Co-Complexes of MASP-1 and MASP-2 Associated with the Soluble Pattern-Recognition Molecules Drive Lectin Pathway Activation in a Manner Inhibitable by MAp44

Abstract

The lectin pathway of complement is an integral component of innate immunity. It is activated upon binding of mannan-binding lectin (MBL) or ficolins (H-, L-, and M-ficolin) to suitable ligand patterns on microorganisms. MBL and ficolins are polydisperse homo-oligomeric molecules, found in complexes with MBL-associated serine proteases (MASP-1, -2, and -3) and MBL-associated proteins (MAp19 and MAp44). This scenario is far more complex than the well-defined activation complex of the classical pathway, C1qC1r2C1s2, and the composition of the activating complexes of the lectin pathway is ill defined. We and other investigators recently demonstrated that both MASP-1 and MASP-2 are crucial to lectin pathway activation. MASP-1 transactivates MASP-2 and, although MASP-1 also cleaves C2, MASP-2 cleaves both C4 and C2, allowing formation of the C3 convertase, C4bC2a. Juxtaposition of MASP-1 and MASP-2 during activation must be required for transactivation. We previously presented a possible scenario, which parallels that of the classical pathway, in which MASP-1 and MASP-2 are found together in the same MBL or ficolin complex. In this study, we demonstrate that, although MASPs do not directly form heterodimers, the addition of MBL or ficolins allows the formation of MASP-1–MASP-2 co-complexes. We find that such co-complexes have a functional role in activating complement and are present in serum at varying levels, impacting on the degree of complement activation. This raises the novel possibility that MAp44 may inhibit complement, not simply by brute force displacement of MASP-2 from MBL or ficolins, but by disruption of co-complexes, hence impairing transactivation. We present support for this contention.

Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes

“…Thus, intercomplex activation appears a prerequisite for physiological activation of the cascade, yet we cannot exclude that intracomplex activation in higher-order oligomers also plays a role. We recently demonstrated that colocalization of MASP-1 and -2 in higher-order oligomeric MBL complexes can drive activation when complexes are bound on a ligand or antibody surface (18). In light of the present observations, we conclude that activation by heterocomplexes is a specific instance of the general principle that we demonstrate here, i.e., juxtaposition-and concentration-dependent activation.…”

“…We recently found that colocalization of MASP-1 and MASP-2 in higher-order oligomeric MBL complexes can drive activation of complement when complexes are bound on a ligand or antibody surface (18). However, in that study we neither demonstrated intracomplex activation directly nor ruled out activation between these complexes.…”

Essential Role for the Lectin Pathway in Collagen Antibody–Induced Arthritis Revealed through Use of Adenovirus Programming Complement Inhibitor MAp44 Expression

“…MAp44 blocks interactions between MBL and ficolins with the MASPs by competitive inhibition or displacement, disrupting the activation complexes and thus impairing LP-mediated complement activation (50). The results from in vitro structural and functional studies have been corroborated by in vivo studies showing that MAp44 attenuates myocardial injury and arterial thrombogenesis in MBL-A/C-dependent models (37).…”

CsMAP34, a teleost MAP with dual role: A promoter of MASP-assisted complement activation and a regulator of immune cell activity

“…Previous reports indicated that MASP2 could autonomously initiate the complement cascade by binding MBL436. However, other reports showed that addition of MBL allowed the formation of MASP1 and MASP2 complex, as well as other combinations of MASPs and MAPs837. Meanwhile, reports also showed that MASP1 activated MASP2, thereby activating the lectin pathway21718.…”