The Squamous Cell Carcinoma Antigen 2 Inhibits the Cysteine Proteinase Activity of a Major Mite Allergen, Der p 1

• Published in: The Journal of biological chemistry 2004-02, Vol.279 (7), p.5081-5087
• Main Authors: Sakata, Yasuhisa, Arima, Kazuhiko, Takai, Toshiro, Sakurai, Wataru, Masumoto, Kiyonari, Yuyama, Noriko, Suminami, Yoshinori, Kishi, Fumio, Yamashita, Tetsuji, Kato, Takeshi, Ogawa, Hideoki, Fujimoto, Kazuma, Matsuo, Yo, Sugita, Yuji, Izuhara, Kenji
• Format: Article
• Language: English
• Subjects: Allergens - chemistry; Amino Acid Sequence; Antigens, Dermatophagoides - chemistry; Antigens, Dermatophagoides - metabolism; Antigens, Neoplasm - metabolism; Antigens, Neoplasm - physiology; Arthropod Proteins; Catalysis; Chromatography, Gel; Cysteine - chemistry; Cysteine Endopeptidases - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Dermatophagoides pteronyssinus; DNA, Complementary - metabolism; Dose-Response Relationship, Drug; Humans; Jurkat Cells; Kinetics; Molecular Sequence Data; Peptides - chemistry; Plasmids - metabolism; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Pyroglyphidae - metabolism; Receptors, Interleukin-2 - biosynthesis; Recombinant Proteins - chemistry; Serine - chemistry; Serpins; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Temperature; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M311585200

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.