Polycystin 1 (PC1) is a transmembrane protein that is the product of the PKD1 gene, which is one of two genes that causes autosomal-dominant polycystic kidney disease (ADPKD). Low et al. report that the cytoplasmic domain of PC1 was cleaved, producing an unstable C-terminal fragment that localized to the nucleus. The abundance of this fragment was increased in renal specimens from ADPKD patients. In cell lines expressing either a labeled PC1 protein or a chimeric molecule, the abundance of the C-terminal fragment was increased if the proteasome was inhibited. Coimmunoprecipitation experiments indicated that the C terminus of PC1 interacted with the transcriptional regulator P100 and also with STAT6 (signal transducer and activator of transcription 6). Furthermore, cells cotransfected with the soluble C-terminal PC1 fragment and a STAT6 reporter showed increased STAT6 reporter gene activity compared with that in cells not expressing the PC1 fragment. In confluent Madin-Darby kidney cells subjected to flow, endogenous STAT6 was redistributed from the nucleus to the primary cilia, which is also where a small fraction of P100 is localized and the site of the PC1 full-length protein. However, MDCK cells cultured in the absence of flow exhibited nuclear-localized STAT6. STAT6 abundance was increased in ADPKD renal tissue. Rapidly fixed mouse kidney tissue that had been perfused showed the ciliary localization of STAT6, whereas tissue samples isolated under normal conditions that lack flow (similar to those used for human kidney samples) showed STAT6 in the nucleus. Finally, injection of the soluble PC1 C-terminal tail into zebrafish embryos caused pronephric cyst formation. The authors propose that under normal conditions of flow, PC1 in the cilia sequesters P100 and STAT6, preventing transcription of STAT6-dependent genes. In the absence of flow, the PC1 C-terminal tail is cleaved, releasing a fragment that interacts with P100 and STAT6, translocates to the nucleus, and regulates gene expression. Details of this model and its relevance for ADPKD remain to be fully elucidated.
S. H. Low, S. Vasanth, C. H. Larson, S. Mukherjee, N. Sharma, M. T. Kinter, M. E. Kane, T. Obara, T. Weimbs, Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Dev. Cell 10, 57-69 (2006). [PubMed]