Abstract
Protein trafficking within cilia is mediated by the intraflagellar transport (IFT) machinery composed of large protein complexes. The BBSome consists of eight BBS proteins encoded by causative genes of Bardet-Biedl syndrome (BBS), and has been implicated in the trafficking of ciliary membrane proteins, including G protein-coupled receptors (GPCRs), by connecting the IFT machinery to cargo GPCRs. Membrane recruitment of the BBSome to promote cargo trafficking has been proposed to be regulated by the Arf-like small GTPase ARL6/BBS3, through its interaction with the BBS1 subunit of the BBSome. We here investigated how the BBSome core subcomplex composed of BBS1, BBS2, BBS7, and BBS9 assembles and interacts with ARL6, and found that the ARL6–BBS1 interaction is reinforced by BBS9. BBS1-knockout (KO) cells showed defects in the ciliary entry of other BBSome subunits and ARL6, and in ciliary retrograde trafficking and the export of the GPCRs, Smoothened and GPR161. The trafficking defect of these GPCRs was rescued by the exogenous expression of wild-type BBS1, but not by its mutant lacking BBS9-binding ability. Our data thus indicate that the intact BBSome is required for retrograde trafficking of GPCRs out of cilia.
Highlights
Cilia are specialized cell surface projections that function as cellular antennae by perceiving extracellular stimuli, such as fluid flow, and by receiving and transducing developmental signals, such as the Hedgehog (Hh) signal [1,2]
Because BP folds are found in subunits of the COPI coat protein complex, which are subunits which participate in cargo recognition [33,34], and because GAE domains are found in clathrin adaptor proteins, the AP1 γ-subunit, and GGA proteins [35], Nachury and colleagues proposed that the BBSome functions like a coat protein complex [19]
The BBSome consists of eight Bardet-Biedl syndrome (BBS) proteins encoded by causative genes of BBS, and has been implicated in the trafficking of ciliary membrane proteins, including G protein-coupled receptors (GPCRs), by connecting the intraflagellar transport (IFT) machinery and cargo GPCRs
Summary
Cilia are specialized cell surface projections that function as cellular antennae by perceiving extracellular stimuli, such as fluid flow, and by receiving and transducing developmental signals, such as the Hedgehog (Hh) signal [1,2]. Defects in ciliary assembly and functions cause a variety of congenital disorders, such as Bardet-Biedl syndrome (BBS), Joubert syndrome, nephronophthisis, and Meckel syndrome, which are collectively referred to as ciliopathies [3,4]. These are pleiotropic disorders characterized by a broad spectrum of symptoms, including polycystic kidney, retinal degeneration, polydactyly, morbid obesity, and mental retardation. The composition of proteins and lipids in cilia are greatly different from those of the cell body, because the transition zone at the base of cilia serve as a permeability/diffusion barrier.
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