The Conserved Bardet-Biedl Syndrome Proteins Assemble a Coat that Traffics Membrane Proteins to Cilia

Abstract

Summary The BBSome is a complex of Bardet-Biedl Syndrome (BBS) proteins that shares common structural elements with COPI, COPII and clathrin coats. Here we show that the BBSome constitutes a coat complex that sorts membrane proteins to primary cilia. Biochemically, the BBSome is the major effector of the Arf-like GTPase Arl6/ BBS3. In vivo, the BBSome and Arl6 localize to ciliary punctae and Arl6GTP is required to target the BBSome to cilia. Congruently, GTP-bound Arl6 and acidic phospholipids are sufficient to efficiently recruit the BBSome to chemically defined liposomes. Finally, ultrastructural analyses demonstrate that BBSome binding to liposomes produces distinct patches of polymerized coat. Since we establish that the ciliary targeting signal of somatostatin receptor 3 needs to be directly recognized by the BBSome to mediate targeting to cilia, we propose that trafficking to cilia entails the coupling of BBSome coat polymerization to the recognition of sorting signals.

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

“…3E). This result demonstrates that BBS1 is the BBSome subunit that likely directly interacts with BBS3, consistent with results using in vitro purified proteins (28).…”

“…Indeed, phenotypic characterization of Bbs3 −/− mice revealed that they developed retinal degeneration and are male-infertile because of the absence of sperm flagella. Consistent with these phenotypic similarities, our biochemical analysis demonstrates that BBS3 interacts with the BBSome and is required for the ciliary localization of the BBSome, confirming in vitro data published recently (28). Furthermore, we showed that mutations found in BBS3 patients disrupt BBS3-BBSome interaction, but mutations found in nonsyndromic retinitis pigmentosa only partially decrease the interaction, highlighting the importance of BBS-BBSome interactions.…”

“…S4). showed that BBS3 physically interacts with the BBSome when they used BBS3 with the N-terminal 16 amino acids deleted (28). However, pair-wise interactions of BBS3 with individual BBSome subunits by cotransfection into human 293T cells fail to detect any direct interaction between BBS3 and individual BBSome subunits.…”

“…Studies from Caenorhabditis elegans showed that BBS3 undergoes intraflagellar transport (IFT) (6,27). Jin et al showed that the BBSome directly interacts with the ciliary localization signal of SST3R and serve as coat proteins for ciliary membrane proteins (28). BBS3 is required for the ciliary localization of the BBSome.…”

C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals

“…Interestingly, the functions of various centriolar satellite proteins diverge. Pcm1 and the BBSome promote ciliary membrane biogenesis and the trafficking of ciliary membrane proteins (18,21). Ofd1, on the other hand, appears to regulate ciliogenesis by recruiting components of the distal appendages and IFT particles, although a recent study appeared to suggest an additional negative role of Ofd1 in ciliogenesis (22,23).…”