MRC Harwell Institute, Harwell Science Campus, Oxfordshire, OX11 0RD, UK.
School of Medicine, University of Maryland, Baltimore, MD, 21201, USA.
Nat Commun. 2019 Sep 6;10(1):4072. doi: 10.1038/s41467-019-12067-y.
The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. PKD2 mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD) and affect many cellular pathways. Data underlining the importance of ciliary PC2 localisation in preventing PKD are limited because PC2 function is ablated throughout the cell in existing model systems. Here, we dissect the ciliary role of PC2 by analysing mice carrying a non-ciliary localising, yet channel-functional, PC2 mutation. Mutants develop embryonic renal cysts that appear indistinguishable from mice completely lacking PC2. Despite not entering the cilium in mutant cells, mutant PC2 accumulates at the ciliary base, forming a ring pattern consistent with distal appendage localisation. This suggests a two-step model of ciliary entry; PC2 first traffics to the cilium base before TOP domain dependent entry. Our results suggest that PC2 localisation to the cilium is necessary to prevent PKD.
人类 PKD2 基因座编码多囊蛋白-2（PC2），PC2 是一种 TRPP 通道，定位于几个不同的细胞区室，包括纤毛。PKD2 突变导致常染色体显性多囊肾病（ADPKD），并影响许多细胞途径。由于现有模型系统中细胞内的 PC2 功能被完全消除，因此强调纤毛 PC2 定位在预防 PKD 中的重要性的数据有限。在这里，我们通过分析携带非纤毛定位但具有通道功能的 PC2 突变的小鼠来剖析 PC2 的纤毛作用。突变体发育出胚胎性肾囊肿，与完全缺乏 PC2 的小鼠没有区别。尽管突变细胞中的 PC2 不能进入纤毛，但突变的 PC2 积累在纤毛的基部，形成与远端附属物定位一致的环状模式。这表明了纤毛进入的两步模型；PC2 首先在依赖于 TOP 结构域的进入之前向纤毛基部运输。我们的结果表明，PC2 向纤毛的定位对于预防 PKD 是必要的。
Zotero 插件
