Review Polycystin-1: a master regulator of intersecting cystic pathways 1 1 1,2 Sorin V. Fedeles , Anna-Rachel Gallagher , and Stefan Somlo 1 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA 2 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA Autosomal dominant polycystic kidney disease (ADPKD) belonging to the transient receptor potential (TRP) sensory is the most common potentially lethal monogenic dis- channel family. Together, PC1 and PC2 are thought to 2+ order, with more than 12 million cases worldwide. The function as a Ca -permeable receptor channel complex [4]. two causative genes for ADPKD, PKD1 and PKD2, Cyst formation in ADPKD requires a germline mutation encode protein products polycystin-1 (PC1) and polycys- in either PKD1 or PKD2. Although every cell in the body tin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the Glossary cystic phenotypes in ADPKD, autosomal recessive poly- Autosomal dominant polycystic kidney disease (ADPKD): the most common cystic kidney disease (ARPKD), and isolated autosomal monogenic disorder in which kidneys develop fluid-filled cysts derived from dominant polycystic liver disease (ADPLD). These stu- the tubule epithelial cells. dies showed that the rate for cyst growth was a regu- Autosomal dominant polycystic liver disease (ADPLD): a monogenic condition characterized by the growth of bile duct-derived cystic lesions. lated trait, a process that can be either sped up or slowed Autosomal recessive polycystic kidney disease (ARPKD): a rare pediatric down by alterations in functional PC1. These findings disease characterized by fusiform dilation of the collecting ducts in the kidneys redefine the previous understanding that cyst formation and congenital hepatic fibrosis. Bacterial artificial chromosome (BAC): a DNA construct used in transgenic occurs as an ‘on–off’ process. Here, we review these and mouse technology. BAC transgenic models offer the advantages that they are other related studies with an emphasis on their transla- low copy number and can faithfully reproduce the native splicing and tional implications for polycystic diseases. expression pattern of genes. BACs can be modified by homologous recombination in Escherichia coli and transgenic lines can be readily generated by pronuclear injection. Polycystic kidney disease and related cystic diseases Cilia: apical cellular microtubular projection involved in mechanosensory Autosomal dominant polycystic kidney disease (ADPKD) signaling. In the mammalian kidney, the ‘primary’ cilium (which belongs to the group of immotile ‘9+0’ cilia, i.e., nine peripheral microtubule doublets and no (see Glossary) is part of a spectrum of inherited cystic central pair) is located on the apical surface of epithelial cells and extends into diseases that also includes autosomal dominant polycystic the tubule lumen. liver disease (ADPLD), autosomal recessive polycystic kid- Cystic fibrosis transmembrane receptor (CFTR): a transmembrane protein involved in chloride conductance whose deletion results in cystic fibrosis. ney disease (ARPKD), and an expanding group of reces- Endoplasmic reticulum (ER): a cellular organelle that forms a network of sively inherited syndromic ciliopathies (Table 1). ADPKD membrane sacs called cisternae. It serves many fundamental functions is the most common monogenic disorder that can lead to including protein folding, translocation, and transport. ER-associated degradation (ERAD): a cellular pathway through which mis- kidney failure with an incidence of 1 in 600–800 live births, folded ER proteins are retro-translocated, ubiquitinated, and targeted for and affecting 600 000 people in the USA [1]. In most cases, degradation by the proteasome. ADPKD manifests during adult life and is characterized by Fibrocystin/polyductin (FPC): a large integral membrane protein encoded by PKHD1, the gene responsible for the occurrence of ARPKD. extensive cystic enlargement of both kidneys. The two Immunoglobulin heavy chain binding protein (BiP): an ER Hsp70 chaperone causative genes for ADPKD, PKD1 located on chromosome involved in protein translocation and folding. SEC63 (in addition to ERdj1) 16p13.3 and PKD2 located on chromosome 4q21, were recruits BiP to the translocation site via its DnaJ-like domain and provides the necessary ATPase activity to cycle BiP to the ADP-bound high-affinity peptide isolated by positional cloning and their respective protein interaction state. products, polycystin-1 (PC1) and polycystin-2 (PC2 or Kidney specific promoter Cre (Ksp-Cre): used to specifically inactivate proteins in the thick ascending limb, distal, and collecting duct regions of the nephron. TRPP2) [2,3], have been extensively studied. PC1 and PRKCSH: the gene that encodes the protein kinase C substrate heavy chain PC2 are integral membrane proteins, with PC1 having (which is now known to function as the b-subunit of glucosidase II). It is structural and functional features suggestive of receptor involved in the deglycosylation of N-glycan moieties on nascent polypeptides 2+ as part of the calnexin–calreticulin cycle. function, whereas PC2 is a Ca -permeable cation channel Protein biogenesis: the process through which a protein is translated, translocated into the endoplasmic reticulum, folded, and transported to its physiological cellular location. Corresponding authors: Fedeles, S.V. ([email protected]); SEC63: the gene encoding the ER translocon-associated protein SEC63, Somlo, S. ([email protected]). involved in co-translational protein translocation. Keywords: polycystic kidney disease; polycystic liver disease; polycystin-1 dosage; Unfolded protein response (UPR): the unfolded protein response, which cyst progression; protein biogenesis; chaperone therapy. involves the coordinate transcriptional activation of a set of genes that encode 1471-4914/$ – see front matter ER chaperones and certain cell death signals, occurs as a result of the ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.01.004 accumulation of misfolded proteins in the ER. The UPR is activated by agents 2+ that affect ER homeostasis, such as tunicamycin, thapsigargin, Ca ionophores, and reducing agents. In mammalian cells, UPR activation is mediated by three ER transmembrane proteins that function as proximal sensors, designated IRE1, ATF6, and PERK, of which IRE1 is the most conserved from yeast to humans. Trends in Molecular Medicine, May 2014, Vol. 20, No. 5 251 Review Trends in Molecular Medicine May 2014, Vol. 20, No. 5 a Table 1. Genes and protein products involved in dominant and recessive polycystic diseases Disease (OMIM) Gene Key clinical features Protein products Pathogenetic mechanism of cyst formation ADPKD PKD1 Kidney and bile duct cysts Polycystin-1/ciliary receptor Two-hit model combined MIM 173900 protein involved in with a PC1 dosage- mechanosensation or dependent mechanism chemosensation ADPKD PKD2 Kidney and bile duct cysts Polycystin-2/ciliary and Two-hit model combined MIM 173900 endoplasmic reticulum membrane with a PC1 dosage- protein functioning as a non- dependent mechanism selective cation channel ARPKD PKHD1 Fusiform collecting duct Fibrocystin/polyductin/ciliary, Homozygous inactivation, MIM 263200 dilatations, liver cysts, and plasma membrane protein oriented cell division congenital hepatic fibrosis defects, PC1 dosage- dependent mechanism ADPLD PRKCSH Bile duct cystic dilatations GIIb/ER luminal protein/N-glycan Two-hit model combined MIM 174050 glucose trimming enzyme as part with a PC1 dosage- of the calnexin–calreticulin cycle of dependent mechanism protein folding ADPLD SEC63 Bile duct cystic dilatations SEC63/ER transmembrane protein Two-hit model combined MIM 174050 involved co-translational protein with a PC1-dosage translocation together with SEC61 dependent mechanism a Abbreviations: OMIM, Online Mendelian Inheritance in Man; ADPKD, autosomal dominant polycystic kidney disease; MIM, Mendelian Inheritance in Man; PC1, polycystin- 1; PKD1/2, polycystic kidney disease gene 1/2; PKHD1, polycystic kidney and hepatic disease 1; ARPKD, autosomal recessive polycystic kidney disease; ADPLD, autosomal dominant polycystic liver disease; PRKCSH, protein kinase C substrate heavy chain; GIIb, b subunit of glucosidase II; ER, endoplasmic reticulum. carries this germline mutation, cyst formation is focal, 85% of cases ascertained by clinical presentation. The arising only from a minority of kidney tubules and hepatic PKD1 gene product, PC1, is a very large protein consisting bile ducts. This apparent paradox has been explained by the of 4302 amino acids with a 3074 amino acid extracellular occurrence of somatic second hit mutations in the remaining amino terminus, 197 amino acid cytosolic carboxy termi- normal copy of the affected gene, leading to recessive loss of nus, and 11 transmembrane domains [2,21]. PC1 is prob- function in a subset of tubule epithelial cells that actually ably expressed in most nephron segments, although give rise to cysts in adult tissues [5–10]. Although somatic expression at the tissue level has been difficult to deter- second hit mutations are a generally accepted mechanism mine due to very low protein levels. At the subcellular for human ADPKD, additional factors have been shown to level, PC1 is localized to the primary cilium on the apical influence the extent of cyst formation. Mouse and human surface of epithelial cells (Figure 1) [4,22], in