During DV patterning, a regulatory cascades composed by three dorsal group genes gastrulation-defective, snake and easter, encoding serine proteases, lead to the cleavage of Spatzle (SPZ), that in turn activates the Toll-dorsal signaling pathway ([1]; [2]). Spatzle presumably forms a gradient in the perivitelline fluid. Toll signaling is ultimately responsible for the formation of the embryonic dorsal nuclear gradient. In the nucleus, dorsal controls the expression of zygotic genes in a concentration-dependent manner and this process results in the patterning of the dorsal–ventral embryonic axis. twist is one of the earliest target genes controlled by the highest concentration of dorsal in the mesodermal cells. It is a transcriptional activator that cooperates with dorsal in activating snail in the mesoderm. Dorsal and Twist also cooperate to activate the neurogenic gene, sim (single minded), expressed in the neurectoderm and repressed by Snail in the mesoderm. Natural or experimentally induced infections by fungi or bacteria elicit a specific response in both adult flies and larvae. The proteoglycans of Gram-positive and Gram-negative bacteria are sensed by distinct pattern recognition proteins called PGRPs (peptidoglycan recognition proteins ([3]). Different PRGPs cooperate to activate the Toll pathway. The activation of PGRP-SA by Gram- positive bacteria leads to Spatzle cleavage ([4]). Fungal infection also leads to the cleavage of Spatzle, but the proteolytic cascade in this case involves the circulating serine protease Persephone and its serine protease inhibitor, Necrotic ([5]; [6]; [7]). Circulating PGRP-SA receptor activates the Toll pathway upon detection of Lysine-type PGN which is a major component of the cell wall of many Gram-positive bacterial strains. GNBP1 (Gram-Negative Binding Protein 1) associates with PGRP-SA and this complex activates a downstream proteolytic cascade that leads to the cleavage of Spatzle, which then activates the Toll transmembrane receptor. In addition, four other serine proteases, namely Spirit, Spheroide, and Sphinx1 and 2, were identified in response to both fungi and Gram-positive bacteria infections. Thus, PGRP-SA and GNBP1 define a Gram-positive-specific branch of Toll receptor activation. PGRP-SD also belongs to this branch and is required for the detection of other Gram-positive and negative bacterial strains. In short, the maturation of SPZ activates Toll in both early embryo and immune response and is controlled by different sets of proteases ([8]; [9]). To reproduce biological data during SPZ processing, we define four initial states corresponding the biological process involved. All these initial state lead to the formation of the active form of SPZ.
References
- . 1994. The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo.. Cell. 76(4):677-88.
- . 2003. Binding of the Drosophila cytokine Spätzle to Toll is direct and establishes signaling.. Nature immunology. 4(8):794-800.
- . 2004. Drosophila melanogaster innate immunity: an emerging role for peptidoglycan recognition proteins in bacteria detection.. Cellular and molecular life sciences : CMLS. 61(5):537-46.
- . 2003. Dual activation of the Drosophila toll pathway by two pattern recognition receptors.. Science (New York, N.Y.). 302(5653):2126-30.
- . 2002. A serpin mutant links Toll activation to melanization in the host defence of Drosophila.. The EMBO journal. 21(23):6330-7.
- . 2002. Activation of Drosophila Toll during fungal infection by a blood serine protease.. Science (New York, N.Y.). 297(5578):114-6.
- . 2006. Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic.. Insect biochemistry and molecular biology. 36(1):37-46.
- . 2004. Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria.. Nature immunology. 5(11):1175-80.
- . 2011. The Drosophila Toll signaling pathway.. Journal of immunology (Baltimore, Md. : 1950). 186(2):649-56.