Year: 2019
Type: article
Abstract: Rab and Arl guanine nucleotide‐binding (G) proteins regulate trafficking pathways essential for the formation, function and composition of primary cilia, which are sensory devices associated with Sonic hedgehog (Shh) signalling and ciliopathies. Here, using mammalian cells and zebrafish, we uncover ciliary functions for Rab35, a multitasking G protein with endocytic recycling, actin remodelling and cytokinesis roles. Rab35 loss via siRNAs, morpholinos or knockout reduces cilium length in mammalian cells and the zebrafish left‐right organiser (Kupffer's vesicle) and causes motile cilia‐associated left‐right asymmetry defects. Consistent with these observations, GFP‐Rab35 localises to cilia, as do GEF (DENND1B) and GAP (TBC1D10A) Rab35 regulators, which also regulate ciliary length and Rab35 ciliary localisation. Mammalian Rab35 also controls the ciliary membrane levels of Shh signalling regulators, promoting ciliary targeting of Smoothened, limiting ciliary accumulation of Arl13b and the inositol polyphosphate 5‐phosphatase (INPP5E). Rab35 additionally regulates ciliary PI(4,5)P 2 levels and interacts with Arl13b. Together, our findings demonstrate roles for Rab35 in regulating cilium length, function and membrane composition and implicate Rab35 in pathways controlling the ciliary levels of Shh signal regulators.
Source: EMBO Reports
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Funders: Natur og Univers, Det Frie Forskningsråd, Villum Fonden, European Commission, Science Foundation Ireland, University College Dublin, Universität Heidelberg, Radboud Universiteit, Ministério da Educação e Ciência, Danmarks Frie Forskningsfond, Syddansk Universitet, Ministério da Educação, Novo Nordisk Fonden, National Institutes of Health, Fundação para a Ciência e a Tecnologia, European Regional Development Fund
Awards: G1516346500, G1763632427, G2195151728, G2427613718, G2673245850, G274581676, G2964751290, G323769159, G3840324753, iNOVA4Health - Programa de Medicina Translacional (iBET, CEDOC/FCM, IPOLFG e ITQB), G4724859719, G473357141, G5224927334, G547185811, G5677667711, G6197405755, Dissecting secretory and endocytic membrane transport pathways in targeting proteins to cilia, a prevalent disease-associated cellular organelle, G7123698595, G7593214324, TRAFFICKING PATHWAYS INVOVED IN THE ASSEMBLY AND MAINTENANCE OF PRIMARY CILIA., G7763239512, Regulation of endocytic recycling traffic: implications for ciliogenesis, cell migration and cytokinesis, Excel in Rare Diseases’ Research: Focus on LYSOsomal Disorders and CILiopathies, G7858748947, G7947672452, G7965899483, G7970498868, G862925997, G8839327758, G929281750
OpenAlex ID: W2969596644