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Jang, In-Hwan,Chosa, Naoyuki,Kim, Sung-Hee,Nam, Hyuck-Jin,Lemaitre, Bruno,Ochiai, Masanori,Kambris, Zakaria,Brun, Sylvain,Hashimoto, Carl,Ashida, Masaaki,Brey, Paul T.,Lee, Won-Jae Elsevier 2006 Developmental cell Vol.10 No.1
<P><B>Summary</B></P><P>The Toll receptor was originally identified as an indispensable molecule for <I>Drosophila</I> embryonic development and subsequently as an essential component of innate immunity from insects to humans. Although in <I>Drosophila</I> the Easter protease processes the pro-Spätzle protein to generate the Toll ligand during development, the identification of the protease responsible for pro-Spätzle processing during the immune response has remained elusive for a decade. Here, we report a protease, called Spätzle-processing enzyme (SPE), required for Toll-dependent antimicrobial response. Flies with reduced SPE expression show no noticeable pro-Spätzle processing and become highly susceptible to microbial infection. Furthermore, activated SPE can rescue ventral and lateral development in embryos lacking Easter, showing the functional homology between SPE and Easter. These results imply that a single ligand/receptor-mediated signaling event can be utilized for different biological processes, such as immunity and development, by recruiting similar ligand-processing proteases with distinct activation modes.</P>
Buchon, Nicolas,Poidevin, Mickael,Kwon, Hyun-Mi,Guillou, Auré,lien,Sottas, Valentin,Lee, Bok-Luel,Lemaitre, Bruno National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.30
<P>The Drosophila Toll receptor does not interact directly with microbial determinants, but is instead activated by a cleaved form of the cytokine-like molecule Spätzle. During the immune response, Spätzle is processed by complex cascades of serine proteases, which are activated by secreted pattern-recognition receptors. Here, we demonstrate the essential role of ModSP, a modular serine protease, in the activation of the Toll pathway by gram-positive bacteria and fungi. Our analysis shows that ModSP integrates signals originating from the circulating recognition molecules GNBP3 and PGRP-SA and connects them to the Grass-SPE-Spätzle extracellular pathway upstream of the Toll receptor. It also reveals the conserved role of modular serine proteases in the activation of insect immune reactions.</P>
Peptidoglycan molecular requirements allowing detection by the Drosophila immune deficiency pathway.
Stenbak, Carolyn R,Ryu, Ji-Hwan,Leulier, Franç,ois,Pili-Floury, Sebastien,Parquet, Claudine,Hervé,, Mireille,Chaput, Catherine,Boneca, Ivo G,Lee, Won-Jae,Lemaitre, Bruno,Mengin-Lecreulx, D Williams Wilkins 2004 JOURNAL OF IMMUNOLOGY Vol.173 No.12
<P>Innate immune recognition of microbes is a complex process that can be influenced by both the host and the microbe. Drosophila uses two distinct immune signaling pathways, the Toll and immune deficiency (Imd) pathways, to respond to different classes of microbes. The Toll pathway is predominantly activated by Gram-positive bacteria and fungi, while the Imd pathway is primarily activated by Gram-negative bacteria. Recent work has suggested that this differential activation is achieved through peptidoglycan recognition protein (PGRP)-mediated recognition of specific forms of peptidoglycan (PG). In this study, we have further analyzed the specific PG molecular requirements for Imd activation through the pattern recognition receptor PGRP-LC in both cultured cell line and in flies. We found that two signatures of Gram-negative PG, the presence of diaminopimelic acid in the peptide bridge and a 1,6-anhydro form of N-acetylmuramic acid in the glycan chain, allow discrimination between Gram-negative and Gram-positive bacteria. Our results also point to a role for PG oligomerization in Imd activation, and we demonstrate that elements of both the sugar backbone and the peptide bridge of PG are required for optimum recognition. Altogether, these results indicate multiple requirements for efficient PG-mediated activation of the Imd pathway and demonstrate that PG is a complex immune elicitor.</P>
Roh, Kyung-Baeg,Kim, Chan-Hee,Lee, Hanna,Kwon, Hyun-Mi,Park, Ji-Won,Ryu, Ji-Hwan,Kurokawa, Kenji,Ha, Nam-Chul,Lee, Won-Jae,Lemaitre, Bruno,Sö,derhä,ll, Kenneth,Lee, Bok-Luel American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.29
<P>The insect Toll signaling pathway is activated upon recognition of Gram-positive bacteria and fungi, resulting in the expression of antimicrobial peptides via NF-kappaB-like transcription factor. This activation is mediated by a serine protease cascade leading to the processing of Spätzle, which generates the functional ligand of the Toll receptor. Recently, we identified three serine proteases mediating Toll pathway activation induced by lysine-type peptidoglycan of Gram-positive bacteria. However, the identities of the downstream serine protease components of Gram-negative-binding protein 3 (GNBP3), a receptor for a major cell wall component beta-1,3-glucan of fungi, and their order of activation have not been characterized yet. Here, we identified three serine proteases that are required for Toll activation by beta-1,3-glucan in the larvae of a large beetle, Tenebrio molitor. The first one is a modular serine protease functioning immediately downstream of GNBP3 that proteolytically activates the second one, a Spätzle-processing enzyme-activating enzyme that in turn activates the third serine protease, a Spätzle-processing enzyme. The active form of Spätzle-processing enzyme then cleaves Spätzle into the processed Spätzle as Toll ligand. In addition, we show that injection of beta-1,3-glucan into Tenebrio larvae induces production of two antimicrobial peptides, Tenecin 1 and Tenecin 2, which are also inducible by injection of the active form of Spätzle-processing enzyme-activating enzyme or processed Spätzle. These results demonstrate a three-step proteolytic cascade essential for the Toll pathway activation by fungal beta-1,3-glucan in Tenebrio larvae, which is shared with lysine-type peptidoglycan-induced Toll pathway activation.</P>
The <i>Drosophila</i> Amidase PGRP-LB Modulates the Immune Response to Bacterial Infection
Zaidman-Ré,my, Anna,Hervé,, Mireille,Poidevin, Mickael,Pili-Floury, Sé,bastien,Kim, Min-Sung,Blanot, Didier,Oh, Byung-Ha,Ueda, Ryu,Mengin-Lecreulx, Dominique,Lemaitre, Bruno Elsevier 2006 Immunity Vol.24 No.4
<P><B>Summary</B></P><P>The <I>Drosophila</I> host defense against gram-negative bacteria is mediated by the Imd pathway upon sensing of peptidoglycan by the peptidoglycan recognition protein (PGRP)-LC. Here we report a functional analysis of PGRP-LB, a catalytic member of the PGRP family. We show that PGRP-LB is a secreted protein regulated by the Imd pathway. Biochemical studies demonstrate that PGRP-LB is an amidase that specifically degrades gram-negative bacteria peptidoglycan. In agreement with its amidase activity, PGRP-LB downregulates the Imd pathway. Hence, activation of PGRP-LB by the Imd pathway provides a negative feedback regulation to tightly adjust immune activation to infection. Our study also reveals that PGRP-LB controls the immune reactivity of flies to the presence of ingested bacteria in the gut. Our work highlights the key role of PGRPs that encode both sensors and scavengers of peptidoglycan, which modulate the level of the host immune response to the presence of infectious microorganisms.</P>