Drosophila Immunity: A Large-Scale In Vivo RNAi Screen Identifies Five Serine Proteases Required for Toll Activation

• DOI: 10.1016/j.cub.2006.03.020
• Publication Date: 2006-04-20T12:07:09Z
• Authors: Zakaria Kambris; Sylvain Brun; In-Hwan Jang; Hyuck-Jin Nam; Yves Romeo; Kuniaki Takahashi; Won-Jae Lee; Ryu Ueda; Bruno Lemaitre
• Keywords: MESH: Enterococcus faecalis; MESH: Drosophila; MESH: Drosophila Proteins; MESH: RNA Interference; MESH: Carrier Proteins; DEVBIO; [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity; 03 medical and health sciences; Enterococcus faecalis; Animals; Drosophila Proteins; MESH: Animals; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; MESH: Serine Endopeptidases; Gram-Positive Bacterial Infections; 0303 health sciences; Agricultural and Biological Sciences(all); Biochemistry, Genetics and Molecular Biology(all); Serine Endopeptidases; Toll-Like Receptors; 3. Good health; Micrococcus luteus; SIGNALING; CELLIMMUNO; MESH: Gram-Positive Bacterial Infections; Drosophila; RNA Interference; Carrier Proteins; MESH: Toll-Like Receptors; MESH: Micrococcus luteus

Unlike mammalian Toll-like Receptors, the Drosophila Toll receptor does not interact directly with microbial determinants but is rather activated upon binding a cleaved form of the cytokine-like molecule Spatzle (Spz). During the immune response, Spz is thought to be processed by secreted serine proteases (SPs) present in the hemolymph that are activated by the recognition of gram-positive bacteria or fungi . In the present study, we have used an in vivo RNAi strategy to inactivate 75 distinct Drosophila SP genes. We then screened this collection for SPs regulating the activation of the Toll pathway by gram-positive bacteria. Here, we report the identification of five novel SPs that function in an extracellular pathway linking the recognition proteins GNBP1 and PGRP-SA to Spz. Interestingly, four of these genes are also required for Toll activation by fungi, while one is specifically associated with signaling in response to gram-positive bacterial infections. These results demonstrate the existence of a common cascade of SPs upstream of Spz, integrating signals sent by various secreted recognition molecules via more specialized SPs.