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PLoS Biol. 2016 Mar 16;14(3):e1002416. doi: 10.1371/journal.pbio.1002416. eCollection 2016 Mar.

MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone.

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Department of Molecular Biology and Biochemistry and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada.
School of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, United States of America.
Neurogenetics Unit, Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
EA4271 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Université Fédérale Bourgogne Franche-Comté, Dijon, France.
Service de Génétique clinique, CHU Reims, Reims, France.
Service de Génétique clinique, CHRU Strasbourg, Strasbourg, France.
Laboratoire de Génétique moléculaire, Plateau Technique de Biologie, CHU Dijon, Dijon, France.
Centre de Génétique, FHU-TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.
Department of Medicine and Surgery, University of Salerno, Salerno, Italy.


Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module-associated proteins--including the previously uncharacterised mammalian Tmem80--and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ.

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