Revised mechanism of complement lectin-pathway activation revealing the role of serine protease MASP-1 as the exclusive activator of MASP-2

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (26), p.10498-10503
• Main Authors: Héja, Dávid, Kocsis, Andrea, Dobó, József, Szilágyi, Katalin, Szász, Róbert, Závodszky, Péter, Pál, Gábor, Gál, Péter
• Format: Article
• Language: English
• Subjects: Binding sites; Biological Sciences; Blood Coagulation; blood serum; complement; Complement Activation; Complement C3-C5 Convertases - metabolism; Complement system; Enzyme Activation; Enzymes; Humans; immune response; Innate immunity; Lectins; Lectins - metabolism; Mannose-Binding Protein-Associated Serine Proteases - antagonists & inhibitors; Mannose-Binding Protein-Associated Serine Proteases - metabolism; Molecules; Pattern recognition; Physical trauma; Proteases; Proteins; proteolysis; serine proteinases; Signal transduction; Zymogens
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1202588109

The lectin pathway of complement activation is an important component of the innate immune defense. The initiation complexes of the lectin pathway consist of a recognition molecule and associated serine proteases. Until now the autoactivating mannose-binding lectin-associated serine protease (MASP)-2 has been considered the autonomous initiator of the proteolytic cascade. The role of the much more abundant MASP-1 protease was controversial. Using unique, monospecific inhibitors against MASP-1 and MASP-2, we corrected the mechanism of lectin-pathway activation. In normal human serum, MASP-2 activation strictly depends on MASP-1. MASP-1 activates MASP-2 and, moreover, inhibition of MASP-1 prevents autoactivation of MASP-2. Furthermore we demonstrated that MASP-1 produces 60% of C2a responsible for C3 convertase formation.