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The Drosophila Toll Signaling Pathway

Susanna Valanne, Jing-Huan Wang and Mika Rämet
J Immunol January 15, 2011, 186 (2) 649-656; DOI: https://doi.org/10.4049/jimmunol.1002302
Susanna Valanne
*Laboratory of Experimental Immunology, Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland; and
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Jing-Huan Wang
*Laboratory of Experimental Immunology, Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland; and
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Mika Rämet
*Laboratory of Experimental Immunology, Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland; and
†Department of Pediatrics, Tampere University Hospital, 33014 Tampere, Finland
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    FIGURE 1.

    Extracellular cleavage of Spz leading to Toll pathway activation. In early embryogenesis, the protease cascade Gastrulation Defective-Snake activates the protease Easter, which cleaves full-length Spz. In the immune response, three protease cascades lead to the activation of SPE to cleave full-length Spz; the Persephone (PSH) cascade senses virulence factors and is activated by live Gram-positive bacteria and fungi. The other two cascades are activated by pattern recognition receptors binding cell wall components from Gram-positive bacteria and fungi, respectively. All cascades converge at ModSP-Grass for downstream activation of SPE. Upon proteolytical processing, the Spz prodomain is cleaved, exposing the C-terminal Spz parts critical for binding of Toll. Spz binding to the Toll receptor initiates intracellular signaling.

  • FIGURE 2.
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    FIGURE 2.

    Comparison of Drosophila Imd, Toll, and mammalian TLR signaling pathways. Homologies between signaling components are depicted by similar shape. The Imd pathway is activated by DAP-type PGN binding of the PGRP-LC dimer. Other PGRP family members play either negative or positive roles. IMD is connected to the caspase DREDD via the adaptor protein Fas-associated DD protein (FADD). DREDD proteolytically cleaves IMD and Relish. Cleaved IMD associates with the E3-ligase IAP2, E2-ubiquitin-conjugating enzymes UEV1a, Bendless (Ubc13), and Effete (Ubc5) and is K63 polyubiquitinated. This activates the downstream kinase cascade leading to the phosphorylation and activation of Relish and AP-1, which activate the transcription of AMP and stress genes, respectively. Akirin is required for Imd pathway function at the level of Relish (105). Pirk (106), Caspar (107), and Dnr1 (108) are negative regulators of the Imd pathway. The Toll pathway is activated by Spz. One Spz dimer is depicted to bind the N terminus of Toll and to induce a conformational change leading to the formation of a 4Spz:2Toll complex. Intracellular signaling leads to the phosphorylation and degradation of Cactus, which releases Dif and/or Dorsal to translocate to the nucleus and activate transcription. Gprk2 associates with Cactus in a kinase domain (KD)-dependent manner. DEAF-1 is required to induce Toll pathway target genes at or downstream of Dif/Dorsal. Mammalian TLRs are activated by bacterial-, viral-, and self-derived products. Depicted are MyD88-dependent signal transduction events. TLR1, -2, -4, -5, and -6 signal through the plasma membrane, whereas TLR7, -8, and -9 function in the endosome. TLR1, -2, -4, and -6 use the adaptors TIR domain-containing adaptor protein (TIRAP)/MyD88 adaptor-like (Mal) and MyD88, whereas TLR5, -7, -8, and -9 use MyD88 only. MyD88 recruits IRAKs and TRAF6, which activates the TAK1/TAB complex via K63-linked ubiquitination. The activated TAK1 complex stimulates the IKK complex and the MAPK pathway, thereby activating NF-κB and AP-1, respectively. Activated NF-κB translocates to the nucleus to activate transcription. The signal from the endosome activates a complex containing TRAF3 in addition to MyD88, TRAF6, IRAKs, and IKK-α. The activated complex phosphorylates and activates IFN regulatory factor 7 (IRF7) for its nuclear translocation and subsequent transcriptional activation of target genes.

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The Journal of Immunology: 186 (2)
The Journal of Immunology
Vol. 186, Issue 2
15 Jan 2011
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The Drosophila Toll Signaling Pathway
Susanna Valanne, Jing-Huan Wang, Mika Rämet
The Journal of Immunology January 15, 2011, 186 (2) 649-656; DOI: 10.4049/jimmunol.1002302

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The Drosophila Toll Signaling Pathway
Susanna Valanne, Jing-Huan Wang, Mika Rämet
The Journal of Immunology January 15, 2011, 186 (2) 649-656; DOI: 10.4049/jimmunol.1002302
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  • Article
    • Abstract
    • The Toll pathway in the immune response
    • Drosophila Toll receptors
    • Spatzle activation
    • The core Toll signaling pathway
    • RNA interference screening for new components of the Toll pathway
    • Synergistic activation of the Drosophila immune-responsive pathways
    • Comparison of the Drosophila Toll and Imd pathways to mammalian TLR signaling
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