The Role of Mannose-Binding Lectin-Associated Serine Protease-3 in Activation of the Alternative Complement Pathway

Abstract

Mannose-binding lectin (MBL)-associated serine proteases (MASPs) are responsible for activation of the lectin complement pathway. Three types of MASPs (MASP-1, MASP-2, and MASP-3) are complexed with MBL and ficolins in serum. Although MASP-1 and MASP-2 are known to contribute to complement activation, the function of MASP-3 remains unclear. In this study, we investigated the mechanism of MASP-3 activation and its substrate using the recombinant mouse MASP-3 (rMASP-3) and several different types of MASP-deficient mice. A proenzyme rMASP-3 was obtained that was not autoactivated during preparation. The recombinant enzyme was activated by incubation with Staphylococcus aureus in the presence of MBL-A, but not MBL-C. In vivo studies revealed the phagocytic activities of MASP-1/3–deficient mice and all MASPs (MASP-1/2/3)–deficient mice against S. aureus and bacterial clearance in these mice were lower than those in wild-type and MASP-2–deficient mice. Sera from all MASPs-deficient mice showed significantly lower C3 deposition activity on the bacteria compared with that of wild-type serum, and addition of rMASP-3 to the deficient serum restored C3 deposition. The low C3 deposition in sera from all MASPs-deficient mice was probably caused by the low level factor B activation that was ameliorated by the addition of rMASP-3. Furthermore, rMASP-3 directly activated factors B and D in vitro. These results suggested that MASP-3 complexed with MBL is converted to an active form by incubation with bacterial targets, and that activated MASP-3 triggered the initial activation step of the alternative complement pathway.

Lectin pathway of complement activation and relation with clinical complications in critically ill children

“…A critical role of MASP-3 in insulin-like growth factor-binding protein-5 availability during craniofacial, muscle, and neural crest development was suggested based on specific mutations (28)(29)(30). In mice, MASP-1 and MASP-3 play a role in the alternative pathway of complement activation and thus might act as a backup system when the lectin pathway is deficient (31). However, the alternative complement activation pathway functioned normally in a patient deficient in MASP-1 and MASP-3 due to a nonsense mutation in the common part of the MASP1 gene (32).…”

Mannan-Binding Lectin-Associated Serine Protease (MASP)-1 Is Crucial for Lectin Pathway Activation in Human Serum, whereas neither MASP-1 nor MASP-3 Is Required for Alternative Pathway Function

“…Surprisingly, a recent study reported that Masp1 knockout mice (devoid of MASP-1, MASP-3, and MAp44) lack alternative complement pathway activity, and that only pro-fD is found in these animals (6). Both MASP-1 and MASP-3 were suggested to cleave pro-fD to mature fD (6,7). MASP-3 was furthermore suggested to cleave fB directly, circumventing fD altogether (7).…”

“…Both MASP-1 and MASP-3 were suggested to cleave pro-fD to mature fD (6,7). MASP-3 was furthermore suggested to cleave fB directly, circumventing fD altogether (7).…”

Studies of the Pattern Recognition Molecule H-ficolin

“…The deposited components C4b and C3b also function as molecular tags, facilitating phagocytosis. The functions of MASP-3, MAp19, and MAp44 remain unknown, but each of these proteins has been suggested to act as regulators of complement activation, and recently it was suggested that MASP-3 took part in activation of factor B and factor D of the complement system (15).…”