TRG_Cilium_Arf4_1

Cilia are hairlike cellular organelles with motile and sensory functions. They are assembled and maintained by intraflagellar transport (IFT), which uses microtubule-dependent motor proteins to mobilize ciliary cargo and to recycle components back to the basal body. Cilia compartmentalize receptors and signaling machinery, including effectors of phototransduction, olfaction, mechanosensation, as well as the crucial elements of signaling pathways (Inglis,2006). The vesicular trafficking required for the organization of the cilium is modulated by small GTPases of the Rab and Arf families (Jenkins,2007).
A ciliary targeting motif has been extensively characterised in rhodopsin. Mutations in the C-terminal region of rhodopsin were first related to severe forms of retinitis pigmentosa in humans (Berson,1996). Shortly afterwards, it was discovered that such mutations disrupted the conserved terminal motif QV[SA]PA and resulted in aberrant sub-cellular localisation of rhodopsin (Deretic,1998). Subsequently it was shown that sorting and delivery of rhodopsin to the rod outer segments is achieved by the interaction of its C-terminal motif with the GTPase activating protein Arf4 (Deretic,2005). The association of the active Arf4-GTP with the trans-Golgi network membrane depends on the VxPx motif. Budding of the rhodopsin transport carrier vesicle is regulated by the Arf GAP ASAP1. It couples proof-reading of cargo incorporation to vesicle budding through the GTP hydrolysis of Arf4-GTP. Additionally, ASAP1 functions as a scaffold that incorporates other proteins (FIP3 and Rab11) necessary for the liberation of the carrier vesicle and its subsequent delivery to the rod outer segment (Mazelova,2009).
A related ciliary targeting motif has been also identified in proteins like the cyclic nucleotide-gated channel subunit CNGB1b in olfactory neurons and polycystin-2 (PC2), a protein affected in polycystic kidney disease. While the involvement of the motif in the delivery of those proteins to the cilia of the respective cells has been experimentally verified (Geng,2006, Jenkins,2006), it is not yet clear if such transport requires Arf GTPases.