MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone

• DOI: 10.1371/journal.pbio.1002416
• Publication Date: 2016-03-16T20:19:24Z
• Authors: Chunmei Li; Victor L. Jensen; Kwangjin Park; Julie Kennedy; Francesc R. Garci...; Marta Romani; Roberta De Mori; Ange-Line Bruel; Dominique Gaillard; Bérénice Doray; Estelle Lopez; Jean-Baptiste Riv...; Laurence Faivre; Christel Thauvin-...; Jeremy F. Reiter; Oliver E. Blacque; Enza Maria Valente; Michel R. Leroux
• Keywords: Ciliogenesis; Ciliopathy

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