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

大约20年前，在囊性肾脏疾病的发病机制中出现了初级纤毛的概念。到目前为止，几乎所有被确定为遗传性囊性肾脏疾病的致病基因的基因都编码定位于初级纤毛和/或调节纤毛信号的蛋白质。在肾脏中，初级纤毛从上皮细胞的顶面投射到肾小管腔内，并接收和传递信号。此外，纤毛与细胞周期密切相关。它们是在GO中构建的，在有丝分裂重新进入之前必须被重新吸收。纤毛在肾小管上皮细胞的动态平衡和修复中的作用以及纤毛动力学和信号转导的详细机制尚不清楚。最近，我们发现PHD锌指蛋白和E3泛素连接酶JADE-1是已知的WNT信号调节因子，也是组蛋白-乙酰转移酶复合体的组成部分，定位于初级纤毛，与许多纤毛病变蛋白相互作用，在纤毛信号中发挥重要作用。这个项目的首要目标是破译JADE-1及其两个同源基因JADE-2和JADE-3在纤毛发生、纤毛吸收、细胞周期控制和纤毛信号转导方面的分子和细胞功能。此外，我们的目的是了解Jade蛋白通过翻译后修饰的调节，并研究它们在体内和体外肾小管上皮细胞动态平衡和修复过程中的作用。具体地说，我们将(1)研究Jade蛋白及其翻译后修饰对纤毛动力学、纤毛信号和细胞周期调控的影响；(2)基于Jade-1作为转录调节因子和E3泛素连接酶的双重作用，研究Jade-1的转录和翻译后功能；(3)研究Jade蛋白在体内肾脏生理和病理生理条件下的作用，并检测其可能的肿瘤抑制功能。预计该项目不仅将阐明Jade蛋白家族如何调节肾脏的动态平衡，而且可能揭示新的机制和功能，以支持新的治疗原则和策略的发展。

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.