Kurbegovic Almira, Kim Hyunho, Xu Hangxue, Yu Shengqiang, Cruanès Julie, Maser Robin L, Boletta Alessandra, Trudel Marie, Qian Feng
Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Université de Montreal, Faculté de Médecine, Montreal, Quebec, Canada.
Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Mol Cell Biol. 2014 Sep;34(17):3341-53. doi: 10.1128/MCB.00687-14. Epub 2014 Jun 23.
Polycystin-1 (Pc1) cleavage at the G protein-coupled receptor (GPCR) proteolytic site (GPS) is required for normal kidney morphology in humans and mice. We found a complex pattern of endogenous Pc1 forms by GPS cleavage. GPS cleavage generates not only the heterodimeric cleaved full-length Pc1 (Pc1(cFL)) in which the N-terminal fragment (NTF) remains noncovalently associated with the C-terminal fragment (CTF) but also a novel (Pc1) form (Pc1(deN)) in which NTF becomes detached from CTF. Uncleaved Pc1 (Pc1(U)) resides primarily in the endoplasmic reticulum (ER), whereas both Pc1(cFL) and Pc1(deN) traffic through the secretory pathway in vivo. GPS cleavage is not a prerequisite, however, for Pc1 trafficking in vivo. Importantly, Pc1(deN) is predominantly found at the plasma membrane of renal epithelial cells. By functional genetic complementation with five Pkd1 mouse models, we discovered that CTF plays a crucial role in Pc1(deN) trafficking. Our studies support GPS cleavage as a critical regulatory mechanism of Pc1 biogenesis and trafficking for proper kidney development and homeostasis.
多囊蛋白-1（Pc1）在G蛋白偶联受体（GPCR）蛋白水解位点（GPS）处的切割对于人类和小鼠正常的肾脏形态是必需的。我们发现了由GPS切割产生的内源性Pc1形式的复杂模式。GPS切割不仅产生异二聚体切割的全长Pc1（Pc1(cFL)），其中N端片段（NTF）与C端片段（CTF）保持非共价结合，还产生一种新的（Pc1）形式（Pc1(deN)），其中NTF与CTF分离。未切割的Pc1（Pc1(U)）主要位于内质网（ER）中，而Pc1(cFL)和Pc1(deN)在体内均通过分泌途径运输。然而，GPS切割并不是Pc1在体内运输的先决条件。重要的是，Pc1(deN)主要存在于肾上皮细胞的质膜上。通过与五种Pkd1小鼠模型进行功能基因互补，我们发现CTF在Pc1(deN)运输中起关键作用。我们的研究支持GPS切割作为Pc1生物发生和运输的关键调节机制，以实现正常的肾脏发育和体内平衡。
