Affinage

IFT38

Annotated
2026-04-28
28 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IFT38 (CLUAP1) is a subunit of the intraflagellar transport complex B (IFT-B) peripheral subcomplex that is essential for ciliogenesis, Hedgehog signaling, and left-right axis determination. Within IFT-B, IFT38 forms a connecting tetramer with IFT52, IFT57, and IFT88 that bridges the IFT-B1 and IFT-B2 subcomplexes and directly couples the IFT-B complex to the heterotrimeric kinesin-II motor via KIF3B for anterograde intraflagellar transport (PMID:26980730, PMID:29903877, PMID:36411782). IFT38 also tethers IFT80 to the IFT-B complex and interacts with BBSome subunits BBS1, BBS2, and BBS9 to mediate Hedgehog-stimulated export of GPR161 from cilia (PMID:29658880, PMID:31471295). Biallelic loss-of-function mutations in CLUAP1 cause a ciliopathy syndrome with features overlapping Joubert and oral-facial-digital syndromes (PMID:28679688).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Medium

    Initial characterization identified CLUAP1 as a coiled-coil nuclear protein interacting with Clusterin whose depletion causes growth retardation, establishing it as a functionally relevant gene before its ciliary role was recognized.

    Evidence Yeast two-hybrid, cell cycle synchronization, and siRNA knockdown in cultured cells

    PMID:15480429

    Open questions at the time
    • Clusterin interaction not confirmed by reciprocal methods
    • Nuclear localization later superseded by ciliary localization findings
    • No link to cilia or IFT at this stage
  2. 2012 High

    Knockout mouse studies established that Cluap1 is required for primary cilia formation and Sonic hedgehog signaling, repositioning the gene as a ciliary/IFT factor rather than a nuclear protein.

    Evidence Cluap1 mutant mice lacking cilia at E9.5 with neural tube defects and repressed Hedgehog signaling assessed by reporter and qRT-PCR

    PMID:23351563 PMID:23742838

    Open questions at the time
    • Molecular position within the IFT complex not yet defined
    • Mechanism of Hedgehog signaling defect (direct vs. indirect) unresolved
  3. 2014 High

    Live imaging demonstrated that Cluap1 undergoes bidirectional IFT with kinetics matching IFT-B component IFT20, directly proving it is a bona fide IFT particle component and linking its loss to photoreceptor degeneration in zebrafish.

    Evidence High-speed confocal imaging in Xenopus multiciliated cells and zebrafish cluap1 mutant analysis

    PMID:24970261

    Open questions at the time
    • Which IFT-B subcomplex Cluap1 belongs to was not determined
    • Photoreceptor degeneration mechanism not dissected
  4. 2016 High

    Interaction mapping placed IFT38 specifically in the IFT-B peripheral subcomplex (not the core) and showed that its integration into IFT-B is required for ciliogenesis, defining its molecular position within the IFT machinery.

    Evidence Visible immunoprecipitation assay, rescue of Cluap1-deficient MEFs with wild-type vs. binding-deficient mutant

    PMID:26980730

    Open questions at the time
    • Direct binding partners within IFT-B peripheral subcomplex not fully resolved
    • No structural information on the interaction interfaces
  5. 2017 Medium

    Identification of biallelic CLUAP1 mutations in a patient with Joubert/oral-facial-digital spectrum ciliopathy, with functional validation showing reduced IFT activity, established CLUAP1 as a human ciliopathy gene.

    Evidence Exome sequencing plus IFT assay of mutant constructs in Xenopus

    PMID:28679688

    Open questions at the time
    • Single family/case report; additional patients needed to confirm genotype-phenotype spectrum
    • Effect of mutations on IFT-B complex assembly not tested
  6. 2018 High

    Three advances defined IFT38's bridging roles: it forms a connecting tetramer (IFT38-IFT52-IFT57-IFT88) that couples IFT-B to kinesin-II via KIF3B for anterograde transport, tethers IFT80 to IFT-B via its N-terminal β-propeller, and has an interactome extending to actin regulators (Ephrin-B1, TRIP6).

    Evidence Crystal structure of IFT80 (1.8 Å), VIP interaction assay with KIF3B-KO rescue, CRISPR endogenous tagging with MS interactome and actin phenotype

    PMID:29615496 PMID:29658880 PMID:29903877

    Open questions at the time
    • Structural basis of IFT38–KIF3B interface unknown
    • Actin cytoskeletal role not mechanistically dissected
    • Novel interactors (Ephrin-B1, TRIP6) not validated by reciprocal methods
  7. 2019 High

    IFT38 was shown to interact with BBSome subunits BBS1/BBS2/BBS9 specifically for GPR161 export from cilia upon Hedgehog stimulation, separating its cargo-trafficking function from its ciliogenesis role, and to accumulate in a novel cytoplasmic IFT spot during ciliogenesis.

    Evidence VIP assay with IFT38-KO rescue using BBSome-binding-deficient mutant; immunofluorescence and live-cell imaging of cytoplasmic IFT spot in MEFs

    PMID:31471295 PMID:31554018

    Open questions at the time
    • Whether other ciliary GPCRs require the IFT38–BBSome interaction for export is untested
    • Function of the cytoplasmic IFT spot in IFT particle pre-assembly is not established
  8. 2022 Medium

    Deletion analysis clarified that the connecting tetramer mediates mutual stability between IFT-B1 and IFT-B2 subcomplexes, while IFT38 deletion from IFT-B2 does not prevent IFT-B1 assembly, supporting a modular IFT-B assembly pathway.

    Evidence Subunit deletion stability assays and IFT/BBSome trafficking functional assays

    PMID:36411782

    Open questions at the time
    • In vivo validation of modular assembly model not performed
    • How IFT-B2 assembles in the absence of IFT38 is not fully characterized
  9. 2023 Medium

    A systematic screen revealed that IFT38 ablation represses serum-stimulated YAP activation and cell proliferation, uncovering a cilia-independent or cilia-linked role in Hippo/YAP signaling.

    Evidence siRNA screen of 30 ciliary proteins with YAP phosphorylation readout, 2D and 3D spheroid proliferation assays

    PMID:37783116

    Open questions at the time
    • Whether YAP regulation is cilia-dependent or cilia-independent is unresolved
    • Mechanism linking IFT38 to YAP dephosphorylation unknown
    • Single lab finding awaiting independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the IFT38–KIF3B and IFT38–BBSome interfaces, the functional significance of the cytoplasmic IFT spot, whether IFT38's roles in actin organization and YAP signaling are cilia-dependent, and the full genotype-phenotype spectrum of CLUAP1 ciliopathy.
  • No high-resolution structure of IFT38 in complex with kinesin-II or BBSome
  • Cytoplasmic IFT spot function in IFT particle pre-assembly not tested
  • Cilia-dependence of actin and YAP phenotypes not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 4 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4
Partners
BBS1BBS2BBS9IFT52IFT57IFT80IFT88KIF3B
Complex memberships
IFT-B complexIFT-B connecting tetramer (IFT38-IFT52-IFT57-IFT88)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 IFT38/CLUAP1 is an integral component of the IFT-B peripheral subcomplex (not the core), interacting with other IFT-B components; loss of the IFT-B binding ability of CLUAP1 fails to rescue ciliogenesis in Cluap1-deficient mouse embryonic fibroblasts, demonstrating that its integration into the IFT-B peripheral subcomplex is required for ciliogenesis. Visible immunoprecipitation (VIP) assay, subcellular localization comparison between wild-type and Cluap1-deficient cells, rescue experiments with binding-deficient mutant The Journal of biological chemistry High 26980730
2018 IFT38 forms part of an IFT-B-connecting tetramer (IFT38-IFT52-IFT57-IFT88) that directly interacts with the heterotrimeric kinesin-II motor (KIF3A-KIF3B-KAP3), primarily through KIF3B; this interaction is essential for anterograde IFT and ciliogenesis. Visible immunoprecipitation assay, KIF3B-knockout rescue experiments with 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 required specifically for the export of GPR161 from cilia upon Hedgehog signaling stimulation, but is dispensable for ciliogenesis itself. Visible immunoprecipitation assay, IFT38-knockout cell rescue with IFT38 mutant lacking BBSome-binding ability, GPR161 accumulation assay Biology open High 31471295
2018 The N-terminal β-propeller of IFT80 tethers it to the IFT-B complex via IFT38, as revealed by the crystal structure of IFT80 and functional mapping experiments. Crystal structure (1.8 Å resolution), structural mapping, CRISPR/Cas9 knockout rescue experiments eLife High 29658880
2013 Cluap1/IFT38 localizes preferentially to the base and tip of cilia and is required for axoneme growth (ciliogenesis); Cluap1 knockout mice fail to form cilia, have defective Hedgehog signaling, and show disrupted left-right axis specification. Cluap1 knockout mouse generation, immunofluorescence/confocal localization, Patched1-lacZ Hedgehog reporter, tissue-specific rescue experiments Developmental biology High 23742838
2012 Mammalian Cluap1 localizes to primary cilia and is required for ciliogenesis; Cluap1 mutant mouse embryos lack cilia at E9.5, show defects in Sonic hedgehog signaling (pathway is repressed), and exhibit neural tube and turning defects. Cluap1 mutant mouse generation, immunofluorescence, β-galactosidase Hedgehog reporter, qRT-PCR Cilia High 23351563
2014 Cluap1 undergoes bidirectional intraflagellar transport along cilia with similar localization and kinetics as IFT20 (an IFT-B complex component), and loss of cluap1 in zebrafish causes ciliogenesis defects and photoreceptor degeneration. High-speed in vivo confocal imaging of tagged proteins in Xenopus multiciliated cells, zebrafish cluap1 mutant analysis, immunohistochemistry Investigative ophthalmology & visual science High 24970261
2013 CLUAP1/IFT38 contains a divergent N-terminal calponin homology (NN-CH) domain related to NDC80/NUF2, placing it in a novel family of IFT-B subunits (with IFT81 and IFT57) that share evolutionary ancestry with outer kinetochore components. Profile-to-profile sequence comparisons, structural modeling Bioinformatics (Oxford, England) Low 24257188
2004 CLUAP1 encodes a nuclear protein with a coiled-coil domain that interacts with nuclear Clusterin (identified by yeast two-hybrid); its expression peaks in late S to G2/M phases; siRNA-mediated suppression causes growth retardation. Yeast two-hybrid, cell cycle synchronization analysis, siRNA knockdown with growth assay Oncogene Medium 15480429
2017 A missense mutation p.(Met113Arg) in CLUAP1 reduces intraflagellar transport activity while a nonsense mutation p.(Arg230Ter) reduces protein levels; biallelic mutations in CLUAP1 cause a novel ciliopathy syndrome with features overlapping Joubert and oral-facial-digital syndromes. Exome sequencing, Xenopus transfection with mutant CLUAP1 constructs, IFT assay in Xenopus Cold Spring Harbor molecular case studies Medium 28679688
2018 CRISPR/Cas9 knockout of Cluap1/IFT38 reveals a novel role in actin cytoskeletal arrangement; endogenously tagged Cluap1 interactome identifies new binding partners including Ephrin-B1, TRIP6, PDGFA, and CCDC6, linking IFT38 to cytoskeletal rearrangement and intracellular transport in addition to IFT-B complex functions. CRISPR/Cas9 endogenous tagging and knockout, mass spectrometry interactome, actin cytoskeleton phenotype analysis Molecular & cellular proteomics Medium 29615496
2019 During ciliogenesis, Cluap1/IFT38 (along with IFT46 and IFT88) accumulates in a novel noncentriolar cytoplasmic compartment called the 'cytoplasmic IFT spot'; in proliferating non-ciliated cells, Cluap1 localizes to the distal appendage of the mother centriole; the cytoplasmic IFT spot is absent in ciliogenesis-defective cells lacking Cluap1, Kif3a, or Odf2. Immunofluorescence and live-cell imaging in MEFs and mouse embryos, analysis of ciliogenesis-defective mutant cells Genes to cells Medium 31554018
2022 IFT38 functions in the regulation of anterograde IFT and retrograde BBSome trafficking; the connecting tetramer IFT38/IFT57/IFT88/IFT52 mediates mutual stability between IFT-B1 and IFT-B2 subcomplexes; deletion of IFT38 from IFT-B2 does not alter the formation of an intact IFT-B1, supporting a modular IFT-B assembly pathway. IFT-B subunit deletion analysis, stability assays, IFT and BBSome trafficking functional assays iScience Medium 36411782
2023 Ablation of IFT38 (or IFT144) in a ciliary protein mutant cell library particularly robustly represses YAP activation upon LPA and S1P stimulation, attenuates cell proliferation in 2D cultures and tumor spheroids, identifying IFT38 as a regulator of serum-mediated Hippo/YAP pathway signaling. siRNA library screen of 30 ciliary proteins, YAP dephosphorylation/target gene assay, cell proliferation assay in 2D and 3D spheroids Biochemical and biophysical research communications Medium 37783116

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 41 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 7 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
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 Associations between RetNet gene polymorphisms and the efficacy of orthokeratology for myopia control: a retrospective clinical study. Eye and vision (London, England) 2 40091069
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