Bardet–Biedl syndrome proteins 1 and 3 regulate the ciliary trafficking of polycystic kidney disease 1 protein

Abstract

Bardet-Biedl syndrome (BBS) and autosomal dominant polycystic kidney disease (ADPKD) are two genetically distinct ciliopathies but share common phenotypes such as renal cysts. Seven BBS proteins form a complex called the BBSome which is localized at the basal body or ciliary axoneme and regulates the ciliary entry or flagellar exit of several signaling molecules. Here, we demonstrate that, unlike the seven-span somatostatin receptor 3 or the leptin receptor that interacts with all subunits of the BBSome, the ADPKD protein polycystin-1 (PC1) interacts with BBS1, BBS4, BBS5 and BBS8, four of the seven components of the BBSome. Only depletion or mutation of BBS1, but not depletion of BBS5 and BBS8, or knockout of BBS4, impairs ciliary trafficking of PC1 in kidney epithelial cells. Depletion of these BBS proteins affects neither the ciliary length nor the plasma membrane targeting of PC1. Expression of a pathogenic BBS3/Arl6 mutant (T31R) that locks Arl6 in the GDP form leads to stunted cilia and inhibition of PC1 on primary cilia. We propose that the 11-span membrane protein PC1 is a BBSome cargo and that the components of the BBSome may possess subunit-specific functions. Moreover, physical interactions between the BBS and ADPKD proteins may underline the overlapping renal phenotypes in these two diseases.

Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease

“…In this context, polycystins and CDCA might not traffic sufficiently to cilia and thus generate a slow forming cystic phenotype. Interestingly PC1 is reported to interact with BBS1, BBS4, BBS5, and BBS8 and ciliary PC1 expression is reduced in BBS1 knockdown cells and BBS3 mutant cells (Su et al 2014). These findings support the possibility that relative PC1 deficiency may underlie a component of the cystic kidney phenotype in Bardet-Biedl syndrome.…”

Bardet–Biedl syndrome: Is it only cilia dysfunction?

“…PC1 and PC2 form a channel that localizes to the ciliary membrane and in the epithelium lining the renal tubules participate in sensing and transducing fluid flow shear stress into Ca 2+ signaling to control cell proliferation and differentiation [108]. Four members of the BBSome (BBS1, BBS4, BBS5 and BBS8) physically interact with PC1 but depletion of only BBS1 and BBS3 result in defective ciliary targeting of PC1, data that further supports the notion that different BBS proteins have specific functions [109]. In line with these observations, depletion of BBS7 does not affect the ciliary localization of PC1 and PC2 but affects that of dopamine D1 receptor [72].…”

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

“…65 Recently we found that PC1 interacts with several Bardet-Biedl syndrome (BBS) proteins that are part of the BBSome protein complex known to function in the transport of a set of proteins to the cilia. 66 Deficiency of BBS1 and BBS3 affects the ciliary trafficking of PC1. Hence, the polycystins are cargos of the BBSome and physical interactions between the polycystins and BBS proteins may underlie the overlapping renal phenotypes in these two diseases.…”