Year: 2015
Type: article
Abstract: The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein-coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1.
DOI: 10.1172/jci78863
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Yale University, National Institutes of Health, College of Veterinary Medicine, Cornell University, Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University, U.S. Public Health Service, Weill Cornell Medical College, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G2904166436, G305547285, Mechanisms of Polycystin and Cilia Function in ADPKD, Mouse Models of Polycystic Kidney Disease, Progenitor Cells in Lung Development and Repair, Regulation of Triglyceride Metabolism by the transcription factor CREB-H, Genetics of Autosomal Dominant Polycystic Liver Disease, Methods in Nephrologic Research, George M. O'Brien Kidney Center at Yale
OpenAlex ID: W1963767630