The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, Der p 1.
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.
Sakata
Yasuhisa
Y
Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Japan.
Arima
Kazuhiko
K
Takai
Toshiro
T
Sakurai
Wataru
W
Masumoto
Kiyonari
K
Yuyama
Noriko
N
Suminami
Yoshinori
Y
Kishi
Fumio
F
Yamashita
Tetsuji
T
Kato
Takeshi
T
Ogawa
Hideoki
H
Fujimoto
Kazuma
K
Matsuo
Yo
Y
Sugita
Yuji
Y
Izuhara
Kenji
K
D000485:Allergens / Q000737:chemistry; D000595:Amino Acid Sequence; D039741:Antigens, Dermatophagoides / Q000737:chemistry / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism / Q000502:physiology*; D060829:Arthropod Proteins; D002384:Catalysis; D002850:Chromatography, Gel; D003545:Cysteine / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D039981:Pyroglyphidae / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D015843:Serpins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013696:Temperature; D013997:Time Factors
D000485:Allergens; D039741:Antigens, Dermatophagoides; D000951:Antigens, Neoplasm; D060829:Arthropod Proteins; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D010455:Peptides; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; D012694:Serine; D003546:Cysteine Endopeptidases; C451162:Dermatophagoides pteronyssinus antigen p 1; D003545:Cysteine