Essential role of cleavage of Polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure
Essential role of cleavage of Polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure
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DOI：
10.1073/pnas.0708217104
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发表时间：
2007-11
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通讯作者：
Shengqiang Yu;K. Hackmann;Jiangang Gao;Xiaobing He;K. Piontek;M. García-González;L. Menezes;Hangxue Xu;G. Germino;J. Zuo;F. Qian
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作者：
Shengqiang Yu;K. Hackmann;Jiangang Gao;Xiaobing He;K. Piontek;M. García-González;L. Menezes;Hangxue Xu;G. Germino;J. Zuo;F. Qian
多囊蛋白-1 (PC1) 在肾小管形态发生中具有重要功能，其功能的破坏会导致人类常染色体显性多囊肾病的囊肿发生。我们之前已经证明重组人 PC1 在 G 蛋白偶联受体蛋白水解位点区域被顺式自蛋白水解切割。为了研究体内裂解的作用，我们通过基因靶向表达不可裂解的 PC1 的 Pkd1 敲入小鼠 (Pkd1V/V) 来生成。 Pkd1V/V 小鼠表现出亚等位性表型，其特征是出生后成熟阶段的囊肿发生延迟和远端肾单位段参与。我们发现 PC1 在野生型小鼠中普遍存在且不完全切割，因此未切割和切割的 PC1 分子共存。我们的研究确定了裂解对 PC1 功能的关键但有限的作用，并表明两种类型的 PC1 分子在体内具有不同的功能。
Polycystin-1 (PC1) has an essential function in renal tubular morphogenesis and disruption of its function causes cystogenesis in human autosomal dominant polycystic kidney disease. We have previously shown that recombinant human PC1 is cis-autoproteolytically cleaved at the G protein-coupled receptor proteolytic site domain. To investigate the role of cleavage in vivo, we generated by gene targeting a Pkd1 knockin mouse (Pkd1V/V) that expresses noncleavable PC1. The Pkd1V/V mice show a hypomorphic phenotype, characterized by a delayed onset and distal nephron segment involvement of cystogenesis at postnatal maturation stage. We show that PC1 is ubiquitously and incompletely cleaved in wild-type mice, so that uncleaved and cleaved PC1 molecules coexist. Our study establishes a critical but restricted role of cleavage for PC1 function and suggests a differential function of the two types of PC1 molecules in vivo.