title: MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked.
abstract: MASP-3 was discovered 15 years ago as the third mannan-binding lectin (MBL)-associated serine protease of the complement lectin pathway. Lacking any verified substrate its role remained ambiguous. MASP-3 was shown to compete with a key lectin pathway enzyme MASP-2 for MBL binding, and was therefore considered to be a negative complement regulator. Later, knock-out mice experiments suggested that MASP-1 and/or MASP-3 play important roles in complement pro-factor D (pro-FD) maturation. However, studies on a MASP-1/MASP-3-deficient human patient produced contradicting results. In normal resting blood unperturbed by ongoing coagulation or complement activation, factor D is present predominantly in its active form, suggesting that resting blood contains at least one pro-FD activating proteinase that is not a direct initiator of coagulation or complement activation. We have recently showed that all three MASPs can activate pro-FD in vitro. In resting blood, however, using our previously evolved MASP-1 and MASP-2 inhibitors we proved that neither MASP-1 nor MASP-2 activates pro-FD. Other plasma proteinases, particularly MASP-3, remained candidates for that function. For this study we evolved a specific MASP-3 inhibitor and unambiguously proved that activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Dobó
authors.affiliation: Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Szakács
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Oroszlán
authors.affiliation: Institute for Ophthalmic Research, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany.
authors.forename: Elod
authors.initials: E
authors.lastname: Kortvely
authors.affiliation: Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
authors.forename: Bence
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Boros
authors.affiliation: Department of Hematology, Institute of Internal Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032, Debrecen, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Szász
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Závodszky
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Gál
authors.affiliation: Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Pál
mesh_terms: D000818:Animals; D011416:Complement Factor D / Q000235:genetics / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D037582:Complement Pathway, Mannose-Binding Lectin; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D004792:Enzyme Precursors; C084067:MASP1 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases; D011416:Complement Factor D