Imd pathway

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Drosophila melanogaster
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The Imd pathway mediates the response of Drosophila to the presence of diaminopimelic acid-type peptidoglycan (DAP-PGN) found in all Gram negative and many Gram positive bacteria, over lysine-type PGN found in Gram positive bacteria. It operates in the fat-body and hemocytes in response to a systemic infection and is activated upon recognition of DAP-PGN by the PGRP-LC/LE receptors, which leads to activation of the NFkappaB-like transactivator Relish (REL). Elements regulated by the pathway during a systemic infection have been identified by microarray and include a large set of antibacterial peptides genes (De Gregorio et al., 2002; Boutros et al., 2002). In addition, the Imd pathway plays an important role in the relationship many epithelia have with the external world, where it mediates the local inducible immune response (Tzou et al., 2000; Zaidman-Remy et al., 2006). The canonical component of the Imd pathway contains: PGRP-LC (Gottar et al., 2002; Choe et al., 2002; Ramet et al., 2002), IMD (Georgel et al., 2001), DFADD (BG4) (Leulier et al., 2002; Naitza et al., 2002), DREDD (Leulier et al., 2000), REL (Hedengren et al., 1999), Kenny (KEY) and IRD5 (Silverman et al., 2000; Rutschmann et al., 2000; Lu et al., 2001), TAK1 (Vidal et al., 2001; Silverman et al., 2003), TAB2 (Gesellchen et al., 2005; Kleino et al., 2005; Zhuang et al., 2006), Inhibitor of apoptosis 2 (IAP2) (Gesellchen et al., 2005; Kleino et al., 2005; Leulier et al., 2006). Flies lacking these genes are viable but are highly susceptible to Gram negative bacterial infection (Lemaitre et al., 1995). It is not clear if this pathway plays another role beside immunity but overactivation of the Imd pathway induces strong lethality due to apoptosis (Georgel et al., 2001). It should also be noted that the Imd pathway is present and functional in almost all epithelial cells. However, the responses in these tissues are not identical to those observed in the fat body (or in cell culture). In particular, the outputs of Imd signalling are significantly modified in the gut. During Imd signalling in the gut, gene targets producing PGN-digesting PGRP-LB and -SC proteins are expressed but other REL target genes, especially the AMP genes are mostly silent.

In response to infection by Gram-negative bacteria the Imd pathway of the innate immunity response is activated. DAP-PGNs, found on Gram-negative bacteria, are recognised and bind to the PGRP-LC receptor at the plasma membrane or intracellularly bind to the PGRP-LE receptor. This causes the receptor to dimerise/multimerise and activate resulting in the recruitment of the adaptor proteins IMD and DFADD (BG4) along with the caspase 8 orthologue DREDD. Meanwhile, the Ser/Thr MAPK kinase kinase, TAK1 and its partner TAB2 are activated possibly through the IAP2:Bendless (BEN):UEV1a ubiquitin E3 ligase complex. TAK1 and TAB2, in turn phosphorylate the IKKbeta orthologue IRD5. Activated IRD5, in complex with IKKgamma orthologue Kenny (KEY), phosphorylates the NFkappaB orthologue Relish (REL). REL consists of an N-terminal nuclear factor containing domain (REL-68) and an inhibitory C-terminal domain (REL-49) responsible for anchoring REL in the cytoplasm. REL is then cleaved by the caspase, DREDD, releasing the N-terminal domain REL-68. This translocates to the nucleus where it is able to activate transcription of genes encoding antimicrobial peptides.

In addition to being a key component of the Imd pathway, TAK1 kinase is involved in triggering a JNK kinase signalling cascade, starting with the phosphorylation of the JNKK, Hemipterous (HEP). This binds to a scaffolding protein, Connector of kinase to AP-1 (CKA), bringing into close proximity the JNK protein, Basket (BSK) which is phosphorylated by HEP. CKA is also phosphorylated which results in the dissociation of BSK which translocates to the nucleus. Here it binds with a nuclear-residing CKA molecule which additionally recruits the AP-1 transcription factor consisting of the c-Jun orthologue, JRA, and the c-Fos orthologue, Kayak (KAY). BSK may phosphorylate both JRA and KAY which dissociate from CKA and activate transcription of genes involved in the early immune response thought to be involved in wound repair and stress mechanisms. Additionally, the gene responsible for encoding the phosphatase Puckered (PUC) is activated which is responsible for dephosphorylating BSK, an example of a negative regulatory loop.

The Imd pathway mediates the immune response against Gram-negative bacteria infection. During immune challenge, the JNK pathway is activated prior to the activation of the Imd pathway. This early immune response does not require REL activity, in fact, it has been proposed that the main target of the JNK pathway activation, the AP-1 transcription factor, inhibits the activation of REL dependent genes. However, once REL is activated the early response is terminated and a sustained immune response of the Imd pathway is active.

In addition to these core components, many new gene products have been linked to the Imd pathway but their function have not been fully established:

- Amidase PGRPs: Recently, it has been shown that the Imd pathway is down-regulated by the amidase PGRPs, PGRP-LB and PGRP-SC1. They exert their action extracellularly by scavenging peptidoglycan into non-immune stimulatory fragments.
- PGRP-LE: PGRP-LE participates with PGRP-LC in the sensing of DAP-PGN and may play a role in the sensing of monomeric PGN in the cytosol.
- PGRP-LF: PGRP-LF appears to block PGRP-LC-mediated activation of the Imd/JNK pathway possibly by interaction with PGRP-LC at the plasma membrane or by sequestering PGN away from PGRP-LC (Maillet et al., 2008).
- Negative regulators of the Imd pathway: CASPAR, Plenty of SH3s (POSH).
- SCF complex components may be involved in the processing of REL: SKPA, Cullin1 (LIN19), and Slimb (SLMB) (Khush et al., 2002).
- Components of the ubiquitin E3 ligase complex: Bendless (BEN) and UEV1A (Zhou et al., 2005).
- JNK: The Imd pathway can activate the JNK pathway, through the JNKK Hemipterous (HEP), at the level of TAK1 (Boutros et al., 2002; Silverman et al., 2003).
- Nuclear factor Akirin (aka Bhringi (BHR)) (Goto et al., 2008) and GATA zinc finger transcription factor, Serpent (SRP) (Senger et al., 2004) synergize with Relish (REL) and activate transcription.

Literature References
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Hoffmann, JA

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Davis, RJ

Cell 2000
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Immunity 2006
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Perkins, ND

Oncogene 2006
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Kleino, A, Valanne, S, Ulvila, J, Kallio, J, Myllymäki, H, Enwald, H, Stöven, S, Poidevin, M, Ueda, R, Hultmark, D, Lemaitre, B, Rämet, M

EMBO J 2005
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Leulier, F, Rodriguez, A, Khush, RS, Abrams, JM, Lemaitre, B

EMBO Rep 2000
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Annu Rev Biochem 2007
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Rutschmann, S, Jung, AC, Zhou, R, Silverman, N, Hoffmann, JA, Ferrandon, D

Nat Immunol 2000
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Naitza, S, Ligoxygakis, P

Mol Immunol 2004
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Kockel, L, Homsy, JG, Bohmann, D

Oncogene 2001
7568155 A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense

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Proc Natl Acad Sci U S A 1995
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Lemaitre, B

Nat Rev Immunol 2004
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Stronach, B

Dev Dyn 2005
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Gottar, M, Gobert, V, Michel, T, Belvin, M, Duyk, G, Hoffmann, JA, Ferrandon, D, Royet, J

Nature 2002
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Zhuang, ZH, Sun, L, Kong, L, Hu, JH, Yu, MC, Reinach, P, Zang, JW, Ge, BX

Cell Signal 2006
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Dev Cell 2002
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Genes Dev 2001
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Lemaitre, B, Hoffmann, J

Annu Rev Immunol 2007
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Immunity 2000
18474356 The Drosophila peptidoglycan recognition protein PGRP-LF blocks PGRP-LC and IMD/JNK pathway activation

Maillet, F, Bischoff, V, Vignal, C, Hoffmann, J, Royet, J

Cell Host Microbe 2008
17948019 The Drosophila systemic immune response: sensing and signalling during bacterial and fungal infections

Ferrandon, D, Imler, JL, Hetru, C, Hoffmann, JA

Nat Rev Immunol 2007
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Choe, KM, Werner, T, Stöven, S, Hultmark, D, Anderson, KV

Science 2002
16485032 Ubiquitin, TAK1 and IKK: is there a connection?

Chen, ZJ, Bhoj, V, Seth, RB

Cell Death Differ 2006
12147138 Signaling pathways directing the movement and fusion of epithelial sheets: lessons from dorsal closure in Drosophila

Harden, N

Differentiation 2002
15760446 Bacterial recognition and signalling by the Drosophila IMD pathway

Kaneko, T, Silverman, N

Cell Microbiol 2005
16081424 The role of ubiquitination in Drosophila innate immunity

Zhou, R, Silverman, N, Hong, M, Liao, DS, Chung, Y, Chen, ZJ, Maniatis, T

J Biol Chem 2005
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Silverman, N, Zhou, R, Erlich, RL, Hunter, M, Bernstein, E, Schneider, D, Maniatis, T

J Biol Chem 2003
12032070 The Toll and Imd pathways are the major regulators of the immune response in Drosophila

De Gregorio, E, Spellman, PT, Tzou, P, Rubin, GM, Lemaitre, B

EMBO J 2002
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Silverman, N, Zhou, R, Stoven, S, Pandey, N, Hultmark, D, Maniatis, T

Genes Dev 2000
11485985 Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-kappaB-dependent innate immune responses

Vidal, S, Khush, RS, Leulier, F, Tzou, P, Nakamura, M, Lemaitre, B

Genes Dev 2001
15797509 Regulators of the Toll and Imd pathways in the Drosophila innate immune response

Tanji, T, Ip, YT

Trends Immunol 2005
12433364 The Drosophila immune defense against gram-negative infection requires the death protein dFADD

Naitza, S, Rosse, C, Kappler, C, Georgel, P, Belvin, M, Gubb, D, Camonis, J, Hoffmann, JA, Reichhart, JM

Immunity 2002
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Leulier, F, Lhocine, N, Lemaitre, B, Meier, P

Mol Cell Biol 2006
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Dev Cell 2001
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Leclerc, V, Reichhart, JM

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Cell Mol Life Sci 2007
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Mol Cell 1999
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Curr Biol 2002
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