title: Essential role of mannose-binding lectin-associated serine protease-1 in activation of the complement factor D.
abstract: The complement system is an essential component of innate immunity, participating in the pathogenesis of inflammatory diseases and in host defense. In the lectin complement pathway, mannose-binding lectin (MBL) and ficolins act as recognition molecules, and MBL-associated serine protease (MASP) is a key enzyme; MASP-2 is responsible for the lectin pathway activation. The function of other serine proteases (MASP-1 and MASP-3) is still obscure. In this study, we generated a MASP-1- and MASP-3-deficient mouse model (Masp1/3-/-) and found that no activation of the alternative pathway was observed in Masp1/3-/- serum. Mass spectrometric analysis revealed that circulating complement factor D (Df) in Masp1/3-/- mice is a zymogen (pro-Df) with the activation peptide QPRGR at its N terminus. These results suggested that Masp1/3-/- mice failed to convert pro-Df to its active form, whereas it was generally accepted that the activation peptide of pro-Df is removed during its secretion and factor D constitutively exists in an active form in the circulation. Furthermore, recombinant MASP-1 converted pro-Df to the active form in vitro, although the activation mechanism of pro-Df by MASP-1 is still unclear. Thus, it is clear that MASP-1 is an essential protease of both the lectin and alternative complement pathways.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan. minolta@fmu.ac.jp
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Ishida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Iwaki
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kanno
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Endo
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Homma
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D011416:Complement Factor D / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003170:Complement Pathway, Alternative / Q000502:physiology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D037102:Lectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000097604:Ficolins
chemical_list: D011416:Complement Factor D; D037102:Lectins; D037601:Mannose-Binding Lectin; D050606:Mannose-Binding Protein-Associated Serine Proteases; D000097604:Ficolins