Author response: Intraflagellar transport protein IFT172 contains a C-terminal ubiquitin-binding U-box-like domain involved in ciliary signaling
Rattachement africain : dk, fr. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Intraflagellar transport (IFT) is a fundamental process driving ciliogenesis in most eukaryotic organisms. IFT172, the largest protein of the IFT complex, plays a crucial role in cilium formation and is associated with several disease variants causing ciliopathies. While IFT172 is tethered to the IFT-B complex via its N-terminal domains, the function of its C-terminal domains has remained elusive. Here, we reveal that the C-terminal part of IFT172 interacts with IFT-A complex subunits, providing a molecular basis for the role of IFT172 in bridging IFT-A and IFT-B complexes. We determine the crystal structure of the C-terminal part of IFT172, uncovering a conserved U-box-like domain often found in E3 ubiquitin ligases. This domain exhibits ubiquitin-binding properties and auto-ubiquitination activity. The IFT172 auto-ubiquitination activity is reduced in the C1727R patient ciliopathy variant. We use CRISPR-engineered RPE-1 cells to demonstrate that the U-box-like domain is essential for IFT172 protein stability and proper cilium formation. Notably, RPE-1 cells with heterozygous deletion of the U-box domain show altered TGFB signaling responses, particularly in SMAD2 phosphorylation levels and AKT activation. Our findings suggest a novel dual role for IFT172 in both structural support within IFT trains and regulation of ciliary ubiquitination and signaling pathways, providing new insights into the molecular mechanisms underlying IFT172-related ciliopathies.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Author response: Intraflagellar transport protein IFT172 contains a C-terminal ubiquitin-binding U-box-like domain involved in ciliary signaling
- Date Crossref
- 31/01/2025
- Éditeur
- eLife Sciences Publications, Ltd
- Type
- peer-review
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Aarhus University Department of Molecular Biology and Genetics pays non établi dans la noticeUniversité ou école supérieure
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University of Southern Denmark Department for Biochemistry and Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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University of Copenhagen Department of Biology pays non établi dans la noticeUniversité ou école supérieure
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Institut des Maladies Génétiques Imagine pays non établi dans la noticeStructure de recherche
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Laboratory of Hereditary and Kidney diseases pays non établi dans la noticeStructure de recherche
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European Molecular Biology Laboratory pays non établi dans la noticeStructure de recherche
Department of Molecular Biology and Genetics — Aarhus University, Department for Biochemistry and Molecular Biology — University of Southern Denmark et Department of Biology — University of Copenhagen, avec 3 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.