Factor D.

Complement factor D (FD) is a serine protease that plays an essential role in the activation of the alternative pathway (AP) by cleaving complement factor B (FB) and generating the C3 convertases C3(H O)Bb and C3bBb. FD is produced mainly from adipose tissue and circulates in an activated form. On the contrary, the other serine proteases of the complement system are mainly synthesized in the liver. The activation mechanism of FD has long been unknown. Recently, a serendipitous discovery in the mechanism of FD activation has been provided by a generation of Masp1 gene knockout mice lacking both the serine protease MASP-1 and its alternative splicing variant MASP-3, designated MASP-1/3-deficient mice. Sera from the MASP-1/3-deficient mice had little-to-no lectin pathway (LP) and AP activity with circulating zymogen or proenzyme FD (pro-FD). Sera from patients with 3MC syndrome carrying mutations in the MASP1 gene also had circulating pro-FD, suggesting that MASP-1 and/or MASP-3 are involved in activation of FD. Here, we summarize the current knowledge of the mechanism of FD activation that was finally elucidated using the sera of mice monospecifically deficient for MASP-1 or MASP-3. Sera of the MASP-1-deficient mice lacked LP activity, but those of the MASP-3-deficient mice lacked AP activity with pro-FD. This review illustrates the pivotal role of MASP-3 in the physiological activation of the AP via activation of FD.