MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked

Sci Rep. 2016 Aug 18;6:31877. doi: 10.1038/srep31877.


MASP-3 was discovered 15 years ago as the third mannan-binding lectin (MBL)-associated serine protease of the complement lectin pathway. Lacking any verified substrate its role remained ambiguous. MASP-3 was shown to compete with a key lectin pathway enzyme MASP-2 for MBL binding, and was therefore considered to be a negative complement regulator. Later, knock-out mice experiments suggested that MASP-1 and/or MASP-3 play important roles in complement pro-factor D (pro-FD) maturation. However, studies on a MASP-1/MASP-3-deficient human patient produced contradicting results. In normal resting blood unperturbed by ongoing coagulation or complement activation, factor D is present predominantly in its active form, suggesting that resting blood contains at least one pro-FD activating proteinase that is not a direct initiator of coagulation or complement activation. We have recently showed that all three MASPs can activate pro-FD in vitro. In resting blood, however, using our previously evolved MASP-1 and MASP-2 inhibitors we proved that neither MASP-1 nor MASP-2 activates pro-FD. Other plasma proteinases, particularly MASP-3, remained candidates for that function. For this study we evolved a specific MASP-3 inhibitor and unambiguously proved that activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Complement Factor D / genetics
  • Complement Factor D / metabolism*
  • Complement Pathway, Alternative*
  • Complement Pathway, Mannose-Binding Lectin*
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Humans
  • Mannose-Binding Protein-Associated Serine Proteases / genetics
  • Mannose-Binding Protein-Associated Serine Proteases / metabolism*
  • Mice
  • Mice, Knockout


  • Enzyme Precursors
  • MASP1 protein, human
  • Mannose-Binding Protein-Associated Serine Proteases
  • Complement Factor D