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• W4249065362 abstract "What is the BBSome? The BBSome (pronounced bee-bee-zome) is a stable protein complex that functions in primary cilium biogenesis. The BBSome was discovered in 2007 by biochemical purification of BBS4-containing complexes from mammalian cells and is composed of seven highly conserved Bardet–Biedl Syndrome (BBS) proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9) as well as a novel protein, BBIP10, each present in stoichiometric amounts (Figure 1). Except for BBS5, which contains two pleckstrin homology domains and binds phosphatidylinositol 3-phosphate, the BBSome subunits do not contain any informative domains. What happens if I do not have a BBSome? A homozygous mutation in any BBSome subunit (except BBIP10) will make you blind, obese and deaf, will obliterate your sense of smell, will make you grow extra digits and toes and cause your kidneys to fail. While this constellation of symptoms made little sense at first sight, work in a variety of organisms has cemented the hypothesis that BBS proteins in general and the BBSome in particular function in some aspect of primary cilium biogenesis. Primary — or non-motile — cilia are microtubule-based projections found on many cell types that act like tiny antennae receiving signaling inputs for the cell. For example, cilia sense photons and odorants by concentrating rhodopsin and olfactory receptors on their surface, and cilia are therefore required for vision and olfaction. Cilia are also required for Hedgehog signaling, which plays an essential role in the patterning of limbs and digits. The first demonstration that the BBSome functions in primary cilium biogenesis was from studies in the worm, where bbs mutants have shorter sensory cilia due to a lack of coordination in intra-flagellar transport (IFT) — the transport of proteins between the tip and base of the ciliary shaft. Remarkably, these bbs mutant worms are obese just like human bbs patients! In zebrafish, loss of BBSome function leads to situs inversus (the inversion of organ laterality) because of defects in the primary cilia that line the Kupffer's vesicle, an embryonic structure that establishes left–right asymmetry during development. That is all very interesting, but what does the BBSome really do? While the short answer is that the biochemical activity of the BBSome is still a mystery, recent studies have converged on a role for the BBSome in the vesicular trafficking of membrane proteins to the primary cilium. In one study, we found that the BBSome binds to Rabin8, the GTP/GDP exchange factor for the small GTPase Rab8. Since Rab8 localizes to the cilium, is required for ciliogenesis and mediates the docking and fusion of rhodopsin carrier vesicles with the connecting cilium of photoreceptors, we have proposed that the BBSome acts upstream of Rab8 in vesicular transport to the cilium. In another study, the Mykytyn group showed that the G-protein-coupled receptors somatostatin receptor type 3 (Sstr3) and melanin-concentrating hormone receptor 1 (Mchr1) failed to reach the primary cilium of hippocampal neurons in bbs knockout mice. The requirement for the BBSome in the transport of signaling receptors to the cilium begs the question of whether the BBSome is directly involved in vesicular trafficking to the cilium. Does the BBSome function in cargo selection, vesicle transport, vesicle docking and fusion at the base of the cilium, or intraflagellar transport? Regardless of its specific function, a general role for the BBSome in trafficking signaling receptors to the primary cilium is in line with the pleiotropic phenotype of BBS. What about the BBS proteins that are not found in the BBSome? Bardet–Biedl syndrome is a very rare disease (1/100,000 live births) that can be caused independently by homozygous mutations in any of 14 known genes (BBS1 to BBS14) and several more BBS genes remain to be identified. Besides the BBSome subunits, there is BBS3/Arl6 (Arf-like GTPase), BBS11/TRIM32 (an E3 ubiquitin ligase) and three proteins similar to type II chaperonins, BBS6, BBS10 and BBS12. More recently, hypomorphic mutations in two additional genes (MKS1 and CEP290) were reported to be associated with BBS (representing BBS13 and BBS14, respectively). Null mutations in these genes cause Meckel–Gruber syndrome (MKS), a related lethal developmental disorder. How conserved is the BBSome? All BBSome subunits are conserved throughout ciliated organisms, from the unicellular green algae Chlamydomonas to man, and are absent in non-ciliated organisms (plants, fungi and amoebae). This pattern of conservation is a signature for proteins that perform fundamental functions in primary cilium assembly — such as the 16 polypeptide complex that mediates IFT. The small GTPase Arl6/BBS3 is also highly conserved within ciliated organisms and absent from plants and fungi, thus highlighting a possible role for Arl6/BBS3 in cilium biogenesis. Meanwhile, other BBS proteins that are not components of the BBSome, such as BBS6, BBS10, BBS11 and BBS12, are found only in chordates. Where is the BBSome localized and how does it get there? The principal localization of the BBSome is in the primary cilium. To date, three BBSome subunits have been localized to the primary cilium in mammalian cells and four BBSome subunits have been shown to undergo IFT in worm sensory cilia. Interestingly, BBS4 is also found in tiny cytoplasmic foci in mammalian cells called centriolar satellites. Because BBS4 interacts with the centriolar satellite component PCM-1 and the BBSome is not required for centriolar satellite function, it is thought that centriolar satellites transport the BBSome within the cytoplasm and deliver it to the base of the cilium where the BBSome interacts with Rabin8 and associates with the ciliary membrane. However, the true function of centriolar satellites has remained elusive and the relationship between the BBSome and PCM-1 is still hypothetical. Does the BBSome function outside of primary cilia? In zebrafish, loss of BBSome function leads to cell-autonomous defects in the retrograde transport of melanosomes. Also, in mouse models of BBS, a small proportion of motile cilia on airway epithelia have puzzling structural abnormalities characterized by the accumulation of vesicles inside the ciliary shaft. However, BBS patients are not known to suffer from respiratory problems and defects in mucus clearance that are characteristic of primary cilliary dyskinesia, a disorder of motile cilia. Anything related to signaling? This is one of the most exciting aspects of primary cilium biology and BBSome function. In the ear of bbs knockout animals, hair cells frequently fail to align with one another, a characteristic of defective planar cell polarity (PCP). Although cilia are now known to be essential for PCP in vertebrates, no one knows the identity of the relevant signals sensed and transduced by cilia. Do cilia sense a morphogen gradient that instructs polarity within the plane of the epithelium? Or are cilia facilitating planar cell polarization established at cell–cell contacts by relaying a permissive signal? On the obesity front, bbs mutant mice are unable to transduce leptin signals in specialized hypothalamic neurons that control feeding behavior. Since the leptin receptor was found to interact with a BBSome subunit, it has been hypothesized that the leptin receptor may get trafficked to cilia by the BBSome. However, to this date, no one has succeeded in visualizing the leptin receptor in cilia of the relevant neuronal cell types. Nonetheless, the discovery that IFT dysfunction also causes unregulated weight gains in mice makes the ciliary hypothesis of leptin signaling extremely appealing. What remains to be explored? Nearly everything! What are the membrane proteins that require the BBSome for their trafficking? Does the BBSome function only in trafficking to cilia or is it also involved in IFT or trafficking out of cilia? What is the molecular activity of the BBSome? Does it have any enzymatic activity? What is the function of the BBS proteins that do not belong to the BBSome? In particular, does BBS3/Arl6 function in vesicular trafficking? How and where is the BBSome assembled? Do the type II chaperonin-like BBS proteins BBS6, BBS10 and BBS12 play a role in the folding or assembly of BBSome subunits?" @default.
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• W4249065362 date "2009-06-01" @default.
• W4249065362 modified "2023-10-17" @default.
• W4249065362 title "The BBSome" @default.
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• W4249065362 doi "https://doi.org/10.1016/j.cub.2009.04.015" @default.
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