Ciliopathy-associated mutations of IFT122 impair ciliary protein trafficking but not ciliogenesis
Open accessAbstract
The intraflagellar transport (IFT) machinery containing the IFT-A and IFT-B complexes mediates ciliary protein trafficking. Mutations in the genes encoding the six subunits of the IFT-A complex (IFT43, IFT121, IFT122, IFT139, IFT140, and IFT144) are known to cause skeletal ciliopathies, including cranioectodermal dysplasia (CED). As the IFT122 subunit connects the core and peripheral subcomplexes of the IFT-A complex, it is expected to play a pivotal role in the complex. Indeed, we here showed that knockout (KO) of the IFT122 gene in hTERT-RPE1 cells using the CRISPR/Cas9 system led to a severe ciliogenesis defect, whereas KO of other IFT-A genes had minor effects on ciliogenesis but impaired ciliary protein trafficking. Exogenous expression of not only wild-type IFT122 but also its CED-associated missense mutants, which fail to interact with other IFT-A subunits, rescued the ciliogenesis defect of IFT122-KO cells. However, IFT122-KO cells expressing CED-type IFT122 mutants showed defects in ciliary protein trafficking, such as ciliary entry of Smoothened in response to Hedgehog signaling activation. The trafficking defects partially resembled those observed in IFT144-KO cells, which demonstrate failed assembly of the functional IFT-A complex at the base of cilia. These observations make it likely that, although IFT122 is essential for ciliogenesis, CED-type missense mutations underlie a skeletal ciliopathy phenotype by perturbing ciliary protein trafficking with minor effects on ciliogenesis per se.
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The IFT-A complex interacts with the tubby domain proteins TULP3 and TUB to mediate ciliary targeting of certain transmembrane proteins, including G protein-coupled receptors.
“Furthermore, the IFT-A complex interacts with the tubby domain proteins TULP3 and TUB to mediate ciliary targeting of certain transmembrane proteins, including G protein-coupled receptors (GPCRs) 56, 58, 64–69.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [66]
The Introduction states that the IFT-A core is associated with TULP3, and the Results report impaired ciliary entry of the GPCR SMO in cells lacking an IFT-A subunit. However, the paper does not describe an interaction with TUB or establish that TULP3 and TUB mediate GPCR targeting through IFT-A. (LLM, conf=0.85)
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Cellular signalling by primary cilia in development, organ function and disease
Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B., & Christensen, S. T. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0116-9 · Cited by 845 · see citing works
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Self-citation
- Authors
- Takahara, M., Katoh, Y., Nakamura, K., Hirano, T., Sugawa, M., Tsurumi, Y., & Nakayama, K.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Nakayama, Kazuhisa
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-12-06
- Volume
- 27
- Issue
- 3
- Pages
- 516-528
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2772819251
- Cited by
- 62
- References
- 52
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 6 · 2021: 5 · 2020: 10 · 2019: 5 · 2018: 7 · 2017: 1
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (15H04370, 15K07929)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- intraflagellar transport, IFT-A complex, ciliogenesis, ciliary protein trafficking, cranioectodermal dysplasia, skeletal ciliopathy, missense mutations, Smoothened, Hedgehog signaling
- MeSH terms
- Ciliopathies, Carrier Proteins, Cell Line, Cytoskeletal Proteins, Humans, Microtubule-Associated Proteins, Mutation, Proteins, Signal Transduction, Mutation, Missense, Protein Transport, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins
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