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

Abstract

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...

Bardet–Biedl syndrome

“…Bardet-Biedl syndrome E Forsythe and PL Beales BBS1, BBS2, BBS4, BBS5, BBS7, BBS8 and BBS9 form the BBSome complex [45][46][47] and BBS6, BBS10 and BBS12 form the chaperonin complex. 48 The remaining known disease-causing genes have variable predicted functions as outlined in Table 2. No phenotypic difference has been ascertained between patients harbouring disease-causing mutations in genes associated with the BBSome compared with individuals with mutations in genes associated with the chaperonin complex.…”

Accumulation of the Raf-1 Kinase Inhibitory Protein (Rkip) Is Associated with Cep290-mediated Photoreceptor Degeneration in Ciliopathies

“…IFT and other ciliary proteins, such as Bardet-Biedl syndrome proteins, retinitis pigmentosa GTPase regulator, and nephronophthisis-associated proteins facilitate cilia formation and maintenance by cooperating with small GTPases such as Rab8A (3)(4)(5)(6)(7)(8).…”

The role of primary cilia in the development and disease of the retina

“…The BBSome, comprised of BBS1, 2, 4, 5, 7, 9, and TTC8 (BBS8), is thought to function as a coat complex to sort cilium proteins into membrane domains. 137 Another class of BBS proteins, the chaperonin-like proteins MKKS (BBS6), BBS10 and BBS12, are thought to regulate the assembly of the BBSome 138 and LZTFL1 (BBS17) regulates trafficking of the BBSome into the cilium. 139 The activity of the BBSome is regulated by Arf-like GTPase ARL6 (BBS3) 137 which is found throughout the IS, OS and ONL.…”