Function of endo-lysosomal proteinases in epithelial cells

上皮细胞具有多种防御机制，通过角化来抵抗刺激、应激和感染。其中牙龈上皮细胞是口腔中的主要细胞，由角化鳞状细胞组成。最近，在上皮细胞中发现了一个新的调节宿主防御的重要基因。这就是所谓的“组织蛋白酶”。组织蛋白酶是位于内体和/或溶酶体中的蛋白酶的家族名称。例如，已知组织蛋白酶C是Papillon-Lefevre综合征的负责基因，其特征在于严重的牙周炎和掌跖角化病。此外，组织蛋白酶L缺陷小鼠由于基底角质形成细胞的过度增殖而表现出表皮增生。另一方面，为了研究溶酶体内天冬氨酸蛋白酶组织蛋白酶E的生理作用，我们产生了组织蛋白酶E缺陷小鼠。他们自发发展为特应性皮炎样皮肤病变，表皮增厚。此外，组织蛋白酶E缺陷型小鼠在不同的遗传背景中表现出上皮细胞上的癌症。这些结果表明，组织蛋白酶E缺陷小鼠不仅在皮肤上皮细胞中显示异常，而且在牙龈上皮细胞中也显示异常的可能性。然而，组织蛋白酶E缺乏的分子机制仍有待确定。在这项研究中，我们分析了组织蛋白酶E的生理和/或病理功能的上皮细胞，包括皮肤和牙龈。我们的最终目标是应用这些组织蛋白酶的诊断和治疗药物的发展。

Epithelial cells are thought to have several defense mechanisms by cornification against stimulation, stress and infection. Among them, gingival epithelial cells are major cells in oral cavity, which consist of keratinizing squamous cells. Recently, a new important gene regulating host defense in epithelial cells has been identified. It is so called "cathepsin". Cathepsin is a family name of protainases localized in endosomes and/or lysosomes. For example, it is known that cathepsin C is the responsible gene for Papillon-Lefevre syndrome, which is characterized by severe periodontitis and palmoplantar keratoderma. Moreover, deficient mice for cathepsin L exhibit epidermal hyperplasia due to a hyper-proliferation of basal keratinocytes. On the other hand, to investigate the physiological role of the endo-lysosomal aspartic proteinase cathepsin E, we have generated cathepsin E-deficient mice. They spontaneously developed atopic dermatitis-like skin lesions with thickened epidermis. Furthermore, cathepsin E-deficient mice showed a cancer on epithelial cells in a different genetic background. These results suggest the possibility that cathepsin E-deficient mice show abnormalities not only in skin epithelial cells, but also in gingival epithelial cells. However, the molecular mechanisms of cathepsin E deficiency remain to be determined. In this study, we analyzed physiological and/or pathological functions of cathepsin E in epithelial cells including the skin and gingiva. Our final goal is application for the development of diagnosis and therapeutic agents targeting at these cathepsins.