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Small Mannose-Binding Lectin-Associated Protein Plays a Regulatory Role in the Lectin Complement Pathway¹

Daisuke Iwaki^*, Kazuko Kanno^*, Minoru Takahashi^*, Yuichi Endo^*, Nicholas J. Lynch, Wilhelm J. Schwaeble, Misao Matsushita, Masaru Okabe and Teizo Fujita^2,*

^* Department of Immunology, Fukushima Medical University, Fukushima, Japan; Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, United Kingdom; Genome Information Research Center, Osaka University, Suita, Osaka, Japan; and Institute of Glycotechnology and Department of Applied Biochemistry, Tokai University, Hiratsuka, Japan

Mannose-binding lectin (MBL) and ficolins are pattern recognition proteins acting in innate immunity, and they trigger the activation of the lectin complement pathway through MBL-associated serine proteases (MASPs). Upon activation of the lectin pathway, MASP-2 cleaves C4 and C2. A truncated form of MASP-2, named small MBL-associated protein (sMAP), is also associated with MBL/ficolin-MASP complexes. To clarify the role of sMAP, we have generated sMAP-deficient (sMAP^–/–) mice by targeted disruption of the sMAP-specific exon. Because of the gene disruption, the expression level of MASP-2 was also decreased in sMAP^–/– mice. When recombinant sMAP (rsMAP) and recombinant MASP-2 (rMASP-2) reconstituted the MBL-MASP-sMAP complex in deficient serum, the binding of these recombinant proteins to MBL was competitive, and the C4 cleavage activity of the MBL-MASP-sMAP complex was restored by the addition of rMASP-2, whereas the addition of rsMAP attenuated the activity. Therefore, MASP-2 is essential for the activation of C4 and sMAP plays a regulatory role in the activation of the lectin pathway.

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¹ This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by Core Research for Evolutional, Science, and Technology, Japan Science and Technology Agency.

² Address correspondence and reprint requests to Dr. Teizo Fujita, Department of Immunology, Fukushima Medical University, 1-Hikariga-oka, Fukushima City 960-1295, Japan. E-mail address: tfujita{at}fmu.ac.jp

³ Abbreviations used in this paper: MBL, mannose-binding lectin; MASP, MBL-associated serine protease; sMAP, small MBL-associated protein; CUB, C1r/C1s/Uegf/bone morphogenetic protein; EGF, epidermal growth factor; CCP, complement control protein; SCR, short consensus repeat; ES, embryonic stem; WT, wild type; rsMAP, recombinant mouse sMAP; MASP-2i, inactive mouse MASP-2 mutant.