Polycystin-1 regulates von Hippel Lindau partner Jade-1: A potential role for Jade-1 in autosomal dominant polycystic kidney disease

Jade-1 is a transcriptional co-activator that is stabilized by the von Hippel Lindau (VHL) tumor suppressor. Stabilization of Jade-1 is abrogated by VHL mutations associated with renal disease. VHL renal disease includes premalignant renal cysts which progress to clear-cell renal carcinomas. A second genetic cause of renal cyst formation is autosomal dominant polycystic kidney disease (ADPKD), which results from mutation of the PKD1 or PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2). Consequently, regulation of Jade-1 by the polycystins was examined to elucidate the role of Jade-1 in renal cystogenesis. Jade-1 binds both PC1 and PC2. The interaction between Jade-1 and PC1 requires the PC1 coiled-coil domain and full-length Jade-1. Binding between Jade-1 and PC2 utilizes the Jade-1 PHD fingers. Confocal microscopy suggests that GFP-tagged Jade-1 co-localizes with PC1 at the plasma membrane and with PC2 most likely in the ER. Furthermore, PC1 but not PC2 regulates Jade-1 protein levels. Wild-type PC1 (PC1wt) increases, whereas the cytoplasmic tail of PC1 (cPC1) decreases Jade-1 abundance. This differential regulation suggests a dominant-negative effect of cPC1, with potential physiological relevance. Cleavage of PC1 at the GPS site produces N- and C-terminal fragments (NTF and CTF). PC1-CTF decreases Jade-1 protein in the same manner as cPC1. Disease-associated PC1 mutations prevent Jade-1 regulation, suggesting a correlation with ADPKD. PC1wt increases, while PC1-CTF decreases Jade-1 protein half-life. In concordance, ubiquitination of Jade-1 is decreased with PC1wt but increased with PC1-CTF. This modification is the first example of a regulatory role for PC1 in the ubiquitin-proteasome pathway. PC1wt increases while PC1-CTF decreases Jade-1 transcriptional activity, measured by CAT assay. Jade-1 is therefore a transcriptional effector of PC1. Additionally, Jade-1 may be regulated by the polycystins through a pathway involving PKCgamma. This kinase phosphorylates Jade-1 in vitro and induces expression of higher molecular weight Jade-1 in vivo. Jade-1 protein fate is thus intricately regulated by both PC1 and VHL, in a disease-relevant manner. Consequently, Jade-1 may be a target of cystogenic pathways in ADPKD and VHL disease and may play a global role in renal cystogenesis.