Polycystin-1, STAT6, and P100 Function in a Pathway that Transduces Ciliary Mechanosensation and Is Activated in Polycystic Kidney Disease

• Published in: Developmental cell Vol. 10; no. 1; pp. 57 - 69
• Main Authors: Low, Seng Hui, Vasanth, Shivakumar, Larson, Claire H., Mukherjee, Sambuddho, Sharma, Nikunj, Kinter, Michael T., Kane, Michelle E., Obara, Tomoko, Weimbs, Thomas
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 2006; Cell Press
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Blotting, Northern - methods; Blotting, Western - methods; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cilia - drug effects; Cilia - metabolism; Danio rerio; Dose-Response Relationship, Drug; Embryo, Mammalian; Embryo, Nonmammalian; Enzyme Activation - physiology; Epithelium - drug effects; Epithelium - metabolism; Fluorescent Antibody Technique - methods; Fundamental and applied biological sciences. Psychology; Gene Expression - physiology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; HUMDISEASE; Immunoprecipitation - methods; Interleukin-4 - pharmacology; Kidney - metabolism; Kidney - pathology; Kidney - ultrastructure; Kidneys; Luciferases - metabolism; Malformations of the urinary system; Mechanotransduction, Cellular - physiology; Medical sciences; Models, Biological; Molecular and cellular biology; Molecular Biology - methods; Mutagenesis - physiology; Nephrology. Urinary tract diseases; Nuclear Proteins - metabolism; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Protein Binding; Protein Structure, Tertiary; Proteins - physiology; SIGNALING; STAT6 Transcription Factor - metabolism; Trans-Activators - physiology; Transfection - methods; Translocation, Genetic; TRPP Cation Channels; Zebrafish; HUMDISEASE; SIGNALING; Kidney disease; Urinary system disease; Polycystic kidney; Cyst; Development; Benign neoplasm; Genetic disease
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2005.12.005

Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.