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TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome

Nils J. Lambacher 1 Ange-Line Bruel 2, 3 Teunis J. P. van Dam 4 Katarzyna Szymańska 5 Gisela G. Slaats 6 Stefanie Kuhns 1 Gavin J. Mcmanus 1 Julie E. Kennedy 1 Karl Gaff 1 Ka Man Wu 6 Robin van der Lee 4 Lydie Burglen 7, 8 Diane Doummar 9 Jean-Baptiste Rivière 2 Laurence Faivre 2, 3 Tania Attié-Bitach 10, 11 Sophie Saunier 10, 11 Alistair Curd 5 Michelle Peckham 5 Rachel H. Giles 6 Colin A. Johnson 5 Martijn A. Huynen 4, * Christel Thauvin-Robinet 2, 3, * Oliver E. Blacque 12, *
* Auteur correspondant
1 School of Biology & Environmental Science and Conway Institute of Biomolecular & Biomedical Research, University College Dublin
2 GAD - Génétique des Anomalies du Développement
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 Radboud University Medical Center [Nijmegen]
5 LIBACS - Leeds Institute of Biomedical & Clinical Sciences
6 University Medical Center [Utrecht]
7 Service de neuropédiatrie et pathologie du développement
8 Service de Génétique et d'Embryologie Médicale
9 Service de neuropédiatrie [Trousseau]
10 CHU Necker - Enfants Malades [AP-HP]
11 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
12 Proteome Research Centre, UCD Conway Institute for Biomolecular and Biomedical Research,
Abstract : The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome' (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral-facial-digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM-107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super-resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture.
Keywords : evolution transport nephrocystins complex mutations membrane ciliogenesis c. elegans primary cilium caenorhabditis-elegans
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01409162
Contributeur : Gad - Université de Bourgogne <>
Soumis le : lundi 5 décembre 2016 - 17:00:07
Dernière modification le : mercredi 19 août 2020 - 11:17:17

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UNIV-BOURGOGNE | UNIV-PARIS5 | USPC | CNRS | UNIV-PARIS | UP-SANTE

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Nils J. Lambacher, Ange-Line Bruel, Teunis J. P. van Dam, Katarzyna Szymańska, Gisela G. Slaats, et al.. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nature Cell Biology, Nature Publishing Group, 2016, 18 (1), pp.122 - 131. ⟨10.1038/ncb3273⟩. ⟨hal-01409162⟩

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