Endocytic Control of Cellular Signaling at the Primary Cilium

Primary cilia are dynamic signaling organelles that project from the cell surface to sense diverse chemical, physical and morphogenetic cues. Ciliary defects therefore cause diseases (ciliopathies) that affect multiple organs in developing and adult organisms. Cilia-mediated signaling involves the orchestrated movement of signaling proteins in and out of the ciliary compartment, including movement of receptors such as the Sonic Hedgehog (Shh) receptor Patched 1 (PTCH1), Smoothened (SMO), and various other G protein-coupled receptors (GPCRs), as well as transforming growth factor β (TGF-β) receptors I and II (TGF-β-RI/II). We provide here a current understanding of trafficking events associated with cilia-mediated signaling, with emphasis on the involvement of clathrin-dependent receptor-mediated endocytosis in regulating ciliary Shh and TGF-β signaling. Primary cilia play important roles in coordinating various cellular and developmental signaling pathways, and their dysfunction is associated with diseases called ciliopathies. Signaling by primary cilia involves orchestrated trafficking of membrane receptors in and out of cilia by mechanisms that are not fully understood. Proteins and lipids destined to the cilium are transported in Golgi-derived vesicles or endosomes to the periciliary membrane region where vesicles are exocytosed. Kinesin-2 and cytoplasmic dynein-2 mediated intraflagellar transport (IFT) mediates trafficking of proteins within cilia, but some ciliary membrane proteins move within the ciliary membrane largely by diffusion. The periciliary membrane is often invaginated, forming a pocket-like structure that is a hotspot for the exocytosis and endocytosis of vesicles destined to or derived from the ciliary membrane. Clathrin-dependent endocytosis at the ciliary pocket mediates the clearance of specific membrane receptors from the ciliary compartment, and is important for regulating cilia-mediated Shh and TGF-β signaling.