Kidney Disease Center, The First Affiliated Hospital-College of Medicine-National Key Clinical Department of Kidney Diseases, Institute of Nephrology, Zhejiang University, Hangzhou, China.
Harvard Center for Polycystic Kidney Disease Research-Renal Division, Department of Medicine, Brigham and Women's Hospital-Harvard Medical School, Boston, Massachusetts, USA.
FASEB J. 2019 Sep;33(9):9945-9958. doi: 10.1096/fj.201900338R. Epub 2019 Jun 3.
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder causing renal failure. Mutations of polycystic kidney disease 1 () account for most ADPKD cases. Defective ciliary localization of polycystin-1 (PC1), a large integral membrane protein encoded by , underlies the pathogenesis of a subgroup of patients with ADPKD. However, the mechanisms by which PC1 and other ciliary proteins traffic to the primary cilium remain poorly understood. A ciliary targeting sequence (CTS) that resides in ciliary receptors is considered to function in the process. It has been reported that the VxP motif in the intracellular C-terminal tail of PC1 functions as a CTS in an ADP ribosylation factor 4 (Arf4)/ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1)-dependent manner. However, other recent studies have revealed that this motif is dispensable for PC1 trafficking to cilia. In this study, we identified a novel CTS consisting of 8 residues (RHKVRFEG) in the PC1 C tail. We found that this motif is sufficient to bind protein phosphatase 1 (PP1)α, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1α and impair ciliary localization of PC1. Additionally, short hairpin RNA-mediated knockdown of PP1α results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1α in the regulation of ciliary structure and function.-Luo, C., Wu, M., Su, X., Yu, F., Brautigan, D. L., Chen, J., Zhou, J. Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.
常染色体显性多囊肾病（ADPKD）是导致肾衰竭的最常见遗传疾病。多囊肾病 1 （PKD1）的突变导致大多数 ADPKD 病例。多囊蛋白-1 （PC1）的纤毛定位缺陷，PC1 是一种由 编码的大型完整膜蛋白，是 ADPKD 亚组患者发病机制的基础。然而，PC1 和其他纤毛蛋白向初级纤毛运输的机制仍知之甚少。纤毛靶向序列（CTS）位于纤毛受体中，被认为在该过程中起作用。据报道，PC1 细胞内 C 末端尾部的 VxP 基序在依赖 ADP 核糖基化因子 4（Arf4）/ArfGAP 与含有 SH3 结构域、锚蛋白重复和 PH 结构域 1（ASAP1）的蛋白 1（PP1）的情况下作为 CTS 发挥作用。然而，其他最近的研究表明，该基序对于 PC1 向纤毛的运输是可有可无的。在这项研究中，我们在 PC1 C 尾部鉴定了一个由 8 个残基（RHKVRFEG）组成的新 CTS。我们发现该基序足以与蛋白磷酸酶 1（PP1）α结合，PP1α 是磷酸蛋白磷酸酶（PPP）家族中普遍表达的磷酸酶。该 CTS 基序的突变破坏了与 PP1α 的结合，并损害了 PC1 的纤毛定位。此外，短发夹 RNA 介导的 PP1α 敲低导致 PC1 的纤毛定位减少和纤毛伸长，表明 PP1α 在调节纤毛结构和功能中起作用。-罗，C.，吴，M.，苏，X.，于，F.，布劳提根，D. L.，陈，J.，周，J. 蛋白磷酸酶 1α 与多囊蛋白-1 的一个新的纤毛靶向序列相互作用并调节多囊蛋白-1 的运输。
