Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.

常染色体显性遗传性多囊性肾病（ADPKD）是最常见的遗传性肾脏疾病，主要由PKD1或PKD2的种系突变引起，导致终末期肾脏疾病。河马信号通路调节器官的生长和细胞增殖。在本文中，我们通过与河马信号传导因子PDZ结合基序（TAZ）的转录共激活因子，证明了ADPKD中囊肿发生的调控机制。TAZ在Pkd1缺陷小鼠的肾囊壁上皮细胞周围高表达。损失塔兹在Pkd1基因缺陷的小鼠减少了囊肿的形成。在野生型中，TAZ与PKD1相互作用，后者使β-catenin失活。相反，在缺乏PKD1的细胞中，TAZ与AXIN1相互作用，因此增加了β-catenin的活性。TAZ与AXIN1在PKD1缺陷细胞中的相互作用导致TAZ与β-catenin的核积累，从而上调c-MYC表达。我们的发现表明，PKD1-TAZ-Wnt-β-catenin-c-MYC信号轴在囊肿发生中起关键作用，并且可能是针对ADPKD的潜在治疗靶标。