Helping polycysin-1 reach the surface

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited nephropathy that often progresses to end-stage renal disease. Mutations in either the gene encoding polycystin-1 (PC1, PKD1) or polycystin-2 (PC2, PKD2) underlie this disease, with PKD1 mutations associated with more severe disease and earlier onset. The extent of PC1 maturation is indicative of disease severity in individuals with PKD1 mutations. PC1 forms a complex with PC2; however, it is not clear if this interaction influences PC1 function. Vladimir Gainullin and colleagues at the Mayo Clinic determined that PC1 interacts with PC2 within the ER and that this interaction is essential for PC1 maturation and surface localization. In mice, complete loss of PC2 prevented PC1 maturation, while mice heterozygous for Pkd2 exhibited a nonequimolar reduction in mature PC1 levels. Interbreeding of Pkd1 and Pkd2 mouse models revealed that reduction of both PC1 and PC2 in the kidney results in severe, rapidly progressive disease. Together, these results indicate that PC2 is required for PC1 function and that mature PC1 levels dictate disease severity of PKD2 as well as PKD1. The accompanying image shows optical sectioning (z-stack (top), XZ plane (bottom)) of a confocal image of ciliated renal cortical tubule epithelial cells cotransfected with mCherry-PC1 (left) and GFP-PC2 (middle). The merged image (right) shows that surface PC1(red) and PC2 (green) colocalize in primary cilia, while PC1 is also present on the plasma membrane. Nuclei stained blue with DAPI.

Published January 9, 2015, by Corinne Williams

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Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner
Vladimir G. Gainullin, … , Cynthia J. Hommerding, Peter C. Harris
Vladimir G. Gainullin, … , Cynthia J. Hommerding, Peter C. Harris
Published February 2, 2015; First published January 9, 2015
Citation Information: J Clin Invest. 2015;125(2):607-620. https://doi.org/10.1172/JCI76972.
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Category: Research Article

Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited nephropathy responsible for 4%–10% of end-stage renal disease cases. Mutations in the genes encoding polycystin-1 (PC1, PKD1) or polycystin-2 (PC2, PKD2) cause ADPKD, and PKD1 mutations are associated with more severe renal disease. PC1 has been shown to form a complex with PC2, and the severity of PKD1-mediated disease is associated with the level of the mature PC1 glycoform. Here, we demonstrated that PC1 and PC2 first interact in the ER before PC1 cleavage at the GPS/GAIN site and determined that PC2 acts as an essential chaperone for PC1 maturation and surface localization. The chaperone function of PC2 was dependent on the presence of the distal coiled-coil domain and was disrupted by pathogenic missense mutations. In Pkd2–/– mice, complete loss of PC2 prevented PC1 maturation. In Pkd2 heterozygotes, the 50% PC2 reduction resulted in a nonequimolar reduction (20%–25%) of the mature PC1 glycoform. Interbreeding between various Pkd1 and Pkd2 models revealed that animals with reduced levels of functional PC1 and PC2 in the kidney exhibited severe, rapidly progressive disease, illustrating the importance of complexing of these proteins for function. Our results indicate that PC2 regulates PC1 maturation; therefore, mature PC1 levels are a determinant of disease severity in PKD2 as well as PKD1.

Authors

Vladimir G. Gainullin, Katharina Hopp, Christopher J. Ward, Cynthia J. Hommerding, Peter C. Harris

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