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Serine Proteases in the Lectin Pathway of the Complement System

ABSTRACT: The complement system plays a crucial role in host defense against pathogen infections and in the recognition and removal of damaged or altered self-components. Complement system activation can be initiated by three different pathways—classical, alternative, and lectin pathways—resulting in a proteolytic cascade, which culminates in multiple biological processes including opsonization and phagocytosis of intruders, inflammation, cell lysis, and removal of immune complexes and apoptotic cells. Furthermore, it also functions as a link between the innate and adaptive immune responses. The lectin pathway (LP) activation is mediated by serine proteases, termed mannan-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with the pattern recognition molecules (PRMs) that recognize carbohydrates or acetylated compounds on surfaces of pathogens or apoptotic cells. These result in the proteolysis of complement C2 and C4 generating C3 convertase (C4b2a), which carries forward the activation cascade of complements, culminating in the elimination of foreign molecules. This chapter presents an overview of the complement system focusing on the characterization of MASPs and its genes, as well as its functions in the immune response.

SUBMITTER: Chakraborti S

PROVIDER: S-EPMC7120406 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Project description:Serine proteases (SPs) are typically synthesized as precursors, termed proenzymes or zymogens, and the fully active form is produced via limited proteolysis by another protease or by autoactivation. The lectin pathway of the complement system is initiated by mannose-binding lectin (MBL)-associated SPs (MASP)-1, and MASP-2, which are known to be present as proenzymes in blood. The third SP of the lectin pathway, MASP-3, was recently shown to be the major activator, and the exclusive "resting blood" activator of profactor D, producing factor D, the initiator protease of the alternative pathway. Because only activated MASP-3 is capable of carrying out this cleavage, it was presumed that a significant fraction of MASP-3 must be present in the active form in resting blood. Here, we aimed to detect active MASP-3 in the blood by a more direct technique and to quantitate the active to zymogen ratio. First, MASPs were partially purified (enriched) from human plasma samples by affinity chromatography using immobilized MBL in the presence of inhibitors. Using this MASP pool, only the zymogen form of MASP-1 was detected by Western blot, whereas over 70% MASP-3 was in an activated form in the same samples. Furthermore, the active to zymogen ratio of MASP-3 showed little individual variation. It is enigmatic how MASP-3, which is not able to autoactivate, is present mostly as an active enzyme, whereas MASP-1, which has a potent autoactivation capability, is predominantly proenzymic in resting blood. In an attempt to explain this phenomenon, we modeled the basal level fluid-phase activation of lectin pathway proteases and their subsequent inactivation by C1 inhibitor and antithrombin using available and newly determined kinetic constants. The model can explain extensive MASP-3 activation only if we assume efficient intracomplex activation of MASP-3 by zymogen MASP-1. On the other hand, the model is in good agreement with the fact that MASP-1 and -2 are predominantly proenzymic and some of them is present in the form of inactive serpin-protease complexes. As an alternative hypothesis, MASP-3 activation by proprotein convertases is also discussed.

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Serine Proteases in the Lectin Pathway of the Complement System

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