Trafficking to the Ciliary Membrane: How to Get Across the Periciliary Diffusion Barrier?

Abstract

The primary cilium organizes numerous signal transduction cascades and an understanding of signaling receptors trafficking to cilia is now emerging. A defining feature of cilia is the periciliary diffusion barrier that separates the ciliary and plasma membranes despite the topological continuity between these two membranes. Although lateral transport through this barrier may take place, polarized exocytosis to the base of the cilium has been the prevailing model for delivering membrane proteins to cilia. Key players for this polarized exocytosis model include the GTPases Rab8 and Rab11, the exocyst and possibly the intraflagellar tranport machinery. Sorting membrane proteins to cilia critically relies on the recognition of ciliary targeting signals by sorting machines such as the BBSome coat complex or the GTPase Arf4. Finally, signaling at the cilium entails the bidirectional movement of proteins between cytoplasm and cilia and ubiquitination may promote exit from cilia. Keywords CILIA; FLAGELLA; SIGNALING DIFFUSION BARRIERTHE CENTRAL PROBLEM: SEPARATION BETWEEN THE SIGNALING COMPARTMENT AND THE SITE OF PROTEIN SYNTHESISCilia and flagella are some of the most ancient eukaryotic structures and thus define the cenancestral eukaryote in the same way as nuclei and mitochondria do (Cavalier-Smith 2002). Although the structural organization of cilia and flagella appears fairly invariant, consisting of a core of nine microtubule doublets ensheathed within the ciliary membrane, the functions of cilia and flagella are remarkably diverse. Flagella and motile cilia (these Copyright © 2010 by Annual Reviews. All rights reserved DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. FUTURE ISSUESWhere is the sorting decision made for proteins targeted to the cilium versus the plasma membrane? Are ciliary membrane proteins packaged into vesicles distinct from those of plasma membrane resident proteins at the level of the TGN, or is there an intermediate step (plasma membrane, recycling endosomes) in sorting? What is the molecular machinery that recognizes ciliary targeting sequences and sorts proteins to the cilium? How is this machinery regulated? This and the previous question are likely to shed light on the mechanisms that regulate the dynamic trafficking of signaling proteins (e.g., Smo) to the primary cilium. What is the molecular nature of the periciliary diffusion barrier? It will be important to determine how many membrane proteins reach the cilium by crossing this barrier versus utilizing the polarized exocytosis route. How are proteins removed from cilia? Is there a specific machinery involved in endocytosis of ciliary proteins? Is this step regulated by ubiquitination? NIH Public Access Author ManuscriptAnnu Rev Cell Dev Biol. Author manuscript; available in PMC 2011 November 10. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript terms can be used interchange...

Accumulation of the Raf-1 Kinase Inhibitory Protein (Rkip) Is Associated with Cep290-mediated Photoreceptor Degeneration in Ciliopathies

“…This transport may be governed by IFT or diffusion (25)(26)(27)(28). Macromolecular protein complexes at the TZ of cilia govern the stringently regulated transport of proteins (29,30). Consistently, the TZ-associated proteins are also involved in cilia-dependent retinal degenerative diseases (31).…”

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

“…The mouse rod OS is completely renewed within 10 days (2). Not surprisingly, mutations impairing protein trafficking to the OS cause various types of photoreceptor degeneration, and considerable research efforts have been made to elucidate mechanisms of protein trafficking to the OS (1,5,6).…”

Structural Characterization of Bardet-Biedl Syndrome 9 Protein (BBS9)

“…The microtubule bundle, termed the axoneme, forms the structural scaffold of this finger-like projection and is surrounded by the lipid bilayer except at its base, where it originates from the mother centriole in the cytoplasm (1). Unlike motile cilia, the role of the primary cilium is not locomotion but rather signal transduction and, as a consequence, is essential to Hedgehog and non-canonical Wnt signaling pathways (2).…”

“…Unlike motile cilia, the role of the primary cilium is not locomotion but rather signal transduction and, as a consequence, is essential to Hedgehog and non-canonical Wnt signaling pathways (2). Despite being continuous with the plasma membrane, the membrane of the primary cilium has a unique composition of proteins, namely an enrichment of specific G-protein-coupled receptors involved in signaling (1,3). How this organelle maintains the integrity and specificity of its compartment remains an active area of investigation, although a septin diffusion barrier has been shown to play a critical role (4,5).…”

“…The genes coding for seven of these proteins were originally identified based on their mutation in a rare, autosomal recessive genetic disorder termed Bardet-Biedl syndrome (BBS (8)). BBS is a pleiotropic disease characterized by mental retardation, polycystic kidneys, obesity, vision problems, and hypogonadism (1,8). Evidence for BBSome function was seen in BBS2 and BBS4 knock-out mice, where a G-protein-coupled receptor resident of the ciliary membrane, somatostatin receptor type 3, fails to localize to the primary cilium in neurons (9).…”