Transport and barrier mechanisms that regulate ciliary compartmentalization and ciliopathies.

Primary cilia act as cell surface antennae, coordinating cellular responses to sensory inputs and signalling molecules that regulate developmental and homeostatic pathways. Cilia are therefore critical to physiological processes, and defects in ciliary components are associated with a large group of inherited pleiotropic disorders — known collectively as ciliopathies — that have a broad spectrum of phenotypes and affect many or most tissues, including the kidney. A central feature of the cilium is its compartmentalized structure, which imparts its unique molecular composition and signalling environment despite its membrane and cytosol being contiguous with those of the cell. Such compartmentalization is achieved via active transport pathways that bring protein cargoes to and from the cilium, as well as gating pathways at the ciliary base that establish diffusion barriers to protein exchange into and out of the organelle. Many ciliopathy-linked proteins, including those involved in kidney development and homeostasis, are components of the compartmentalizing machinery. New insights into the major compartmentalizing pathways at the cilium, namely, ciliary gating, intraflagellar transport, lipidated protein flagellar transport and ciliary extracellular vesicle release pathways, have improved our understanding of the mechanisms that underpin ciliary disease and associated renal disorders. The compartmentalized structure of primary cilia is maintained via interconnected barrier and active transport systems and underlies its unique composition and function. This Review describes the major compartmentalizing pathways that occur at the cilium and how insights into cilia transport and barrier mechanisms have shed light on the mechanisms underlying ciliary diseases. Key points: Cilia at the cell plasma membrane serve motility, sensory and signalling roles that are essential for cell and tissue formation, homeostasis and function. Cilia defects cause ciliopathy disorders that affect many tissue types. The unique and dynamic molecular composition of the ciliary organelle and its biochemically compartmentalized state are established and maintained via interconnected barrier and active transport systems. The ciliary base, which encompasses the transition zone and basal body regions, and associated 'gating' complexes (MKS, NPHP, TAF and NUP modules), establish barriers to regulate the movement of cytosolic and membrane proteins into and out of cilia. Membrane and cytosolic proteins move into and out of cilia by binding to cargo adaptor complexes (intraflagellar transport (IFT)-A, IFT-B and the BBSome) present on kinesin-2 and cytoplasmic dynein-driven IFT trains that run bidirectionally along ciliary microtubules. Myristoyl-anchored and palmitoyl-anchored membrane proteins enter cilia via lipidated IFT, which involves shuttling carriers (UNC119B and PDE6D), cargo displacement factors (ARL3) and associated regulators (RP2 and ARL13B). Extracellular vesicles that bud from the ciliary membrane regulate ciliary structure, composition and function by dispatching molecules and membrane from the organelle. Ciliary extracellular vesicles may serve as waste disposal and/or cell–cell communication devices. Better knowledge of the ciliary compartmentalization pathways is essential for understanding mechanisms of ciliary disease such as the renal ciliopathies that include autosomal dominant polycystic kidney disease and nephronophthisis. [ABSTRACT FROM AUTHOR]