In the late 1980s, a new activation pathway of the complement system, the lectin pathway, was discovered. The complement system is a proteolytic cascade system which forms an effector arm of innate immunity (Ricklin et al. 2010). The complement system is capable of labeling and eliminating invading pathogens (e.g., bacteria, fungi) and dangerously altered host cells (e.g., cancer cells, apoptotic cells). In this way, the complement system contributes to the protection against infection and to the maintenance of the homeostasis of the body. There are three ways through which the complement cascade can be activated. The classical and the alternative pathways of complement activation had been known for decades, when (in 1987) Ikeda showed that a blood-borne lectin (mannose binding lectin = MBL) is capable of initiating the complement activation (Ikeda et al. 1987). First it was assumed that a complex consisting of MBL and the proteases of the classical pathway (C1r and C1s) is responsible for the cleavage of C4 and C2, the components of the classical pathway C3 convertase (C4bC2a). Later, it was discovered that MBL is associated in serum with a novel protease: MBL-associated serine protease (MASP). It became gradually evident that the MASP fraction is not homogeneous, it contains at least two components, and the minor component called MASP-2 is the enzyme which has C1s-like activity through cleaving C4 and C2. The formerly discovered major protease component was then renamed as MASP-1. The physiological role of MASP-1 was a debated issue for a long time. Unlike MASP-2, MASP-1 cannot cleave C4; consequently, it cannot initiate the complement cascade alone. Later, a third protease component of the MBL-MASPs complexes (MASP-3) has also been discovered. Besides the protease components, there are two noncatalytic proteins associated with MBL and with the other pattern recognition molecules: MAp19 (aka MAP-2, sMAP) and MAp44 (aka MAP-1).
Gene Structure and Domain Organization
The Role of MASP-1 in the Activation of the Complement System
It was also demonstrated that MASP-1 is capable of activating zymogen MASP-3 (Megyeri et al. 2013). Recently, it was shown that MASP-3 is responsible for activation of profactor D in resting blood (Dobó et al. 2016). In this way, a crucial link was revealed between the lectin and alternative pathway activation (Fig. 3). Although there is no direct proof that MASP-1 is the physiological activator of MASP-3, we cannot exclude this possibility.
One of the most debated functions of MASP-1 is its ability to cleave C3. Early after its discovery, it was shown that MASP-1 can directly cleave C3 (Matsushita and Fujita 1995). It was suggested that this activity of MASP-1 bypasses the formation of the C3 convertase complexes and might have physiological relevance. However, measuring the catalytic efficiency (kcat/KM value) of the C3 cleavage revealed that MASP-1 is much less efficient in cleaving C3 than a bona fide C3 convertase (C3bBb) (Ambrus et al. 2003). There is three orders of magnitude difference between the corresponding kcat/KM values. Surprisingly, MASP-1 showed 30-fold higher activity on C3(NH3), a molecule which resembles hydrolyzed C3, than on intact C3. We do not know the physiological relevance of these reactions, but we cannot exclude that the weak C3 cleaving ability of MASP-1 is enough for triggering the alternative pathway activation in certain pathophysiological situations.
The Role of MASP-1 in Blood Coagulation
Proinflammatory Effects of MASP-1 Activation
Bradykinin is a potent inflammatory mediator peptide which is liberated from kininogens by the action of proteases. In the blood, high-molecular-weight kininogen is digested by plasma kallikrein during contact system activation resulting in the production of bradykinin. It was shown that MASP-1 also can cleave high-molecular-weight kininogen and liberate bradykinin (Fig. 5) (Dobó et al. 2011). The efficiency of this reaction is lower than the efficiency of the plasma kallikrein-mediated cleavage. However, on the site of infection where the local concentration of complement proteins is high, the MASP-1-mediated bradykinin release can boost the proinflammatory activity of the complement system.
Regulation of MASP-1 Activity
The activity of the early complement proteases in the blood is mainly regulated by serpins (serine protease inhibitors). C1-inhibitor is a serpin which regulates the complement, the coagulation and the kallikrein-kinin systems. It inhibits all the members of the C1r/C1s/MASPs family except MASP-3. The presence of heparin, a naturally occurring glycosaminoglycan, facilitates the interaction between serpins and proteases. It was demonstrated that antithrombin, a serpin which inhibits thrombin, is a very efficient inhibitor of MASP-1 in the presence of heparin (Paréj et al. 2013). It seems that both C1-inhibitor and antithrombin are equally important physiological inhibitors of MASP-1. Another potential inhibitor which regulates plasma proteases is α2-macroglobulin. The role of α2-macroglobulin in the regulation of the lectin pathway is controversial. It was shown that MASP-1 cleaves the bait region of α2-macroglobulin in vitro and a complex is formed between the protease and the inhibitor in fluid phase. However, α2-macroglobulin was unable to prevent complement activation on activating surfaces using normal human serum.
MASP-1 is an abundant protease of the lectin pathway of complement system in the blood. The main function of MASP-1 is the initiation of the lectin pathway activation. MASP-1 is the exclusive activator of MASP-2 in normal human serum and it also contributes to C3 convertase formation by C2 cleavage. MASP-1 has a high autoactivating potential, it can cleave MASP-3 and, to a much lesser extent, C3. MASP-1 is an atypical, promiscuous complement protease, since it has many substrates outside the complement system. MASP-1 can induce coagulation by activating prothrombin and cleaving fibrinogen, Factor XIII, and TAFI. MASP-1 can directly activate endothelial cells through cleaving protease-activated receptors on the surface of the cells. The activated endothelial cells produce cytokines and adhesion molecules which facilitate recruitment and activation of neutrophils, the major cellular elements of innate antimicrobial immunity. MASP-1 also can cleave high-molecular-weight kininogen and liberate bradykinin, a highly inflammatory vasoactive peptide. Taken together, MASP-1 is a versatile protease which initiates the activation of the lectin pathway of the complement system and its activity on noncomplement substrates contributes to mount an even more powerful immune response.
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