title: Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function.
abstract: The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.
authors.affiliation: Department of Biomedicine, Aarhus University, DK-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: Annette G
authors.initials: AG
authors.lastname: Hansen
authors.forename: Duygu
authors.initials: D
authors.lastname: Duman
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
mesh_terms: D000009:Abdominal Muscles / Q000002:abnormalities / Q000201:enzymology / Q000276:immunology; D000015:Abnormalities, Multiple / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D000818:Animals; D001763:Blepharoptosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D018389:Codon, Nonsense; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology*; D019465:Craniofacial Abnormalities / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D003398:Craniosynostoses / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D003456:Cryptorchidism / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D002658:Developmental Disabilities / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D005124:Eye Abnormalities / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D006330:Heart Defects, Congenital / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D006618:Hip Dislocation, Congenital / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000502:physiology*; D013285:Strabismus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015533:Transcriptional Activation / Q000235:genetics / Q000276:immunology
chemical_list: D018389:Codon, Nonsense; C084067:MASP1 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases