Small mannose-binding lectin-associated protein plays a regulatory role in the lectin complement pathway

Abstract

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 Fujita2* 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
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) 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
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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. The Journal of Immunology, 2006, 177: 8626–8632. T he complement system mediates a chain reaction of proteolysis and assembly of protein complexes, playing a major role in biodefense as a part of both the innate and adaptive immune systems. The mammalian complement system consists of three activation pathways: the classical path- way, alternative pathway, and lectin pathway (1, 2). The lectin pathway provides the primary line of defense against invading pathogens. The pathogen recognition components of this path- way, mannose-binding lectin (MBL)3 and ficolins, bind to ar- rays of carbohydrates on the surfaces of bacteria, virus

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