The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, der p 1
The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, der p 1
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DOI：
10.1074/jbc.m311585200
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发表时间：
2004-02-13
影响因子：
4.8
通讯作者：
Izuhara, K
中科院分区：
文献类型：
--
作者：
Sakata, Y;Arima, K;Izuhara, K
鳞状细胞癌抗原1（SCCA 1）和SCCA 2属于卵清蛋白-丝氨酸蛋白酶抑制剂家族。虽然SCCA 1和SCCA 2是密切同源的，但这两种分子具有不同的性质; SCCA 1抑制半胱氨酸蛋白酶，如组织蛋白酶K、L和S，而SCCA 2抑制丝氨酸蛋白酶，如组织蛋白酶G和人肥大细胞糜酶。尽管已经发现了SCCA 1和SCCA 2的几种内在靶蛋白酶，但SCCA 1和SCCA 2的生物学作用仍然未知。螨变应原Der p 1是最具免疫优势的变应原之一，也是一种半胱氨酸蛋白酶，可能参与过敏性疾病的发病机制。我们最近发现，SCCA 1和SCCA 2诱导的两个相关的Th 2型细胞因子，IL-4和IL-13，在支气管上皮细胞和SCCA的表达增强支气管哮喘患者。在这项研究中，我们探讨了SCCA蛋白靶向Der p 1的可能性，结果发现SCCA 2而不是SCCA 1抑制Der p 1的催化活性。进一步分析了SCCA 2对Der p 1的抑制机制。SCCA 2有助于自杀底物样机制，而不形成共价复合物，导致不可逆的损害的催化活性的Der p 1，SCCA 1对木瓜蛋白酶。此外，对Der p 1切割的抗性也有助于SCCA 2的抑制机制。这些结果表明，SCCA 2作为一个跨类丝氨酸蛋白酶抑制剂靶向外源性半胱氨酸蛋白酶来自屋尘螨，它可能有保护作用，对螨引起的生物反应。
The squamous cell carcinoma antigens 1 (SCCA1) and SCCA2 belong to the ovalbumin-serpin family. Although SCCA1 and SCCA2 are closely homologous, these two molecules have distinct properties; SCCA1 inhibits cysteine proteinases such as cathepsin K, L, and S, whereas SCCA2 inhibits serine proteinases such as cathepsin G and human mast cell chymase. Although several intrinsic target proteinases for SCCA1 and SCCA2 have been found, the biological roles of SCCA1 and SCCA2 remain unknown. A mite allergen, Der p 1, is one of the most immunodominant allergens and also acts as a cysteine proteinase probably involved in the pathogenesis of allergic diseases. We have recently shown that both SCCA1 and SCCA2 are induced by two related Th2-type cytokines, IL-4 and IL-13, in bronchial epithelial cells and that SCCA expression is augmented in bronchial asthma patients. In this study, we explored the possibility that SCCA proteins target Der p 1, and it turned out that SCCA2, but not SCCA1, inhibited the catalytic activities of Der p 1. We furthermore analyzed the inhibitory mechanism of SCCA2 on Der p 1. SCCA2 contributed the suicide substrate-like mechanism without formation of a covalent complex, causing irreversible impairment of the catalytic activity of Der p 1, as SCCA1 does on papain. In addition, resistance to cleavage by Der p 1 also contributed to the inhibitory mechanism of SCCA2. These results suggest that SCCA2 acts as a cross-class serpin targeting an extrinsic cysteine proteinase derived from house dust mites and that it may have a protective role against biological reactions caused by mites.