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.

• Authors: Xuefeng Su, Kaitlin Driscoll, Gang Yao, Anas Raed, Maoqing Wu, Philip L Beales, Jing Zhou
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 20 Pg. 5441-51 (Oct 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24939912 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Bbs1 protein, human
• Bbs1 protein, mouse
• Microtubule-Associated Proteins
• TRPP Cation Channels
• polycystic kidney disease 1 protein
• ARL6 protein, human
• ADP-Ribosylation Factors
• Arl6 protein, mouse

Topics

• ADP-Ribosylation Factors (genetics, metabolism)
• Animals
• Cell Line
• Cilia (metabolism)
• Gene Knockout Techniques
• HEK293 Cells
• Humans
• Kidney (metabolism)
• Mice
• Microtubule-Associated Proteins (genetics, metabolism)
• Protein Transport
• TRPP Cation Channels (genetics, metabolism)