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Sö,derhä,ll, Irene,Wu, Chenglin,Novotny, Marian,Lee, Bok Luel,Sö,derhä,ll, Kenneth American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.10
<P>Melanization is an important immune component of the innate immune system of invertebrates and is vital for defense as well as for wound healing. In most invertebrates melanin synthesis is achieved by the prophenoloxidase-activating system, a proteolytic cascade similar to vertebrate complement. Even though melanin formation is necessary for host defense in crustaceans and insects, the process needs to be tightly regulated because of the hazard to the animal of unwanted production of quinone intermediates and melanization in places where it is not suitable. In the present study we have identified a new melanization inhibition protein (MIP) from the hemolymph of the crayfish, Pacifastacus leniusculus. Crayfish MIP has a similar function as the insect MIP molecule we recently discovered in the beetle Tenebrio molitor but interestingly has a completely different sequence. Crayfish MIP as well as Tenebrio MIP do not affect phenoloxidase activity in itself but instead interfere with the melanization reaction from quinone compounds to melanin. Importantly, crayfish MIP in contrast to Tenebrio MIP contains a fibrinogen-like domain, most similar to the substrate recognition domain of vertebrate l-ficolins. Surprisingly, an Asp-rich region similar to that found in ficolins that is likely to be involved in Ca2+ binding is present in crayfish MIP. However, crayfish MIP did not show any hemagglutinating activity as is common for the vertebrate ficolins. A mutant form of MIP with a deletion lacking four Asp amino acids from the Asp-rich region lost most of its activity, implicating that this part of the protein is involved in regulating the prophenoloxidase activating cascade. Overall, a new negative regulator of melanization was identified in freshwater crayfish that shows interesting parallels with proteins (i.e. ficolins) involved in vertebrate immune response.</P>
A Novel 43-kDa Protein as a Negative Regulatory Component of Phenoloxidase-induced Melanin Synthesis
Zhao, Mingyi,Sö,derhä,ll, Irene,Park, Ji Won,Ma, Young Gerl,Osaki, Tsukusa,Ha, Nam-Chul,Wu, Chun Fu,Sö,derhä,ll, Kenneth,Lee, Bok Luel American Society for Biochemistry and Molecular Bi 2005 The Journal of biological chemistry Vol.280 No.26
Ju, Jin Sung,Cho, Mi Hyang,Brade, Lore,Kim, Jung Hyun,Park, Ji Won,Ha, Nam-Chul,Sö,derhä,ll, Irene,Sö,derhä,ll, Kenneth,Brade, Helmut,Lee, Bok Luel Williams Wilkins 2006 JOURNAL OF IMMUNOLOGY Vol.177 No.3
<P>Determination of structures and functions of pattern recognition proteins are important for understanding pathogen recognition mechanisms in host defense and for elucidating the activation mechanism of innate immune reactions. In this study, a novel 40-kDa protein, named LPS recognition protein (LRP), was purified to homogeneity from the cell-free plasma of larvae of the large beetle, Holotrichia diomphalia. LRP exhibited agglutinating activities on Escherichia coli, but not on Staphylococcus aureus and Candida albicans. This E. coli-agglutinating activity was preferentially inhibited by the rough-type LPS with a complete core oligosaccharide. LRP consists of 317 aa residues and six repeats of an epidermal growth factor-like domain. Recombinant LRP expressed in a baculovirus system also showed E. coli agglutination activity in vitro and was able to neutralize LPS by inhibition of LPS-induced IL-6 production in mouse bone marrow mast cells. Furthermore, E. coli coated with the purified LRP were more rapidly cleared in the Holotrichia larvae than only E. coli, indicating that this protein participates in the clearance of E. coli in vivo. The three amino-terminal epidermal growth factor-like domains of LRP, but not the three carboxyl epidermal growth factor-like domains, are involved in the LPS-binding activity. Taken together, this LRP functions as a pattern recognition protein for LPS and plays a role as an innate immune protein.</P>
Peptidoglycan activation of the proPO-system without a peptidoglycan receptor protein (PGRP)?
Liu, Haipeng,Wu, Chenglin,Matsuda, Yasuyuki,Kawabata, Shun-ichiro,Lee, Bok Luel,Sö,derhä,ll, Kenneth,Sö,derhä,ll, Irene Elsevier 2011 DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY Vol.35 No.1
<P><B>Abstract</B></P><P>Recognition of microbial polysaccharide by pattern recognition receptors triggers the prophenoloxidase (proPO) cascade, resulting in melanin synthesis and its deposition on the surface of invading pathogens. Several masquerade-like proteins and serine proteinase homologues have been shown to be involved in the proPO activation in insects. In this study, a novel serine proteinase homologue, <I>Pl</I>-SPH2, was found and isolated as a 30kDa protein from hemocytes of the freshwater crayfish, <I>Pacifastacus leniusculus</I>, by its binding property to a partially lysozyme digested or TCA-treated insoluble Lysine (Lys)-type peptidoglycan (PGN) and soluble polymeric Lys-type PGN. Two other proteins, the <I>Pl</I>-SPH1 and lipopolysaccharide- and β-1,3-glucan-binding protein (LGBP) were also found in the several different PGN-binding assays. However no PGRP homologue was detected. Neither was any putative PGRP found after searching available crustacean sequence databases. If RNA interference of <I>Pl</I>-SPH2, <I>Pl</I>-SPH1 or LGBP in the crayfish hematopoietic tissue cell culture was performed, it resulted in lower PO activity following activation of the proPO-system by soluble Lys-type PGN. Taken together, we report for the first time that Lys-type PGN is a trigger of proPO-system activation in a crustacean and that two <I>Pl</I>-SPHs are involved in this activation possibly by forming a complex with LGBP and without a PGRP.</P>
A Synthetic Peptidoglycan Fragment as a Competitive Inhibitor of the Melanization Cascade
Park, Ji Won,Je, Byung-Rok,Piao, Shunfu,Inamura, Seiichi,Fujimoto, Yukari,Fukase, Koichi,Kusumoto, Shoichi,Sö,derhä,ll, Kenneth,Ha, Nam-Chul,Lee, Bok Luel American Society for Biochemistry and Molecular Bi 2006 The Journal of biological chemistry Vol.281 No.12
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>
Kim, Chan-Hee,Kim, Su-Jin,Kan, Hongnan,Kwon, Hyun-Mi,Roh, Kyung-Baeg,Jiang, Rui,Yang, Yu,Park, Ji-Won,Lee, Hyeon-Hwa,Ha, Nam-Chul,Kang, Hee Jung,Nonaka, Masaru,Sö,derhä,ll, Kenneth,Lee, Bok Lu American Society for Biochemistry and Molecular Bi 2008 The Journal of biological chemistry Vol.283 No.12
<P>The recognition of lysine-type peptidoglycans (PG) by the PG recognition complex has been suggested to cause activation of the serine protease cascade leading to the processing of Spätzle and subsequent activation of the Toll signaling pathway. So far, two serine proteases involved in the lysine-type PG Toll signaling pathway have been identified. One is a modular serine protease functioning as an initial enzyme to be recruited into the lysine-type PG recognition complex. The other is the Drosophila Spätzle processing enzyme (SPE), a terminal enzyme that converts Spätzle pro-protein to its processed form capable of binding to the Toll receptor. However, it remains unclear how the initial PG recognition signal is transferred to Spätzle resulting in Toll pathway activation. Also, the biochemical characteristics and mechanism of action of a serine protease linking the modular serine protease and SPE have not been investigated. Here, we purified and cloned a novel upstream serine protease of SPE that we named SAE, SPE-activating enzyme, from the hemolymph of a large beetle, Tenebrio molitor larvae. This enzyme was activated by Tenebrio modular serine protease and in turn activated the Tenebrio SPE. The biochemical ordered functions of these three serine proteases were determined in vitro, suggesting that the activation of a three-step proteolytic cascade is necessary and sufficient for lysine-type PG recognition signaling. The processed Spätzle by this cascade induced antibacterial activity in vivo. These results demonstrate that the three-step proteolytic cascade linking the PG recognition complex and Spätzle processing is essential for the PG-dependent Toll signaling pathway.</P>