Identification of a polycystin-1 cleavage product, P100, that regulates store operated Ca entry through interactions with STIM1.
Identification of a polycystin-1 cleavage product, P100, that regulates store operated Ca entry through interactions with STIM1.
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DOI：
10.1371/journal.pone.0012305
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发表时间：
2010-08-23
期刊：
影响因子：
3.7
通讯作者：
Qian F
中科院分区：
文献类型：
--
作者：
Woodward OM;Li Y;Yu S;Greenwell P;Wodarczyk C;Boletta A;Guggino WB;Qian F
常染色体显性多囊肾病（ADPKD）是一种遗传性疾病，导致大肾囊肿和最终肾功能衰竭。PKD1或PKD2/TRPP2基因及其各自的蛋白产物polycytin -1 （PC1）和polycytin -2 （PC2）的突变都会导致ADPKD。众所周知，PC2是一种非选择性阳离子通道，但PC1的功能和PC1裂解产物的功能尚不清楚。在这里，我们鉴定了一个内源性的PC1切割产物P100，一个在野生型和表位标记的PKD1敲入小鼠中都发现的100 kDa片段。在MDCK和CHO细胞中，全长人PC1 （FL PC1）和由此产生的P100和c末端片段（CTF）切割产物的表达显著降低了由thapsigargin诱导的储存耗尽引起的储存操作Ca2+进入（SOCE）。对P100和CTF在SOCE抑制中的作用的探索发现，P100在非洲爪蟾卵母细胞中表达时直接抑制SOCE电流，而CTF则不，P100在含有引起R4227X突变的疾病时也不。有趣的是，我们还发现，在表达PC1的MDCK细胞中，ER Ca2+传感器蛋白STIM1向细胞外周的易位显著改变。此外，P100与STIM1共免疫沉淀，而CTF不。CHO细胞中P100的表达再现了FL PC1对STIM1易位的抑制作用。这些数据描述了一种新的多囊蛋白-1切割产物P100，它通过直接抑制STIM1易位来减少SOCE；具有ADPKD结果的函数。
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder resulting in large kidney cysts and eventual kidney failure. Mutations in either the PKD1 or PKD2/TRPP2 genes and their respective protein products, polycystin-1 (PC1) and polycystin-2 (PC2) result in ADPKD. PC2 is known to function as a non-selective cation channel, but PC1's function and the function of PC1 cleavage products are not well understood. Here we identify an endogenous PC1 cleavage product, P100, a 100 kDa fragment found in both wild type and epitope tagged PKD1 knock-in mice. Expression of full length human PC1 (FL PC1) and the resulting P100 and C-Terminal Fragment (CTF) cleavage products in both MDCK and CHO cells significantly reduces the store operated Ca2+ entry (SOCE) resulting from thapsigargin induced store depletion. Exploration into the roles of P100 and CTF in SOCE inhibition reveal that P100, when expressed in Xenopus laevis oocytes, directly inhibits the SOCE currents but CTF does not, nor does P100 when containing the disease causing R4227X mutation. Interestingly, we also found that in PC1 expressing MDCK cells, translocation of the ER Ca2+ sensor protein STIM1 to the cell periphery was significantly altered. In addition, P100 Co-immunoprecipitates with STIM1 but CTF does not. The expression of P100 in CHO cells recapitulates the STIM1 translocation inhibition seen with FL PC1. These data describe a novel polycystin-1 cleavage product, P100, which functions to reduce SOCE via direct inhibition of STIM1 translocation; a function with consequences for ADPKD.
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影响因子：
64.5
作者：
Park CY;Hoover PJ;Mullins FM;Bachhawat P;Covington ED;Raunser S;Walz T;Garcia KC;Dolmetsch RE;Lewis RS
通讯作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
64.8
作者：
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通讯作者：
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