The PHD-finger ubiquitin ligase Jade-1 as modulator of ciliary signaling and cell cycle progression: Studying the role of Jade-family proteins in the pathogenesis of cystic kidney disease and kidney cancer

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Almost 20 years ago the concept of primary cilia in the pathogenesis of cystic kidney diseases emerged. Virtually all genes that have been identified as disease genes in hereditary cystic kidney diseases up to now, encode for proteins that localized to primary cilia and/or modulate ciliary signaling. In the kidney, primary cilia project from the apical surface of epithelial cells into the lumen of renal tubules and receive and transmit signals. In addition, cilia are tightly connected with the cell cycle. They are built in Go and have to be reabsorbed prior to mitotic re-entry. The detailed mechanisms of ciliary dynamic and signaling as well as the function of cilia in the homeostasis and repair of renal tubular epithelium are not well understood. Recently, we could show that the PHD zinc finger protein and E3 ubiquitin ligase Jade-1, a known regulator of WNT signaling and a component of histone-acetyl-transferase-complexes, localizes to primary cilia, interacts with numerous ciliopathy-proteins and plays an important role in ciliary signaling. The overarching goal of this project is to decipher the molecular and cellular functions of Jade-1 and both of its paralogs, Jade-2 and Jade-3, with regard to ciliogenesis, ciliary resorption, cell cycle control and ciliary signaling. Moreover, we aim to understand the regulation of Jade proteins through posttranslational modifications and to investigate their impact during homeostasis and repair of renal tubular epithelium in vivo and in vitro. Specifically, we will (1) study the impact of Jade proteins and their posttranslational modifications regarding ciliary dynamics, ciliary signaling and cell cycle regulation, (2) investigate transcriptional and posttranslational functions of Jade-1 based on its dual role as transcriptional regulator and E3 ubiquitin ligase, and (3) study the role of Jade proteins in the kidney in vivo under physiological and pathophysiological conditions and examine their putative tumor suppressor function. It is expected that this project will not only elucidate how the Jade protein family modulates kidney homeostasis, but may uncover novel mechanisms and functions to support the development of new therapeutic principles and strategies.