Fig. 2.

Protease cascades leading to Toll activation. The active form of the Toll ligand Spätzle results from a specific cleavage triggered by any of four serine protease cascades. In these illustrations, horizontal red arrows denote proteolytic conversion of the zymogens to their active forms and a reddish glow denotes the active form of a protease. (left) In early embryogenesis, positional cues laid out during oogenesis establish the dorsoventral axis through the localized activation of Toll on the ventral side of the embryo. The protease cascade that triggers this Toll activation involves Nudel, Gastrulation defective (gd), Snake, and Easter. Nudel, directly or indirectly activates the Gastrulation defective protease, which then activates Snake. With the involvement of the sulfotransferase Pipe, activated Snake cleaves and activates Easter. Activated Easter processes Spätzle, completing generation of a functional ligand for Toll. (middle, right) A similar mechanism operates in innate immunity, where three protease cascades converge at the activation step for the Spätzle processing enzyme (SPE). In the case of fungi and Gram-positive bacteria, the cell wall components β-1,3-glucan and Lys-type peptidoglycan, respectively, are recognized by circulating pathogen recognition receptors and trigger separate, but related protease cascades. The serine protease ModSP integrates signals from these recognition molecules and activates the protease Grass, which activates SPE. Other immune factors, such as the serine proteases Spirit, Sphinx, and Spheroide may function between Grass and SPE. In addition to recognizing PAMPs, the innate immune system is capable of sensing fungi and bacteria via the zymogen Persephone. Virulence factors (proteases) secreted from microbes cleave Persephone, resulting in activation of SPE. At several points in the pathways shown, serpins are known to provide negative regulation of these immune protease cascades. Necrotic inhibits Persephone and Spn1 inhibits upstream of Grass, with ModSP a likely target.