The subcellular localization of TRPP2 modulates its function
The subcellular localization of TRPP2 modulates its function
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DOI：
10.1681/asn.2007070730
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发表时间：
2008-07-01
影响因子：
13.6
通讯作者：
Kramer-Zucker, Albrecht G.
中科院分区：
文献类型：
--
作者：
Fu, Xiao;Wang, Yan;Kramer-Zucker, Albrecht G.
TRPP 2，也称为多囊蛋白-2，是一种钙渗透性非选择性阳离子通道，在常染色体显性多囊肾病中突变，但也参与心脏发育、肾小管分化和左-右（L-R）轴决定的调节。为了进一步了解TRPP 2如何发挥组织特异性功能，本研究利用了斑马鱼幼虫中TRPP 2的PACS依赖性运输。PACS蛋白识别TRPP 2羧基末端结构域内的酸性簇，其经历磷酸化并介导TRPP 2向高尔基体和内质网（ER）的回收。人TRPP 2与PACS蛋白的相互作用可以被Ser 812 Ala突变（TRPP 2（S812 A））抑制，从而允许TRPP 2到达其他亚细胞区室，并且被Ser 812 Asp突变（TRPP 2（S812 D））增强，从而将TRPP 2捕获在ER中。发现TRPP 2（S812 A）突变体拯救TRPP 2缺陷斑马鱼幼虫的包囊形成至与野生型TRPP 2相同的程度，而TRPP 2（S812 D）突变体在使TRPP 2缺陷鱼的扭曲体轴正常化方面显著更有效。令人惊讶的是，TRPP 2（S812 D）突变体比野生型或TRPP 2（S812 A）更有效地挽救了L-R不对称的异常，这表明TRPP 2的ER定位在正常L-R不对称的发展中起着重要作用。总之，这些发现支持TRPP 2假设不同的亚细胞定位发挥组织特异性功能的假设。
TRPP2, also known as polycystin-2, is a calcium permeable nonselective cation channel that is mutated in autosomal dominant polycystic kidney disease but has also been implicated in the regulation of cardiac development, renal tubular differentiation, and left-to-right (L-R) axis determination. For obtaining further insight into how TRPP2 exerts tissue-specific functions, this study took advantage of PACS-dependent trafficking of TRPP2 in zebrafish larvae. PACS proteins recognize an acidic cluster within the carboxy-terminal domain of TRPP2 that undergoes phosphorylation and mediate retrieval of TRPP2 to the Golgi and endoplasmic reticulum (ER). The interaction of human TRPP2 with PACS proteins can be inhibited by a Ser812Ala mutation (TRPP2(S812A)), thereby allowing TRPP2 to reach other subcellular compartments, and enhanced by a Ser812Asp mutation (TRPP2(S812D)), thereby trapping TRPP2 in the ER. It was found that the TRPP2(S812A) mutant rescued cyst formation of TRPP2-deficient zebrafish larvae to the same degree as wild-type TRPP2, whereas the TRPP2(S812D) mutant was significantly more effective in normalizing the distorted body axis of TRPP2-deficient fish. Surprisingly, the TRPP2(S812D) mutant rescued the abnormalities of L-R asymmetry more effectively than either wild-type or TRPP2(S812A), suggesting that the ER localization of TRPP2 plays an important role in the development of normal L-R asymmetry. Taken together, these findings support the hypothesis that TRPP2 assumes distinct subcellular localizations to exert tissue-specific functions.