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DROSOPHILA

 

Drosophila Toll
  • Drosophila Toll is a type I transmembrane receptor that was originally reported to control the dorsoventral patterning in the developing fly embryo (Hashimoto et al,1988).
  • In Drosophila,six members of the Toll family have been identified – Toll,18-wheeler (18W),MstProx,SDSDm2245,Tollo and Tehao (Hashimoto et al,1988;Eldon et al,1994;Mitcham et al,1996;Zheng et al,2000).Within this family,Toll and Tehao are most similar,sharing 61% sequence identity within their intracellular domains.
Structure:
  • The extracellular region of Toll contains multiple leucine rich repeats and carboxy terminal cysteine rich domains.The intacellular domain of Toll contains a PEST domain and a C-terminal inhibitory domain (Gay et al,1991).The cytoplasmic domain of Toll also contains domains that share striking homology with the mammalian typeI IL-1 receptor (IL-1R) (Eldon et al,1994,Gay et al,1991).
Ligand:
  • Genetic complementation studies have suggested that a secreted protein termed Spätzle (Morisato et al,1994) is the ligand for Toll. Spätzle is initially synthesized by a precursor protein that is cleaved by the protease Easter,to generate a biologically-active carboxy terminal peptide fragment of Spätzle (DeLotto,1998).
Signaling :
  • Receptor signaling by Toll is believed to be initiated by ligand-dependent receptor dimerization.

 

  • Toll engagement causes recruitment to the membrane of the adaptor protein Tube and protein kinase Pelle (Edwards et al,1997).Tube is homologous to mammalian adaptor protein MyD88 and Pelle is homologous to mammalian IL-1 receptor associated kinase (IRAK).
 
  • By analogy to mammalian signaling pathways,Pelle may activate Drosophila ortholog of mammalian TRAF-6.Drosophila TRAF-6 (dTRAF-6) was recently cloned (Liu et al,1999).
 
  • A new molecule termed ECSIT ( Evolutionarily Conserved Signaling Intermediate In Toll pathways) was identified (Edwards et al,1997).Immunoprecipitation studies demonstrated that the Drosophila ortholog of ECSIT (dECSIT) and dTRAF-6 directly associate with each other.
 
  • Overexpression of either a wild type ECSIT or a constitutively active Toll protein in Schneider cells induced expression of anti microbial peptides,suggesting that both participate in same innate immune response signaling pathway in Drosophila.
 
  • Toll receptor signaling ultimately leads to release of NF-ƙB like proteins Dorsal and Dorsal like immunity factor (DIF) from the cytoplasmic anchoring I-ƘB like protein Cactus (Kidd,1992;Geisler et al,1992).Kim et al recently reported the identification of I-ƘB kinase like protein termed DLAK
(Drosophila LPS activated kinase),that can phosphorylate recombinant Cactus in vitro.
 
  • Following its release from Cactus,Dorsal and DIF translocate to the nucleus whereupon they induce gene transcription.
Function :
  • Toll signaling has been identified as an essential element of an effective anti-fungal immune response in the fly (Lemaitre et al,1996)
 
  • Toll mutant flies died after exposure to Aspergillus fumigatus and death was attributed to uncontrolled fungal growth.
  • Interestingly,Toll mutant flies succumbed to fungal but not bacterial (E.coli) infection.In contrast,18W mutant flies exhibited increased lethality following following exposure to a bacterial challenge (Rodriguez et al,1997).