Ciliogenesis membrane dynamics and organization

Abstract

Ciliogenesis is a complex multistep process used to describe assembly of cilia and flagella. These organelles play essential roles in motility and signaling on the surface of cells. Cilia are built at the distal ends of centrioles through the formation of an axoneme that is surrounded by the ciliary membrane. As is the case in the biogenesis of other cellular organelles, regulators of membrane trafficking play essential roles in ciliogenesis, albeit with a unique feature that membranes are organized around microtubule-based structures. Membrane association with the distal end of the centriole is a critical initiating step for ciliogenesis. Studies of this process in different cell types suggests that a singular mechanism may not be utilized to initiate cilium assembly. In this review, we focus on recent insights into cilium biogenesis and the roles membrane trafficking regulators play in described ciliogenesis mechanisms with relevance to human disease.

Keywords: Autophagy; Ciliogenesis; Ciliopathy; Membrane trafficking; centriole; cilia.

Figure 1.. Ciliogenesis mechanisms

A)Intracellular ciliogenesis. In the cytoplasm a ciliary vesicle (CV) organizes at the distal appendages of centrioles prior to axoneme and ciliary membrane formation at the sheath stage. In the mature cilium a ciliary pocket membrane partially embeds the organelle in the cell. B) Extracellular ciliogenesis. Mature centrioles migrate and dock to the plasma membrane via distal appendages followed by axoneme formation. C) Multiciliogenesis. Centriole duplication occurs through the deuterosome. Centrioles develop DAs and SDAs while migrating towards the cell surface to form the axoneme. The transition zone forms prior to axoneme growth at the base of the cilium (A,B,C). Subdistal appendages are organized into the basal foot in multiciliated cells.

Figure 2.. Intracellular ciliogenesis and membrane trafficking regulation

(A) Model showing the stages of intracellular ciliogenesis and requirements of membrane trafficking regulators in associated ciliogenesis processes (1-6) shown in (B). (B) Expanded view of ciliogenesis processes (1-6) shown in (A). (B) Expanded view of ciliogenesis processes (1-6) from (A). (1) Preciliary vesicle (PCV) trafficking to the mother centriole (MC). (2) Docking of PCVs to the MC mediated by distal appendage proteins (DA) proteins. Distal appendage vesicles – DAVs. (3) Uncapping of the mother centriole. TTBK2-mediated phosphorylation of MMP9 promotes ubiquitin proteasomal cascade to remove CP110 and CEP97. Autophagy has also been shown to regulate CP110 MC uncapping. (4) SNARE mediated fusion of DAVs to assemble the ciliary vesicle (CV). (5) Transition zone (TZ) protein association with RAB8 activation and the CV stage. (6) Axoneme and ciliary membrane growth regulation by the IFT-B complex and associated trafficking regulators including ARL13B and RAB GTPases. Extracellular membrane channel (EMC) connects the developing intracellular cilium membrane with the plasma membrane. The ciliary membrane is marked in yellow.