Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia

Berbari, Nicolas F.; Lewis, Jacqueline S.; Bishop, Georgia A.; Askwith, Candice C.; Mykytyn, Kirk

doi:10.1073/pnas.0711027105

Cited by 425 publications

(446 citation statements)

References 47 publications

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“…Seven of the known BBS proteins (BBS1-2, BBS4-5, BBS7-9) have been shown to form a stable complex, the BBSome, and this complex is proposed to function in vesicle trafficking to the ciliary membrane through a Rab8-mediated mechanism (31). Consistent with this, several G-protein-coupled receptors failed to localize to neuronal cilia in Bbs2 and Bbs4 null brains (32). In addition, we have recently demonstrated that one component of the BBSome, BBS1, directly interacts with the leptin receptor and that leptin signaling is attenuated in BBS gene knockout mice, implicating BBS function in a broad range of membrane receptor signaling (33).…”

supporting

confidence: 52%

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

Seo

Baye²,

Schulz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

273

282

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Bardet-Biedl syndrome (BBS) is a human genetic disorder resulting in obesity, retinal degeneration, polydactyly, and nephropathy. Recent studies indicate that trafficking defects to the ciliary membrane are involved in this syndrome. Here, we show that a novel complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins mediates BBSome assembly, which transports vesicles to the cilia. Chaperoninlike BBS proteins interact with a subset of BBSome subunits and promote their association with CCT chaperonins. CCT activity is essential for BBSome assembly, and knockdown of CCT chaperonins in zebrafish results in BBS phenotypes. Many disease-causing mutations found in BBS6, BBS10, and BBS12 disrupt interactions among these BBS proteins. Our data demonstrate that BBS6, BBS10, and BBS12 are necessary for BBSome assembly, and that impaired BBSome assembly contributes to the etiology of BBS phenotypes associated with the loss of function of these three BBS genes.Bardet-Biedl Syndrome | ciliopathy | molecular chaperone | protein trafficking T he primary cilium is a microtubule-based subcellular organelle that projects from the surface of the cell. It plays an essential role in the transduction of extracellular signals (1, 2). In vertebrates, loss of cilia or ciliary dysfunction leads to various defects such as situs inversus, polydactyly, neural tube defects, and obesity (2-4). Ciliary dysfunction is also involved in several human genetic syndromes (2, 3). Bardet-Biedl syndrome (BBS) is one of the most studied human genetic disorders associated with ciliary dysfunction. Individuals with BBS display retinal degeneration, obesity, polydactyly, hypertension, hypogonadism, renal anomalies, and cognitive impairment (5-7). BBS displays autosomal recessive inheritance with extensive genetic heterogeneity.BBS proteins are required for the maintenance of ciliary structure and function. Mutation of BBS genes in mice results in absence of flagella in spermatozoa (8-10) and abnormalities in cilia in brain ependymal cells, airway epithelial cells (11,12) and olfactory neurons (13). At the molecular level, BBS proteins are involved in protein/vesicle trafficking along microtubules. For example, knockdown of BBS genes in zebrafish results in delay in retrograde melanosome transport, which is mediated by dynein motor proteins along the microtubule (14, 15). In C. elegans, mutations in bbs1, bbs7, or bbs8 cause defects in the movement of the intraflagellar transport (IFT) subcomplexes inside the cilium (16). During the last decade, twelve BBS genes (BBS1-12) have been identified (17-26). More recently, hypomorphic mutations in two additional genes (MKS1 and CEP290) were reported to be associated with BBS, representing BBS13 and BBS14, respectively (27). Null mutations in MKS1 and CEP290 cause Meckel-Gruber syndrome, a related but more severe disorder (28-30). Seven of the known BBS proteins (BBS1-2, BBS4-5, BBS7-9) have been shown to form a stable complex, the BBSome, and this complex is pr...

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supporting

confidence: 52%

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

Seo

Baye²,

Schulz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

273

282

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“…BBS proteins are required for proper ciliary localization in neurons of the Mchr1 receptor, involved in regulation of feeding behavior (12). Hypothalamic ciliated neurons may be involved in the leptin resistance recently described in BBS patients and obese BBS knockout mouse models (10,45).…”

Section: Discussionmentioning

confidence: 99%

“…Obesity is a cardinal feature of the disease, for which the ciliary pathogenesis remains to be clarified (8). The hypothesis of defects in the ciliated central nervous system neurons (9) that regulate fat storage has been explored and has gained recent support from studies of animal models (10)(11)(12). Moreover, as the adipocyte has been described to be a nonciliated cell (13) and is not referenced in the list of ciliated cells (http://www.bowserlab.org/primarycilia/cilialist.html), a direct implication of this cell in the pathogenesis of BBS-associated obesity has, so far, not been investigated.…”

mentioning

confidence: 99%

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

Marion

Stoetzel

Schlicht

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

163

172

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Bardet-Biedl syndrome (BBS) is an inherited ciliopathy generally associated with severe obesity, but the underlying mechanism remains hypothetical and is generally proposed to be of neuroendocrine origin. In this study, we show that while the proliferating preadipocytes or mature adipocytes are nonciliated in culture, a typical primary cilium is present in differentiating preadipocytes. This transient cilium carries receptors for Wnt and Hedgehog pathways, linking this organelle to previously described regulatory pathways of adipogenesis. We also show that the BBS10 and BBS12 proteins are located within the basal body of this primary cilium and inhibition of their expression impairs ciliogenesis, activates the glycogen synthase kinase 3 pathway, and induces peroxisome proliferator-activated receptor nuclear accumulation, hence favoring adipogenesis. Moreover, adipocytes derived from BBSpatients' dermal fibroblasts in culture exhibit higher propensity for fat accumulation when compared to controls. This strongly suggests that a peripheral primary dysfunction of adipogenesis participates to the pathogenesis of obesity in BBS.adipogenesis ͉ primary cilium ͉ ciliopathy ͉ obesity

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“…Cilia are microtubule based appendages that extend from the basal bodies of cells and are either motile or immotile [16]. Primary cilia are immotile and are present on almost on all human cell types [17].…”

Section: Bbs Proteins In Ciliary Functionmentioning

confidence: 99%

End Stage Renal Disease, Differential Diagnosis, A Rare Genetic Disorder: Bardet–Biedl Syndrome: Case Report and Review

et al. 2011

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End stage renal disease (ESRD) represents a clinical condition in which there is an irreversible loss of endogenous renal function. Both structural and functional abnormalities of the kidney are associated with increased morbidity, mortality. Bardet-Biedel syndrome (BBS) is one of the rare genetic disorders with prevalence of 1 in 1, 40,000-1 in 1,60,000 worldwide. ESRD in BBS patients is the final stage of the disease, increasing mortality in youth.

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Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia

Cited by 425 publications

References 47 publications

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly

Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation

End Stage Renal Disease, Differential Diagnosis, A Rare Genetic Disorder: Bardet–Biedl Syndrome: Case Report and Review

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