Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7 Implications in the Pathogenesis of Gelatinous Drop-Like Corneal Dystrophy
Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7 Implications in the Pathogenesis of Gelatinous Drop-Like Corneal Dystrophy
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DOI：
10.2353/ajpath.2010.100149
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Kinoshita, Shigeru
中科院分区：
文献类型：
--
作者：
Nakatsukasa, Mina;Kawasaki, Satoshi;Kinoshita, Shigeru
凝胶样滴状营养不良(GDLD)是一种罕见的常染色体隐性角膜营养不良，其特征是角膜上皮下淀粉样蛋白沉积。以往的临床和实验室观察强烈表明GDLD的上皮屏障功能显著降低。尽管肿瘤相关钙信号转导2(TACSTD2)基因被认为是GDLD的致病基因，但该致病基因的功能丧失导致GDLD的病理后果的机制仍不清楚。在本研究中，我们研究了TACSTD2基因与上皮屏障功能的功能关系。通过免疫沉淀和邻近连接实验，我们获得了TACSTD2蛋白直接与claudin 1和7蛋白结合的证据。此外，TACSTD2基因功能的丧失导致紧密连接相关蛋白在病变的角膜和培养的角膜上皮细胞中的表达减少和亚细胞定位的改变，包括Claudin 1、4、7和ZO1和occludin。这些结果表明，TACSTD2基因的功能丧失通过降低GDLD角膜中紧密连接相关蛋白的表达和改变其亚细胞定位来损害上皮屏障功能。(Am J Pathol2010,177：1344-1355；DOI：10.2353/ajpath.2010.100149)
Gelatinous drop-like dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterized by subepithelial amyloid depositions on the cornea. Previous clinical and laboratory observations have strongly suggested that epithelial barrier function is significantly decreased in GDLD. Despite the decade-old identification of the tumor-associated calcium signal transducer 2 (TACSTD2) gene as a causative gene for GDLD, the mechanism by which the loss of function of this causative gene leads to the pathological consequence of this disease remains unknown. In this study, we investigated the functional relationship between the TACSTD2 gene and epithelial barrier function. Through the use of immunoprecipitation and a proximity ligation assay, we obtained evidence that the TACSTD2 protein directly binds to claudin 1 and 7 proteins. In addition, the loss of function of the TACSTD2 gene leads to decreased expression and change in the subcellular localization of tight junction-related proteins, including claudin 1, 4, 7, and ZO1 and occludin, both in diseased cornea and cultured corneal epithelial cells. These results indicate that loss of function of the TACSTD2 gene impairs epithelial barrier function through decreased expresskin and altered subcellular localization of tight junction-related proteins in GDLD corneas. (Am J Pathol 2010, 177:1344-1355; DOI: 10.2353/ajpath.2010.100149)