title: 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, C1qC1r(2)C1s(2), 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.
authors.affiliation: Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. sdegn@microbiology.au.dk
authors.forename: Søren E
authors.initials: SE
authors.lastname: Degn
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Jensen
authors.forename: Tomasz
authors.initials: T
authors.lastname: Olszowski
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
mesh_terms: D002460:Cell Line; D037582:Complement Pathway, Mannose-Binding Lectin / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D037102:Lectins / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000378:metabolism*; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism*; D011485:Protein Binding; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015533:Transcriptional Activation; D000097604:Ficolins
chemical_list: D003165:Complement System Proteins; D037102:Lectins; D037601:Mannose-Binding Lectin; D050606:Mannose-Binding Protein-Associated Serine Proteases; D051192:Receptors, Pattern Recognition; D000097604:Ficolins; C084067:MASP1 protein, human; C105296:MASP2 protein, human