Autosomal dominant polycystic kidney disease is a common inherited renal disorder that results from mutations in either PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Downregulation or overexpression of PKD1 or PKD2 in mouse models results in renal cyst formation, suggesting that the quantity of PC1 and PC2 needs to be maintained within a tight functional window to prevent cystogenesis. Here we show that enhanced PC2 expression is a common feature of PKD1 mutant tissues, in part due to an increase in Pkd2 mRNA. However, our data also suggest that more effective protein folding contributes to the augmented levels of PC2. We demonstrate that the unfolded protein response is activated in Pkd1 knockout kidneys and in Pkd1 mutant cells and that this is coupled with increased levels of GRP94, an endoplasmic reticulum protein that is a member of the HSP90 family of chaperones. GRP94 was found to physically interact with PC2 and depletion or chemical inhibition of GRP94 led to a decrease in PC2, suggesting that GRP94 serves as its chaperone. Moreover, GRP94 is acetylated and binds to histone deacetylase 6 (HDAC6), a known deacetylase and activator of HSP90 proteins. Inhibition of HDAC6 decreased PC2 suggesting that HDAC6 and GRP94 work together to regulate PC2 levels. Lastly, we showed that inhibition of GRP94 prevents cAMP-induced cyst formation in vitro. Taken together our data uncovered a novel HDAC6-GRP94-related axis that likely participates in maintaining elevated PC2 levels in Pkd1 mutant cells.

中文翻译：

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多囊蛋白 1 依赖性调节多囊蛋白 2 通过 GRP94，位于内质网的 HSP90 家族成员

常染色体显性遗传多囊肾病是一种常见的遗传性肾脏疾病，由PKD1或PKD2突变引起，分别编码多囊蛋白 1 (PC1) 和多囊蛋白 2 (PC2)。小鼠模型中PKD1或PKD2的下调或过表达导致肾囊肿形成，这表明 PC1 和 PC2 的数量需要保持在一个严格的功能窗口内以防止囊肿形成。在这里，我们表明增强的 PC2 表达是PKD1突变组织的共同特征，部分原因是Pkd2的增加mRNA。然而，我们的数据也表明更有效的蛋白质折叠有助于提高 PC2 的水平。我们证明未折叠蛋白反应在Pkd1敲除肾脏和Pkd1中被激活突变细胞，这与 GRP94 水平的增加有关，GRP94 是一种内质网蛋白，是 HSP90 伴侣蛋白家族的成员。发现 GRP94 与 PC2 发生物理相互作用，并且 GRP94 的消耗或化学抑制导致 PC2 的减少，这表明 GRP94 作为其伴侣。此外，GRP94 被乙酰化并与组蛋白脱乙酰酶 6 (HDAC6) 结合，这是一种已知的脱乙酰酶和 HSP90 蛋白的激活剂。HDAC6 的抑制降低了 PC2，表明 HDAC6 和 GRP94 共同调节 PC2 水平。最后，我们发现抑制 GRP94 可防止体外 cAMP 诱导的囊肿形成。总之，我们的数据揭示了一个新的 HDAC6-GRP94 相关轴，它可能参与维持Pkd1突变细胞中升高的 PC2 水平。