A serpin regulates dorsal-ventral axis formation in the Drosophila embryo

Extracellular serine protease cascades have evolved in vertebrates and invertebrates to mediate rapid, local reactions to physiological or pathological cues [1]. The serine protease cascade that triggers the Toll signaling pathway in Drosophila embryogenesis shares several organizational characteristics with those involved in mammalian complement and blood clotting [2]. One of the hallmarks of such cascades is their regulation by serine protease inhibitors (serpins) [3]. Serpins act as suicide substrates and are cleaved by their target protease, forming an essentially irreversible 1:1 complex [4]. The biological importance of serpins is highlighted by serpin dysfunction diseases, such as thrombosis caused by a deficiency in antithrombin [5]. Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation. Female flies deficient in Serpin-27A produce embryos that lack dorsal-ventral polarity and show uniform high levels of Toll signaling. Since this serpin has been recently shown to restrain an immune reaction in the blood of Drosophila [6, 7], it demonstrates that proteolysis can be regulated by the same serpin in different biological contexts.