Microbes and Infection 11 (2009) 631e636 www.elsevier.com/locate/micinf
Review
Bacterial detection by Drosophila peptidoglycan recognition proteins Bernard Charroux, Thomas Rival, Karine Narbonne-Reveau, Julien Royet* Institut de Biologie du De´veloppement de Marseille-Luminy (IBDML), UMR 6216 CNRS, Universite´ de la Me´diteranne´e Aix-Marseille II, Parc Scientifique de Luminy-Case 907, F-13288 Marseille Cedex 9, France Received 5 March 2009; accepted 12 March 2009 Available online 1 April 2009
Abstract The mechanisms and molecular effectors of pathogen recognition systems in diverse hosts are highly conserved. Both plant and animal recognition of pathogens relies on sensing of Pathogen-Associated Molecular Patterns (PAMPs) by Pattern Recognition Molecules (PRMs). To detect bacteria, these sensor molecules can recognize a wide array of molecules ranging from lipopolysaccharides (LPS) to peptidoglycan (PGN) or proteins. In contrast to that of mammals, the repertoire of bacterial motifs recognized by the immune system of the fruit fly seems to be much narrower. Works published so far indicate that it is limited to bacterial PGN and its derivatives. The mode of detection of PGN by host proteins is also simpler in the fly immune system than it is in the mammalian counterpart. Although PGN can be detected by Toll-like receptors, Nucleotide-binding oligomerization domain proteins and Peptidoglycan Recognition proteins (PGRPs) in vertebrates, PGRP family members are, so far, the only PGN sensors identified in Drosophila. Interactions between PGN and PGRPs induce multiple processes required to mount a specific and is implicated in multiple processes require to induce a specific and fine-tuned bacterial immune response in fly. Here, we present an overview of our current knowledge of PGRP and their bacterial detection in Drosophila. Ó 2009 Elsevier Masson SAS. All rights reserved. Keywords: PGRP; PGN; Drosophila; Innate immunity; Signaling pathways
1. PGRP genes and protein organization The name Peptidoglycan Recognition Protein was first introduced by the Ashida’s group when working on Bombyx mori [1]. They purified a 19 kDa protein present in the silkworm hemolymph that binds Gram-positive bacteria and more specifically the bacterial PGN. PGRPs have been now identified in mollusks, echinoderms, and in several groups of vertebrates (fish, amphibians, birds and many mammals) [2e 8]. However, plants and lower metazoa, such as nematodes, do not have PGRPs. Drosophila genome contains 13 PGRP genes which are organized for most of them in clusters, suggesting that some of them have been generated by gene duplication [9]. The PGRP transcripts are classified into short (S) and long (L) subfamilies and are often alternatively spliced to generate
* Corresponding author. E-mail address:
[email protected] (J. Royet). 1286-4579/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.micinf.2009.03.004
up to 19 peptides in flies. All PGRPs across species have at least one C-terminal PGRP domain (w165 amino-acid residues) homologous to bacteriophage and bacterial type 2 amidases [10,11]. This suggests that animal PGRPs and prokaryotic type 2 amidases may have evolved from a common primordial ancestor gene. PGRP-S are w200 amino-acids long, have a signal peptide and one PGRP domain, whereas most PGRP-L are at least twice as large and possess one or two C-terminal PGRP domains. Both PGRP-S and PGRP-L contain an N-terminal sequence that is unique for a given PGRP and has no homology with other PGRPs or any other proteins. In almost all PGRPs, two closely spaced conserved Cys can be found in the middle of their PGRP domain forming a disulfide bond, which is needed for the structural integrity and activity of PGRPs [12e19]. Finally, some Drosophila PGRPs, e.g., PGRP-LC or PGRP-LF, are transmembrane [20e22] or intracytoplasmic (PGRP-LE) [23] molecules, whereas most other PGRPs have a signal peptide and are secreted proteins.
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2. Mechanisms of PGN detection by PGRPs In Drosophila, PGN and derived muropeptides are, so far, the only identified PGRP ligands. PGN is an essential cell wall component of virtually all bacteria and is a well-known target for recognition by pattern recognition receptors. PGN is a polymer of b(1-4)-linked N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), cross-linked by short peptide chains, called stem peptides. The nature of the third residue of the stem peptide is an important distinctive feature of Gram-positive versus Gram-negative bacteria: whereas most Gram-positive bacteria have a Lysine in this position, it is replaced by a m-DAP (meso-Di-aminopimelic) residue in Gram-negative bacteria and bacilli. Crystal structures of several free and liganted Drosophila and human PGRPs revealed a peptidoglycan-binding groove on the face of the PGRP domain, whose walls are formed by two a-helices and the floor by a b-sheet platform [13e18,24e 27]. The minimum peptidoglycan fragment that binds to PGRPs is a muramyl-tripeptide. Muramyl-dipeptide or a peptide without MurNAc does not bind to PGRPs. Most of the interactions are with the peptide part of the muropeptides, but MurNAc is also needed for efficient binding. Crystallographic studies also revealed how PGRPs discriminate between the Lys and DAP-type PGN. The only difference between Lys and DAP-type is the presence of an additional carboxylate at the carbon 1 of DAP. Discrimination between Lys- and DAP-type peptidoglycan is based on three aminoacid residues in the peptidoglycan-binding groove of Drosophila PGRPs [13,28]. All DAP-type binding PGRPs include a conserved Arg residue which is found in the base of the PGN docking cleft of these receptors, that makes direct ionic contacts with the terminal carboxy group of DAP. On the contrary, Lys specific PGRPs encode a Thr in this position. It has been shown that mutating the Arg254 of PGRP-LE reduces its affinity for DAP-type PGN [13]. Other studies implicated two other conserved residues (Gly393 and Trp394) in the specific recognition of DAP-type PGN. Switching these residues to Asn and Phe, like as found in PGRP-SA, changes the preference from DAP- to Lys-type PGN [28]. However, some PGRPs have other amino acids in the above-mentioned positions and their specificity cannot be predicted. It should be noted that in PGRP-LCa and PGRP-LD, the PGN-binding groove is modified by AA residues deletion or insertion. In the case of PGRP-LCa, a short peptide insertion present in the PGN-binding cleft is sufficient to prevent PGN recognition by PGRP-LCa [29], whereas the binding properties of PGRP-LD have not yet been characterized. It is of interest that mammalian PGLYRPs bind both Gram-positive, Gram-negative bacteria, and fungi [30], and some insect PGRPs (e.g., Holotrichia diomphalia PGRP-1) bind fungal b-glucan [31]. The binding sites for these non-PGN ligands are unknown and may lie outside of the peptidoglycan-binding groove (Fig. 1). Another characteristic feature of Gram-negative PGN is the presence of an anhydro form, the 1,6-anhydro-MurNAc, at the reducing end of the glycan chain. This form is also present in a PGN fragment, the tracheal cytotoxin (TCT, GlcNAc-1,
6-anhydro-MurNAc-L-Ala-D-isoGlu-DAP-D-Ala). The anhydro configuration is detected by Arg233 in Drosophila PGRPLE and is required for the formation of PGRP-LE:LE and PGRP-LCx:LCa dimers (see next section) [27]. 3. PGRP-SA, SD and GNBP-1 cooperate to detect bacteria upstream of the Toll pathway Insight on PGRP function in invertebrates came from genetic studies aimed at dissecting signaling cascades that control antimicrobial peptides production. In Drosophila melanogaster, the expression of the genes encoding most immune proteins is under the control of two NF-kB-dependant signaling pathways [32,33]. The Toll cascade responds to Gram-positive bacteria and fungal pathogens while the Immune Deficiency (IMD) pathway preferentially recognizes Gram-negative bacteria. The identification of the PGRP-SA mutation Semmelweis in 2001, allowed the dissection of the Toll pathway into a fungal and a bacterial branches (Fig. 1) Indeed, whereas PGRP-SA mutants respond normally to fungal challenge, they are impaired in response to the Grampositive bacteria Micrococcus luteus. On the other hand, recent reports have identified Gram-negative Binding Protein-3 (GNBP-3) as one of the receptor to fungi upstream of the Toll signaling complex [34]. The recognition complex upstream of the Toll receptor also implicates other proteins. Among them is the misnamed GNBP-1 that displays mutant phenotypes similar to those of PGRP-SA [35]. It is proposed that GNBP-1, which share sequence homology with glucanases, could enzymatically degrade Gram-positive PGN, making it accessible to PGRP-SA recognition [36]. Nevertheless, It is now clear that the strict reliance of M. luteus recognition by PGRPSA is rather the exception than the rule. Indeed, most other Gram-positive bacteria species are not only recognized by PGRP-SA but rather through two partly redundant receptors, PGRP-SA and PGRP-SD [37]. PGRP-SD has been shown to cooperate with PGRP-SA and GNBP-1 for the detection of some Gram-positive bacteria species such as Staphylococcus aureus. It was reported that PGRP-SD enhances the binding of PGRP-SA and GNBP-1 to Gram-positive PGN and that the three proteins could be found as a ternary complex [38]. Works in other insects suggest that lysozyme digestion of Gram-positive bacteria PGN facilitates PGRP-SA binding and clustering which in turn recruits GNBP-1 [39]. Further biochemical and structural analysis will be required to decipher the precise role of each of the three partners in the detection of the various Gram-positive bacteria species which all have specific PGN. As expected for a bacterial receptor upstream of the Toll pathway, PGRP-SA preferentially binds and responds to Lys-type PGN. However, Dap-type PGN can also, to a lesser extend, stimulates the Toll pathway. This activation is PGRP-SA dependent, which is consistent with the weak interaction between DAP-type PGN and PGRP-SA. PGRP-SD is also required for both Lys-type and DAP-type activation of the Toll pathway [40]. This is however more surprising since PGRP-SD has a much higher binding affinity for DAP-type PGN than for Lys-type PGN.
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Fig. 1. PGRPs and Drosophila immunity. Bacteria containing Lys-type PGN are recognized, in the circulating hemolymph, by the secreted PGRP-SA and SD proteins. This interaction leads to the induction of a protease cascade that, in turn, cleaves the pro-Spa¨tzle into an active ligand for the Toll Receptor. Toll pathway activation triggers AMP gene transcription. Extracellular DAP-type PGN containing bacteria are directly recognized by the PGRP-LC or PGRP-LE membrane receptor, therefore inducing the IMD pathway. However, since over-activation of the IMD pathway is detrimental to the animal, various mechanisms modulate the intensity of the IMD pathway. By cleaving the PGN into inactive muropeptides, the PGRP-SC1/2 and LB amidases reduces the intensity of IMD pathway activation. By sequestering circulating PGN, PGRP-LF prevents continuous activation of the IMD pathway. Other PGRPs act by directly killing bacteria (PGRPSB1) or by facilitating phagocytosis of DAP-type PGN containing bacteria. Precise molecular mechanisms implicating PGRP in the phagocytosis process need to be further dissected. Finally, one intracytosolic isoform of PGRP-LE is required to mediate autophagic elimination of intracellular pathogens such as Listeria monocytogenes.
4. PGRP-LC and LE are pattern recognition receptors for DAP-type PGN The strong similarities between mammalian TNF-a and Drosophila IMD pathways suggested that a TNF receptor-like molecule could be the upstream component of the Gramnegative arm of the fly immune response. However, mutant flies for the TNF-a ortholog (Eiger) or its receptor (Wengen) are as competent as wild type to fight Gram-negative bacteria infection [41,42]. Consistently, genetic studies unequivocally demonstrate that a PGRP family member, PGRP-LC, is the main IMD pathway transmembrane receptor. PGRP-LC mutant flies are unable to transcribe IMD pathway-dependent genes after immune challenge and are highly susceptible to infection by Gram-negative species [20,21,43]. As expected for a Gramnegative bacteria receptor, PGRP-LC shows a stronger binding affinity for DAP-type PGN than for Lys-type PGN. These results indicate that Drosophila’s ability to discriminate between Gram-positive and Gram-negative bacteria does not
rely on lipopolysaccharide detection, but rather on the recognition of specific forms of PGN [44]. Two different elicitors have been shown to activate the IMD pathway in vivo: injection of either monomeric, such as TCT, or polymeric DAP-type PGN in adult flies trigger a strong AMP production [44e46]. Interestingly, these two muropeptides are not recognized in vivo by the same receptor complex. Through alternative splicing, the PGRP-LC locus can generate three distinct proteins: PGRPLCx, -LCa and -LCy. These isoforms can form homo- or heterodimers that contain identical N-terminal cytoplasmic signaling and transmembrane domains but unique extracellular PGRP motifs. Whereas polymeric PGN is recognized by a PGRP-LCx homodimer, TCT is detected by an heterodimeric PGRP-LCa or PGRP-LCx complex [23,46]. TCT first binds to the PGN-binding groove of PGRP-LCx. In the absence of a functional PGN-binding groove (see above), PGRP-LCa binds to the TCT-PGRP-LCx complex by interacting with a docking site created by the carbohydrate residue of TCT in combination with some residues of PGRP-LCx [24,29].
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PGN can also be detected intracellularly by Drosophila via the PGRP-LE intracellular receptor [47]. TCT binding to PGRP-LE which induces its homo-multimerisation via a headto-tail type interaction [27] is sufficient to trigger IMD pathway activation. It is not yet apparent how TCT gain access to intracellular PGRP-LE but the implication of bacterial type III secretion system can be proposed. PGRP-LE must have its own intrinsic ability to interact with and activate IMD pathway components. To support this idea, a conserved RHIM-like motif, known to be essential to mediate IMD signaling, is found both in PGRP-LE and in the intracytoplasmic domain of PGRP-LC [23]. In both cases (LCa/LCx and LE/LE dimers), multimerisation of PGRP-L molecules seems to be required to trigger downstream signaling by mechanisms that are not yet completely clear. Another essential function has been recently attributed to intracellular PGRP-LE. Kurata and collaborators demonstrate that PGRP-LE is able to recognize cytosolic Listeria monocytogenes via DAP-type PGN [48]. This recognition step is essential to induce the autophagic machinery that, in turn, inhibits intracellular growth of the bacteria by degradation of the bacteria (Fig. 1). Induction of autophagy after detection of the bacteria through PGRP-LE is independent of the Toll and IMD pathways, suggesting the existence of a distinct innate immune pathway responsible for this function. This finding defines a new pathway leading from the intracellular bacteria recognition by PGRP to the induction of autophagy to host defense. It would be interesting to know whether mammalian NOD proteins, that are intracellular PGN detectors, are also implicated in autophagy mediated clearance of intracellular bacteria. 5. Downregulation of immune response by PGRPs The only conserved function of insect and mammalian PGRPs is an N-acetylmuramoyl-L-alanine amidase enzymatic activity that hydrolyzes the amide bond between MurNAc and L-Ala in PGN and removes the stem peptides from the glycan chain. Drosophila PGRP-SC1, SB1 and PGRP-LB and mammalian PGLYRP-2 have proven amidase activity and many other PGRPs are predicted to function as amidases based on conserved amino-acid residues in the amidase active site [30]. PGRPs with amidases activity perform at least two distinct functions in Drosophila immune response. They can be directly bactericidal but they can also modulate the intensity of the immune response by reducing the amount of immunogenic muropeptides. It was recently reported that PGRP-SB1 shows antibacterial activity. PGRP-SB1 is highly active against DAP-type PGN, but lack activity to most Lyscontaining PGNs [49]. The bactericidal effect of PGRP-SB1 is dependent on its enzymatic activity, as the zinc co-factor is essential. The bactericidal mode of action is thus different from non-enzymatic vertebrate PGRPs that have also been reported to be antibacterial [50]. Although the role of PGRPs with Pattern Recognition Receptor (PRR) function has been well documented in flies, the function of hydrolytic PGRPs in vivo remained elusive for a while. Steiner’s group has shown
that hydrolysis of PGN by PGRP-SC1 in vitro produces muropeptides that have lost immuno-stimulatory properties [51]. They also suggested that some amidase PGRPs could act in vivo as scavenger receptors implicated in the termination of the immune response. Recent in vivo studies give ground to this hypothesis. Indeed, flies in which the soluble catalytic PGRP-SC1 or PGRP-LB have been down-regulated by RNA interference present a specific over-activation of the IMD pathway after bacterial challenge [52,53]. More interestingly, systemic tolerance to ingested Gram-negative bacteria or to PGN was observed in wild type flies but not in PGRP-SC1/2 or in PGRP-LB depleted flies. This indicates that these proteins, which are mainly expressed in the gut, mediate the balance between homeostasis and immune reaction by modulating the response to commensal or pathogenic bacteria. In addition to their function as PRR, some PGRPs can therefore control IMD signaling pathway activation levels by decreasing the immuno-stimulatory activity of PGN. In the absence of this control, infection can lead to developmental defects and larval death through over-activation of the IMD pathway [53]. In this respect, PGRPs with amidase activity act as detoxifying enzymes for bacterial PGN in flies. Similar functions have been attributed to enzymes that reduce the immunogenic potential of LPS during vertebrate immune response [54]. PGRP-SA, which has no amidase activity, possesss an L,D-carboxypeptidase activity with specificity for the bond between m-DAP and D-Ala of the stem peptide present in all Gram-negative and Gram-positive rod PGN [19]. The biologic significance of this carboxypeptidase activity is not yet clear. The dampening of the immune response also implicated PGRP-LF, a protein coded by a gene sitting as a neighbor to PGRP-LC on the third chromosome. PGRP-LF is a transmembrane protein, with two PGRP domains closely related to that of PGRP-LCa and x and devoid of intracellular domain [7]. It was shown that reducing PGRP-LF levels, in the absence of infection, is sufficient to trigger IMD and JNK pathways activation suggesting that the function of PGRP-LF is to prevent constitutive activation of these pathways in wild type flies [22]. A model would be that PGRP-LF keeps the Drosophila IMD pathway silent by sequestering circulating peptidoglycan and suggests that PGRP-LF would have a similar function than of decoy receptors of mammalian cytokine receptors. 6. PGRPs and phagocytosis In addition to their previously mentioned function, PGRPLC and PGRP-SC1 are also involved in phagocytosis. Downregulation of PGRP-LC in S2 blood-like cells diminishes uptake of E. coli although to a much less extend of what is observed with Eater phagocytic receptor [43]. In addition, Drosophila mutants with reduced PGRP-SC1 levels have impaired phagocytosis index for S. aureus [55]. It remains to be understood how the PGN that is buried underneath the outer LPS membrane can be accessible for recognition by the transmembrane receptor PGRP-LC to allow phagocytosis and
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signaling to take place. It is also unclear how the secreted protein PGRP-SC1 function as a phagocytic receptor. One possibility could be that PGRP-SC1 acts as an opsonin and therefore binds to bacteria. The PGRP-SC1-bacterial complex will then be recognize by a transmembrane phagocytic receptor. Further work will be needed to dissect these mechanisms. 7. Concluding remarks Over the last years, the role of PGRPs in PGN detection in various invertebrates, but mainly in Drosophila, has been the subject of intense studies. This work has put together a very precise description of the various functions of different PGRP family members in the Drosophila immune response. From that, it is now clear that PGN detection by the PGRPs is one of the central bacterial detection mechanisms in flies. PGN detection by the mammalian immune system, that is still controversial, seems to implicate multiple players such as NOD, CD14 and possibly TLR2. For a while, it was supposed that mammalian PGRPs would more act as antimicrobial molecules rather than has signaling pathway components. A recent report indicates that PGLYRP-2 functions as a cytokine-like molecules in a PGN induced arthritis model [56]. Further work will be needed to assess to which extend PGRP functions have been conserved in the course of evolution. Acknowledgments This work was supported by the CNRS, the Agence Nationale de la Recherche (ANR-MIME program to JR), the ACI jeunes chercheurs and the Fondation pour la Recherhe Me´dicale (Programme Equipe FRM to JR) and the Institut Universitaire de France. References [1] H. Yoshida, K. Kinoshita, M. Ashida, Purification of a peptidoglycan recognition protein from hemolymph of the silkworm, Bombyx mori, J. Biol. Chem. 271 (1996) 13854e13860. [2] J.P. Rast, L.C. Smith, M. Loza-Coll, T. Hibino, G.W. Litman, Genomic insights into the immune system of the sea urchin, Science 314 (2006) 952e956. [3] M.S. Goodson, M. Kojadinovic, J.V. Troll, T.E. Scheetz, T.L. Casavant, M.J. McFall, Identifying components of the NF-kappaB pathway in the beneficial Euprymna scolopes-Vibrio fischeri light organ symbiosis, Appl. Environ. Microbiol. 71 (2005) 6934e6946. [4] C.-C. Tydell, N. Yount, D. Tran, J. Yuan, M.E. Selsted, Isolation, characterization, and antimicrobial properties of bovine oligosaccharidebinding protein. A microbicidal granule protein of eosinophils and neutrophils, J. Biol. Chem. 277 (2002) 19658e19664. [5] Y. Sang, B. Ramanathan, C.R. Ross, F. Blecha, Gene silencing and overexpression of porcine peptidoglycan recognition protein long isoforms: involvement in beta-defensin-1 expression, Infect. Immun. 73 (2005) 7133e7141. [6] R. Dziarski, Peptidoglycan recognition proteins (PGRPs), Mol. Immunol. 12 (2004) 877e886. [7] C. Persson, S. Oldenvi, H. Steiner, Peptidoglycan recognition protein LF: a negative regulator of Drosophila immunity, Insect. Biochem. Mol. Biol. 37 (2007) 1309e1316.
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