Polycystin-1: a master regulator of intersecting cystic pathways

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD). These studies showed that the rate for cyst growth was a regulated trait, a process that can be either sped up or slowed down by alterations in functional PC1. These findings redefine the previous understanding that cyst formation occurs as an “on-off” process. Here we review these and other related studies with an emphasis on their translational implications for polycystic diseases.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…The findings define essential steps in the biogenesis of mature PC1 protein and extend the hypothesis that PCLD occurs due to reduced effective PC1 function. By extension, the finding that PKHD1 carriers can present with PCLD provides evidence in humans for the hypothesis that the function of the PKHD1 gene product fibrocystin may intersect with polycystin signaling in vivo (7,23,24).…”

“…This hypothesis was validated in vivo by showing that orthologous gene animal models with conditional inactivation of Sec63 and Prkcsh develop both kidney and liver cysts in a PC1 dosage-dependent manner (7). These studies established that the PCLD genes are modifiers of PC1 function, that inadequate effective functional PC1 underlies cyst formation in PCLD, and that PC1 dosage is the rate-limiting determinant of occurrence and severity for both PCLD and ADPKD (7,23).…”

“…We had previously shown that somatic homozygous inactivation of Prkcsh and Sec63 in vivo results in polycystic kidney and liver disease due to defective biogenesis and trafficking of PC1 (7,23,33). This mechanistic understanding indicated that we can validate new candidate genes for PCLD by determining the effects of inactivation of each gene on alterations in its posttranslational maturation of PC1.…”

Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

“…Although PRKCSH and SEC63 are involved in folding and quality control of a large number of integral membrane proteins that transit the ER, cysts result from impaired production of just two of these many-client proteins, PC1 and PC2. Loss of Sec63 or Prkcsh results in the reduction of the effective functional levels of PC1 and PC2, with the dosage of PC1 being a rate-limiting determinant of cysts in ADPLD (14,15).…”

Autosomal dominant polycystic kidney disease: genetics, epidemiology, and treatment

“…[1][2][3] The key feature of the disease, namely, development of multiple fluid-filled cysts within the kidneys, results from focal proliferation of single tubular epithelial cells, as shown in the sequential steps depicted in Figure 1A-C. 4,5 Continued cell proliferation and fluid secretion results in cyst growth throughout the lifetime, causing displacement and loss of the normal renal parenchyma, with increasing impairment of renal function ( Figure 2). Polycystin proteins are expressed in several tissues, including the biliary ducts of the liver, pancreas, endothelial cells, and myocardial smooth muscle cells.…”