Toll pathway

Stable Identifier
Drosophila melanogaster
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In Drosophila, the Toll pathway establishes the embryonic dorsoventral axis and triggers innate immune responses to infection, along with the Imd pathway.

The Toll pathway plays a key role in the response to Gram-positive cocci and Fungi by regulating a large set of genes (including antimicrobial peptide genes, many small peptides with unknown function as well as components of the melanization and clotting cascades) by the fat body and in hemocytes that circulate in the hemolymph (De Gregorio et al., 2002). The canonical component of the Toll pathway contains: Spatzle (SPZ), Toll (TL), Pelle (PLL), Tube (TUB), MYD88, Cactus (CACT), Dorsal (DL), Dorsal-related immunity factor (DIF) (Belvin et al., 1996; Tauszig-Delamasure et al., 2002). Many other functions have been proposed for the Toll pathway including hemocyte differentiation (Evans et al., 2003; Meister, 2004), muscle attachment and motoneuron defects (Halfon et al., 1995).

The Toll pathway is activated after the cleavage of SPZ by serine protease cascades. The proteolytic cascade activating SPZ during dorsoventral patterning has been well delineated and involves the serine proteases: Gastrulation defective (GD); Snake (SNK); and Easter (EA), that directly cleave the full-length Spatzle (SPZ) dimer ligand. This cascade is negatively regulated by the serpin SPN27A that acts at the level of EA (Dissing et al., 2001; LeMosy et al., 2001). The cascades activating SPZ during the immune response are much more complex with branches involved in the sensing of Glucan found in fungi (through GNBP3) or Lysine-type peptidoglycans (PGNs) found in gram positive cocci (through PGRP-SA, GNBP1 and PGRP-SD) and via the serine protease, Persephone (PSH), in the sensing of entomopathogenic fungus via the detection of protease. These proteolytic cascades which are not yet well characterised converge and lead to activation of Spatzle-processing enzyme (SPE) that cleave Spatzle in the hemolymph.

The processed SPZ dimer binds to the extracellular part of the Toll (TL) receptor at the plasma membrane. This causes TL to activate and dimerise through its cytoplasmic domains. In response to this activity, the adaptor proteins MYD88, Tube (TUB), and the Ser/Thr kinase Pelle (PLL) are recruited to the TL receptor cytoplasmic region to form the 'signalling complex'. In addition, during dorsoventral patterning in the embryo, the zinc-finger adaptor protein, Weckle (WEK) forms an extra link between MYD88 and the TL receptor (Chen et al., 2006). PLL is activated, autophosphorylates and recruits the DL/DIF dimer, complexed to the NF-kappaB inhibitor orthologue, Cactus (CACT) to the 'signalling complex'. CACT is complexed to NF-kappaB orthologue dimers of either Dorsal (DL) in dorsoventral polarity and larvae immune response or Dorsal-related immunity factor, Dif (DIF), the main transcription factor in the innate immunity response. The next stage is unclear but it is believed that PLL or an unknown kinase tentatively labelled the 'Cactus kinase' phosphorylate CACT and the DL/DIF dimer. CACT in complex with the DL/DIF dimer dissociates from the 'signalling complex'. The phosphorylated CACT is degraded probably by the 26S proteasome, and the now free phosphorylated DL/DIF dimer translocates to the nucleus to activate transcription of genes encoding a battery of antimicrobial peptides in the immune response or genes that organise dorsoventral patterning.

Literature References
PubMed ID Title Journal Year
11350927 Autoproteolysis and feedback in a protease cascade directing Drosophila dorsal-ventral cell fate

Dissing, M, Giordano, H, DeLotto, R

EMBO J 2001
7750635 The Drosophila toll gene functions zygotically and is necessary for proper motoneuron and muscle development

Halfon, MS, Hashimoto, C, Keshishian, H

Dev Biol 1995
14603309 The immune response of Drosophila

Hoffmann, JA

Nature 2003
14602069 Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis

Evans, CJ, Hartenstein, V, Banerjee, U

Dev Cell 2003
16697918 Pathogen recognition and signalling in the Drosophila innate immune response

Wang, L, Ligoxygakis, P

Immunobiology 2006
11296245 Activation of a protease cascade involved in patterning the Drosophila embryo

LeMosy, EK, Tan, YQ, Hashimoto, C

Proc Natl Acad Sci U S A 2001
14734104 Blood cells of Drosophila: cell lineages and role in host defence

Meister, M

Curr Opin Immunol 2004
15199954 The immune response of Drosophila melanogaster

Leclerc, V, Reichhart, JM

Immunol Rev 2004
11743586 Drosophila MyD88 is required for the response to fungal and Gram-positive bacterial infections

Tauszig-Delamasure, S, Bilak, H, Capovilla, M, Hoffmann, JA, Imler, JL

Nat Immunol 2002
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
16782008 Weckle is a zinc finger adaptor of the toll pathway in dorsoventral patterning of the Drosophila embryo

Chen, LY, Wang, JC, Hyvert, Y, Lin, HP, Perrimon, N, Imler, JL, Hsu, JC

Curr Biol 2006
17201680 The host defense of Drosophila melanogaster

Lemaitre, B, Hoffmann, J

Annu Rev Immunol 2007
8970732 A conserved signaling pathway: the Drosophila toll-dorsal pathway

Belvin, MP, Anderson, KV

Annu Rev Cell Dev Biol 1996
15797509 Regulators of the Toll and Imd pathways in the Drosophila innate immune response

Tanji, T, Ip, YT

Trends Immunol 2005
15229471 The road to Toll

Lemaitre, B

Nat Rev Immunol 2004
14698227 Antimicrobial defences in Drosophila: the story so far

Naitza, S, Ligoxygakis, P

Mol Immunol 2004
17362201 Structure and function of toll receptors and their ligands

Gay, NJ, Gangloff, M

Annu Rev Biochem 2007
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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