Most cells have a single microtubule-based membrane projection called the primary cilium. This cell surface “antenna” is enriched with important molecules such as G-protein coupled receptors (GPCRs) like Smoothened, somatostatin receptors, and rhodopsin, which are central to several signaling pathways. Defects in primary ciliogenesis have been implicated in a wide array of pathological disorders ranging from retinal degeneration to Bardet-Biedl syndrome. The generation of primary cilia involves microtubule organization and polarized membrane trafficking. A classic electron microscopy study provided sequential snapshots of the transport of secretory vesicles to the site of ciliogenesis [4]. The small GTPase Rab8 is involved in membrane trafficking from the TGN and recycling endosome to the plasma membrane [5,6]. Disruption of Rab8 in frog photoreceptor cells blocks rhodopsin transport and results in an accumulation of tubulo-vesicular structures at the base of the retinal rod outer segment, a specialized form of cilia [7,8]. Studies using cultured human retinal pigment epithelium (hRPE) cells have further demonstrated that Rab8 and its guanine nucleotide exchange factor (GEF) Rabin8 play important roles in primary ciliogenesis [9,10]. Rabin8 interacts with BBS1, a component of the BBSome, which is a multi-protein complex implicated in Bardet-Biedl syndrome and is involved in cargo transport to the primary cilia [10,11]. Rabin8 is a direct downstream effector of Rab11 [12], which mediates vesicle transport from the TGN and recycling endosomes [13,14]. The GTP-bound form of Rab11 interacts with Rabin8 and kinetically stimulates its GEF activity toward Rab8. This effect is specific, as other Rab GTPases such as Rab3 and Rab5 do not exhibit any stimulatory effect on Rabin8 activity [12]. Fluorescence microscopic studies revealed that Rab11 is localized near the base of the primary cilia, and its disruption inhibits ciliogenesis [12]. It was therefore proposed that Rab11 modulates Rab8 function by activating Rabin8. This cascade of Rab activation couples cargo transport from the TGN and recycling endosomes to vesicle docking and fusion at the plasma membrane. In another interesting study, it was shown that Rab11, Rabin8, and Rab8 are involved in the de novo generation of primary cilium [15]. Using time-lapse video microscopy, the authors observed the process of Rab8 recruitment into the ciliary membrane during primary ciliogenesis in live cells, and found that Rab8 ciliary membrane localization was preceded by the trafficking of Rabin8 to the centrosome, which in turn was dependent on Rab11.

While the Rab cascade and the exocyst are critical components in the exocytic pathway, they are clearly not the only players. Recently, it was shown that Arf4, Rab11, FIP3, and the Arf GTPase-activating protein ASAP1 are important for the transport of rhodopsins to the retina outer segments [41]. The Arf4-based protein complex is probably involved in the selection and packaging of specific cargos, including GPCRs, for their delivery to the cilia. It will be interesting to know how vesicle packaging and budding are coupled to subsequent transport and docking at the plasma membrane. Once incorporated into the plasma membrane, ciliary cargos are collected by the BBSome, which acts as a planar coat that transports proteins to the cilia [11]. It will be important to determine how vesicle fusion is connected to subsequent cargo entry to the cilia, and how the BBSome is coupled to intraflagellar transport particles (IFTs) for cargo movement within the cilia. The field also awaits a better understanding of the connections between the secretory machinery and cell polarity regulators. While functional analyses [26,34,35] and immunoprecipitation experiments [21] have demonstrated a connection between Rabs and exocyst with Cdc42 and Par proteins, future experiments are called for to elucidate the molecular interactions among these proteins.