

    Evidence VIP assay and KIF3B-binding-deficient rescue in KIF3B-knockout cells; 1.8 Angstrom IFT80 crystal structure with structural mapping

    PMID:29658880 PMID:29903877

    Open questions at the time
    • IFT80–IFT38 interface not validated by interface mutagenesis
    • stoichiometry of motor coupling unresolved
  6. 2019 High

    Defining a signaling-specific output, IFT38 was shown to bind BBSome subunits and to be required for ciliary export of GPR161, and its localization dynamics during ciliogenesis were mapped.

    Evidence VIP assay with separation-of-function IFT38 mutant and GPR161 ciliary localization assay; immunofluorescence of distal appendage and cytoplasmic IFT spot across mutant cells and embryos

    PMID:31471295 PMID:31554018

    Open questions at the time
    • functional role of the cytoplasmic IFT spot unresolved
    • how BBSome binding is coupled to GPR161 cargo selection unknown
  7. 2022 Medium

    Cross-species analysis established that the IFT38 connecting tetramer bridges IFT-B1 and IFT-B2 and governs their mutual stability and BBSome trafficking.

    Evidence Chlamydomonas deletion mutant analysis with IFT-B subunit stability and IFT/BBSome trafficking assays

    PMID:36411782

    Open questions at the time
    • single-organism deletion analysis
    • direct interface contacts within the tetramer not defined
  8. 2023 Medium

    Beyond canonical ciliary transport, IFT38 was implicated in actin organization and in serum/GPCR-driven YAP/Hippo signaling and proliferation.

    Evidence CRISPR knockout with endogenous-tag interactome (Ephrin-B1, TRIP6, PDGFA, CCDC6); RNAi screen with YAP dephosphorylation and proliferation assays

    PMID:29615496 PMID:37783116

    Open questions at the time
    • new interactors not orthogonally validated
    • mechanistic link between IFT38 and YAP regulation unresolved
    • whether these roles are cilia-dependent unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IFT38's ciliary transport function mechanistically connects to its reported roles in actin arrangement and Hippo/YAP signaling remains unresolved.
  • no defined molecular pathway linking IFT38 to YAP regulation
  • interactome partners outside IFT-B not confirmed by reciprocal assays
  • structural model of the IFT38 connecting tetramer interfaces lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 3 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
GO:0005929 cilium 2
Partners
BBS1BBS2BBS9IFT52IFT57IFT80IFT88KIF3B
Complex memberships
IFT-B complexIFT-B connecting tetramer (IFT38-IFT52-IFT57-IFT88)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Cluap1/IFT38 is an integral component of the IFT-B peripheral subcomplex (not the core). Using the visible immunoprecipitation (VIP) assay, IFT38 was mapped to the peripheral subcomplex of the IFT-B complex composed of 10 core and 6 peripheral subunits. Ciliogenesis defects in Cluap1-deficient mouse embryonic fibroblasts were rescued by wild-type Cluap1 but not by a mutant lacking binding ability to other IFT-B components, establishing that IFT-B complex integration is required for Cluap1 function. Visible immunoprecipitation (VIP) assay for protein-protein interaction mapping; rescue of ciliogenesis defect in Cluap1-deficient MEFs with wild-type vs. binding-deficient mutant Cluap1 The Journal of biological chemistry High 26980730
2018 IFT38 is part of an IFT-B-connecting tetramer (IFT38-IFT52-IFT57-IFT88) that directly interacts with heterotrimeric kinesin-II (KIF3A-KIF3B-KAP3), with KIF3B being the primary contributor to IFT-B binding. This interaction is required for ciliogenesis: KIF3B-knockout cells were rescued by wild-type KIF3B but not by a KIF3B mutant compromised in IFT-B binding. Visible immunoprecipitation (VIP) assay; rescue of ciliogenesis defect in KIF3B-knockout cells with wild-type vs. IFT-B-binding-deficient KIF3B mutant The Journal of cell biology High 29903877
2019 IFT38 (from the IFT-B complex) directly interacts with BBSome subunits BBS1, BBS2, and BBS9. This IFT-B–BBSome interaction is specifically required for the export of GPR161 from cilia upon Hedgehog signaling stimulation. IFT38-knockout cells expressing a mutant IFT38 lacking BBS1+BBS2+BBS9 binding had restored ciliogenesis but showed significant accumulation of GPR161 within cilia, similar to BBS1-knockout cells. Visible immunoprecipitation (VIP) assay for interaction identification; phenotypic analysis of IFT38-knockout cells expressing wild-type or binding-deficient IFT38 mutant; GPR161 ciliary localization assay Biology open High 31471295
2018 The N-terminal β-propeller of IFT80 tethers IFT80 to the IFT-B complex via IFT38, as revealed by the 1.8 Å crystal structure of Chlamydomonas IFT80 combined with structural mapping. Crystal structure determination (1.8 Å resolution); structural mapping of IFT-B interactions eLife Medium 29658880
2013 Cluap1/IFT38 protein undergoes bidirectional intraflagellar transport along cilia, with similar localization and kinetics to IFT20 (an IFT-B complex component), establishing it as a bona fide IFT-B cargo that moves anterograde and retrograde within cilia. High-speed in vivo confocal imaging of tagged Cluap1 in Xenopus epidermis multiciliated cells; comparison of IFT kinetics with IFT20 Investigative ophthalmology & visual science Medium 24970261
2013 Cluap1/IFT38 is preferentially localized to the base and tip of cilia and is required for axoneme elongation (not basal body docking) during ciliogenesis. Knockout mice show that the basal body docks normally but the axoneme fails to grow, and Hedgehog signaling is impaired. Cluap1 knockout mouse generation; immunofluorescence localization; Patched1-lacZ reporter for Hedgehog signaling; crown cell-specific Cluap1 rescue experiment Developmental biology High 23742838
2012 Mammalian Cluap1 localizes to primary cilia and is required for cilia formation; Cluap1 mutant mouse embryos lack cilia at E9.5 and exhibit repressed Sonic hedgehog signaling, placing Cluap1 upstream of Shh pathway activity in mammals. Cluap1 knockout mouse generation; immunofluorescence for cilia; qRT-PCR for Shh target genes; β-galactosidase reporter assay for Shh pathway activity Cilia High 23351563
2016 Hypomorphic mutations in CLUAP1 (identified in an LCA patient) reduce but do not abolish cilia function in zebrafish photoreceptors, resulting in photoreceptor cell death. Rescue experiments in cluap1-knockout zebrafish confirmed the hypomorphic nature of the patient mutation, functionally linking CLUAP1 to photoreceptor ciliary maintenance. Whole-exome sequencing; cluap1 knockout zebrafish; mRNA rescue experiments; immunohistochemistry for photoreceptor cell death Genetics in medicine Medium 26820066
2017 Two compound heterozygous CLUAP1 variants cause ciliopathy: p.(Arg230Ter) reduces protein levels and p.(Met113Arg) reduces intraflagellar transport velocity/function when transfected into Xenopus embryos, demonstrating that both variants impair IFT. Exome sequencing; Xenopus embryo transfection with mutant CLUAP1 constructs; functional assay of IFT activity Cold Spring Harbor molecular case studies Medium 28679688
2019 In proliferating cells, Cluap1/IFT38 localizes to the distal appendage of the mother centriole. Upon induction of ciliogenesis, Cluap1 and other IFT-B proteins (IFT46, IFT88) accumulate in a novel non-centriolar cytoplasmic compartment called the 'cytoplasmic IFT spot', which appears early in ciliogenesis and disappears upon completion. This compartment is absent in ciliogenesis-defective cells lacking Cluap1, Kif3a, or Odf2. Immunofluorescence and confocal microscopy of MEFs and mouse embryos; colocalization with IFT46 and IFT88; comparison between wild-type and ciliogenesis-defective cells Genes to cells Medium 31554018
2018 CRISPR/Cas9-mediated knockout of Cluap1/IFT38 reveals a novel role in actin cytoskeleton arrangement. In addition to known IFT-B interactions, endogenous-tag-based interactome analysis identified new Cluap1 binding partners including Ephrin-B1, TRIP6 (cytoskeletal regulators), PDGFA, and CCDC6. CRISPR/Cas9 knockout and endogenous tagging; co-immunoprecipitation and mass spectrometry interactome analysis; actin cytoskeleton phenotyping Molecular & cellular proteomics Medium 29615496
2022 IFT38 functions in regulating anterograde IFT and retrograde trafficking of the BBSome in Chlamydomonas. IFT38 connects IFT-B1 and IFT-B2 subcomplexes as part of a connecting tetramer (IFT38/57/88/52); the stability of IFT-B1 and IFT-B2 is mutually dependent and mediated by this connecting tetramer. Chlamydomonas genetics; deletion mutant analysis; IFT-B subunit stability assays; IFT and BBSome trafficking assays iScience Medium 36411782
2013 CLUAP1/IFT38 contains a divergent N-terminal calponin homology (NN-CH) domain based on profile-to-profile comparisons and structural modeling, placing it in an evolutionarily conserved protein family with IFT57, IFT81, NDC80, and NUF2. Computational profile-to-profile comparison; structural homology modeling Bioinformatics Low 24257188
2023 Depletion of IFT38 (but not most other individual ciliary proteins tested) leads to particularly robust repression of YAP activation upon LPA and S1P stimulation, and attenuates cell proliferation in 2D cultures and tumor spheroids, placing IFT38 as a regulator of serum mitogen-induced Hippo pathway signaling downstream of GPCR activation. siRNA/RNAi-based screen of 30 ciliary proteins; YAP dephosphorylation assay; target gene induction assay; cell proliferation assay in 2D and 3D cultures Biochemical and biophysical research communications Medium 37783116
2004 CLUAP1 was identified as interacting with nuclear Clusterin using yeast two-hybrid. CLUAP1 protein levels increase in late S to G2/M phases of the cell cycle and return to basal in G0/G1. siRNA-mediated suppression of CLUAP1 results in growth retardation. Yeast two-hybrid for interaction with Clusterin; cell cycle synchronization with CLUAP1 protein level measurement; siRNA knockdown with proliferation assay Oncogene Medium 15480429

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Overall Architecture of the Intraflagellar Transport (IFT)-B Complex Containing Cluap1/IFT38 as an Essential Component of the IFT-B Peripheral Subcomplex. The Journal of biological chemistry 100 26980730
2021 Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data. Human genomics 87 33536081
2018 Interaction of heterotrimeric kinesin-II with IFT-B-connecting tetramer is crucial for ciliogenesis. The Journal of cell biology 58 29903877
2019 Requirement of IFT-B-BBSome complex interaction in export of GPR161 from cilia. Biology open 42 31471295
2013 A divergent calponin homology (NN-CH) domain defines a novel family: implications for evolution of ciliary IFT complex B proteins. Bioinformatics (Oxford, England) 37 24257188
2016 Hypomorphic mutations identified in the candidate Leber congenital amaurosis gene CLUAP1. Genetics in medicine : official journal of the American College of Medical Genetics 34 26820066
2013 Cluap1 localizes preferentially to the base and tip of cilia and is required for ciliogenesis in the mouse embryo. Developmental biology 34 23742838
2021 12 Survival-related differentially expressed genes based on the TARGET-osteosarcoma database. Experimental biology and medicine (Maywood, N.J.) 29 33926256
2019 Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice. Journal of bone oncology 28 30956944
2018 Crystal structure of intraflagellar transport protein 80 reveals a homo-dimer required for ciliogenesis. eLife 26 29658880
2014 Cluap1 is essential for ciliogenesis and photoreceptor maintenance in the vertebrate eye. Investigative ophthalmology & visual science 25 24970261
2012 Mammalian Clusterin associated protein 1 is an evolutionarily conserved protein required for ciliogenesis. Cilia 25 23351563
2016 A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease. Neural plasticity 23 26949549
2020 Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data. medRxiv : the preprint server for health sciences 21 33200144
2004 Isolation and characterization of a novel gene CLUAP1 whose expression is frequently upregulated in colon cancer. Oncogene 21 15480429
2018 CRISPR/Cas9-mediated Genomic Editing of Cluap1/IFT38 Reveals a New Role in Actin Arrangement. Molecular & cellular proteomics : MCP 20 29615496
2017 Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome. Cold Spring Harbor molecular case studies 18 28679688
2022 Assembly and stability of IFT-B complex and its function in BBSome trafficking. iScience 13 36411782
2007 Identification of CLUAP1 as a human osteosarcoma tumor-associated antigen recognized by the humoral immune system. International journal of oncology 9 17203229
2018 A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid. Neurotoxicity research 8 29959729
2024 Abundance of selected genes implicated in testicular functions in Camelus dromedarius with high and low epididymal semen quality. Biology of reproduction 6 38145478
2025 Associations between RetNet gene polymorphisms and the efficacy of orthokeratology for myopia control: a retrospective clinical study. Eye and vision (London, England) 3 40091069
2021 Functional Evaluation of Splicing for Variants of Uncertain Significance in Patients with Inherited Retinal Diseases. Genes 3 34209753
2019 Ciliogenesis-coupled accumulation of IFT-B proteins in a novel cytoplasmic compartment. Genes to cells : devoted to molecular & cellular mechanisms 3 31554018
2025 Identification of a Risk Allele at SLC41A3 and a Protective Allele HLA-DPB1*02:01 Associated with Sarcopenia in Japanese. Gerontology 1 40552851
2025 Teaching molecular genetics using Paramecium and RNA interference: research-based learning and project ownership. Journal of microbiology & biology education 0 40996325
2023 COVID-19 progression towards ARDS: a genome wide study reveals host factors underlying critical COVID-19. Genomics & informatics 0 37415451
2023 Identification of the primary ciliary proteins IFT38 and IFT144 to enhance serum-mediated YAP activation and cell proliferation. Biochemical and biophysical research communications 0 37783116

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