Trafficking of ciliary membrane proteins by the intraflagellar transport/BBSome machinery

Abstract

Bardet-Biedl syndrome (BBS) is a rare inherited disease caused by defects in the BBSome, an octameric complex of BBS proteins. The BBSome is conserved in most organisms with cilia, which are microtubule (MT)-based cell organelles that protrude from the cell surface and function in motility and sensing. Cilia assembly, maintenance, and function require intraflagellar transport (IFT), a bidirectional motility of multi-megadalton IFT trains propelled by molecular motors along the ciliary MTs. IFT has been shown to transport structural proteins, including tubulin, into growing cilia. The BBSome is an adapter for the transport of ciliary membrane proteins and cycles through cilia via IFT. While both the loss and the abnormal accumulation of ciliary membrane proteins have been observed in bbs mutants, recent data converge on a model where the BBSome mainly functions as a cargo adapter for the removal of certain transmembrane and peripheral membrane proteins from cilia. Here, we review recent data on the ultrastructure of the BBSome and how the BBSome recognizes its cargoes and mediates their removal from cilia.

Keywords: BBSome; G-protein-coupled receptors; cilia; hedgehog; intraflagellar transport; membrane proteins.

Figure 1:. Model of BBSome-mediated trafficking of ciliary membrane proteins

BBSome cargoes originating from the Golgi or endosome travel to the periciliary membrane (darker gray). Cargoes enter the cilia membrane (lighter gray) by either diffusion or IFT. Once in the cilium, cargoes can be recognized by BBSome. BBSome cargoes Box: Both transmembrane and peripheral membrane proteins are transported in a BBSome-dependent manner. Lipid modifications that allow for membrane association (i.e. palmitoylation and myristoylation), are shown in pink. BBSome cargo recognition Box: Simple Pick-Up: Moving BBSome-IFT trains encountering a membrane-associated cargo bind to its ciliary export sequence and carry it along and out of the cilium. Cargo Activation by Ligand Binding: Binding of an extracellular ligand (pink circle) induces conformational changes (indicated by a pink star) in the cytoplasmic domain of transmembrane receptors. This allows for receptors to be accumulated at the ciliary tip and by recognized be BBSomes, forming a BBSome-coat which can then undergo ciliary export by retrograde IFT trains. BBSome-cargo complexes undergo processive retrograde IFT trafficking, cross through the transition zone (red Y-linkers) and re-enter the plasma membrane. Ye et al. (2018) suggest that transmembrane cargoes frequently dissociate from the BBSome in the space between the TZ and transition fibers (red triangles) and diffuse (green dashed line) back into the cilium proper (51). Only a fraction of these make it past the transition fibers to the periciliary membrane (smaller green arrow). Cargos can then undergo endocytosis for further processing by the cell.