Abstract
Bardet-Biedl syndrome (BBS) is a well-known ciliopathy with mutations reported in 18 different genes. Most of the protein products of the BBS genes localize at or near the primary cilium and the centrosome. Near the centrosome, BBS proteins interact with centriolar satellite proteins, and the BBSome (a complex of seven BBS proteins) is believed to play a role in transporting ciliary membrane proteins. However, the precise mechanism by which BBSome ciliary trafficking activity is regulated is not fully understood. Here, we show that a centriolar satellite protein, AZI1 (also known as CEP131), interacts with the BBSome and regulates BBSome ciliary trafficking activity. Furthermore, we show that AZI1 interacts with the BBSome through BBS4. AZI1 is not involved in BBSome assembly, but accumulation of the BBSome in cilia is enhanced upon AZI1 depletion. Under conditions in which the BBSome does not normally enter cilia, such as in BBS3 or BBS5 depleted cells, knock down of AZI1 with siRNA restores BBSome trafficking to cilia. Finally, we show that azi1 knockdown in zebrafish embryos results in typical BBS phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay. These findings associate AZI1 with the BBS pathway. Our findings provide further insight into the regulation of BBSome ciliary trafficking and identify AZI1 as a novel BBS candidate gene.
Highlights
Primary cilia are organized from centrioles that move to the cell periphery and form basal bodies
Using zebrafish as a model, we show that azi1 morphants are similar to bbs morphants, a finding that further implicates azacytidine-induced protein 1 (AZI1) with the Bardet-Biedl syndrome (BBS) pathway, and makes AZI1 a BBS candidate gene
We show that AZI1 physically binds to the BBSome via BBS4
Summary
Primary cilia are organized from centrioles that move to the cell periphery and form basal bodies. Microtubules extend and protrude from the cell surface to produce a cilium. Primary cilia house several signaling pathway receptors such as Hedgehog, Wnt and PDGFR, and are essential for tissue homeostasis, photoreceptor function, and olfaction [1,2,3]. Defective cilium formation leads to a shared set of phenotypes including retinal degeneration, polydactyly, situs inversus, hydrocephaly, and polycystic kidney disease, which are features of several pleiotropic genetic disorders including Alstrom syndrome (ALMS), Nephronophthisis (NPHP), Joubert Syndrome, and Bardet-Biedl syndrome (BBS) [4,5,6]. Many ciliary proteins form complexes and functional networks. Seven BBS proteins and BBIP10 form a stable octameric complex, the BBSome [12,13]
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