title: Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease.
abstract: 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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Seng Hui
authors.initials: SH
authors.lastname: Low
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Vasanth
authors.forename: Claire H
authors.initials: CH
authors.lastname: Larson
authors.forename: Sambuddho
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Nikunj
authors.initials: N
authors.lastname: Sharma
authors.forename: Michael T
authors.initials: MT
authors.lastname: Kinter
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Kane
authors.forename: Tomoko
authors.initials: T
authors.lastname: Obara
authors.forename: Thomas
authors.initials: T
authors.lastname: Weimbs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002923:Cilia / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004720:Endonucleases; D004789:Enzyme Activation / Q000502:physiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D015847:Interleukin-4 / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008156:Luciferases / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological; D008967:Molecular Biology / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000502:physiology*; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D050396:TRPP Cation Channels; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection / Q000379:methods; D014178:Translocation, Genetic; D015027:Zebrafish
chemical_list: D004720:Endonucleases; D015847:Interleukin-4; D008156:Luciferases; D009687:Nuclear Proteins; D011506:Proteins; D050800:STAT6 Transcription Factor; D050396:TRPP Cation Channels; D015534:Trans-Activators; C095221:SND1 protein, human