The Role of MASP-1/3 in Complement Activation

Abstract

The complement system, which consists of more than 30 plasma and cell surface proteins, is activated by three pathways: the classical, lectin, and alternative pathways, leading to the generation of opsonins and pathogen destruction. In the lectin pathway, mannose-binding lectin (MBL) and ficolins act as pattern recognition molecules for pathogens, resulting in the activation of MBL-associated serine proteases (MASPs: MASP-1, MASP-2, and MASP-3). Among these proteases, MASP-2 is a key enzyme that cleaves C4 and C2 to assemble a C3 convertase (C4b2a). However, the physiological function of MASP-1 and MASP-3 remains unclear. To investigate the roles of MASP-1 and MASP-3, we generated a MASP-1- and MASP-3-deficient (M1/3 KO) mouse model and found that the deficient mice lacked alternative pathway activation because factor D (Df) remained as a proenzyme in the serum. MASP-1 and MASP-3 were able to convert the proenzyme of Df to an active form in vitro. In addition, MASP-1 was able to activate MASP-2 and MASP-3 as C1r activates C1s. Thus, MASP-1 and MASP-3 seem to be involved in activation of both the lectin and alternative pathways.

Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

“…Once activated, MBL or ficolin binds mannose-binding lectin serine peptidases (MASPs), a set of three proteins that cleave C2 and C4 (Sekine et al, 2013). Upon cleavage of C2 and C4, the lectin pathway merges with the classical pathway (Wallis et al, 2010).…”

The Serine Protease Domain of MASP-3: Enzymatic Properties and Crystal Structure in Complex with Ecotin

“…Other physiological molecular partners of MASP-3 in this context remain to be identified. It has also been proposed that murine MASP-1 and/or MASP-3 (since they are encoded by the same MASP1 gene) could be involved in activation of the alternative complement pathway through cleavage of pro-factor D [19], but this remains a controversial issue since a recent study showed that in humans both MASPs are dispensable for activation of the alternative pathway [10]. In addition, activation of MASP-3 by MASP-1 has been recently reported [10], [19], [20].…”

Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future

“…Indeed, due to its cross-talk with the other complement pathways CCP and CAP, components of the CLP might serve as a therapeutic target. The key proteins of the CLP are the mannose-binding lectin-associated serine proteases (MASPs, which are similar to C1r and C1s), which act by cleaving C4 [157]. MASP-2 is the molecule involved in the activation of the CCP, which thus play a major role in the well-established typical CLP [157].…”

“…The key proteins of the CLP are the mannose-binding lectin-associated serine proteases (MASPs, which are similar to C1r and C1s), which act by cleaving C4 [157]. MASP-2 is the molecule involved in the activation of the CCP, which thus play a major role in the well-established typical CLP [157]. In contrast, it has been reported that MASP-3 may be crucial for the proper functioning of the CAP by activating CFD [158], even if this role may be somehow redundant [159].…”