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.
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 expression and altered subcellular localization of tight junction-related proteins in GDLD corneas.
Nakatsukasa
Mina
M
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Kawasaki
Satoshi
S
Yamasaki
Kenta
K
Fukuoka
Hideki
H
Matsuda
Akira
A
Tsujikawa
Motokazu
M
Tanioka
Hidetoshi
H
Nagata-Takaoka
Maho
M
Hamuro
Junji
J
Kinoshita
Shigeru
S
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D062445:Claudin-1; D057167:Claudins; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D042282:Microdissection / Q000379:methods; D016253:Microscopy, Immunoelectron; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000951:Antigens, Neoplasm; C568108:CLDN1 protein, human; C473255:CLDN7 protein, human; D015815:Cell Adhesion Molecules; D062445:Claudin-1; D057167:Claudins; D008565:Membrane Proteins; C499380:TACSTD2 protein, human