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S. Kawasaki, M. Nakatsukasa, K. Yamasaki, H. Fukuoka, A. Matsuda, M. Tsujikawa, H. Tanioka, J. Hamuro, S. Kinoshita; Tacstd2 Protein Directly Binds to Claudin Proteins and is Required for the Proper Subcellular Localization of Tight Junction-Related Proteins; Roles of Tacstd2 Protein in the Pathogenesis of Gelatinous Drop-Like Dystrophy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4651.
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Gelatinous drop-like dystrophy (GDLD) is a rare form of corneal dystrophy characterized by subepithelial amyloid depositions in the cornea with an autosomal recessive inheritance mode. From clinical and laboratory observations, it is strongly implied that epithelial barrier function is significantly decreased in this disease. Despite the decade-old identification of the tumor-associated calcium signal transducer 2 (TACSTD2) gene as a causative gene for GDLD, the mechanism is yet unknown by which the loss of function of this causative gene leads to the pathological consequence of GDLD. The purpose of this study was to elucidate the relationship between the TACSTD2 gene and epithelial barrier function.
To investigate the protein-protein association between the TACSTD2 protein and tight junction (TJ)-related proteins, we performed immunoprecipitation (IP) and proximity ligation assay (PLA). Knockdown of the TACSTD2 gene in SV40-immortalized human corneal epithelial cells (HCE-T) was performed to investigate the role of the TACSTD2 protein in the epithelial barrier function and TJ formation. In addition, claudin genes were also knocked down to investigate their roles in the epithelial barrier function.
Through the use of IP and PLA, we obtained evidence that the TACSTD2 protein directly binds to claudin proteins. We also discovered that the ablated or decreased expression of the TACSTD2 gene leads to decreased expression and altered subcellular localization of claudin proteins, both in diseased cornea and HCE-T cells. In addition, decreased expression of the claudin genes resulted in a significant decrease in the epithelial barrier function of HCE-T cells.
From these results, we conclude that loss of function of the TACSTD2 gene significantly diminishes epithelial barrier function through decreased expression and altered subcellular localization of tight junction-related proteins in GDLD corneas.
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