Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein.
Microbial infection activates two distinct intracellular signalling cascades in the immune-responsive fat body of Drosophila. Gram-positive bacteria and fungi predominantly induce the Toll signalling pathway, whereas Gram-negative bacteria activate the Imd pathway. Loss-of-function mutants in either pathway reduce the resistance to corresponding infections. Genetic screens have identified a range of genes involved in these intracellular signalling cascades, but how they are activated by microbial infection is largely unknown. Activation of the transmembrane receptor Toll requires a proteolytically cleaved form of an extracellular cytokine-like polypeptide, Spätzle, suggesting that Toll does not itself function as a bona fide recognition receptor of microbial patterns. This is in apparent contrast with the mammalian Toll-like receptors and raises the question of which host molecules actually recognize microbial patterns to activate Toll through Spätzle. Here we present a mutation that blocks Toll activation by Gram-positive bacteria and significantly decreases resistance to this type of infection. The mutation semmelweis (seml) inactivates the gene encoding a peptidoglycan recognition protein (PGRP-SA). Interestingly, seml does not affect Toll activation by fungal infection, indicating the existence of a distinct recognition system for fungi to activate the Toll pathway.
Michel
T
T
Institut de Biologie Moleculaire et Cellulaire, UPR 9022 du CNRS, 15 rue Rene Descartes, 67084 Strasbourg Cedex, France.
Reichhart
J M
JM
Hoffmann
J A
JA
Royet
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000378:metabolism; D001413:Bacillus thuringiensis; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D004330:Drosophila / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D013293:Enterococcus faecalis; D005658:Fungi / Q000276:immunology / Q000378:metabolism; D017344:Genes, Insect; D006094:Gram-Positive Bacteria / Q000276:immunology / Q000378:metabolism*; D006458:Hemolymph; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016982:Micrococcus luteus; D008969:Molecular Sequence Data; D009154:Mutation; D011956:Receptors, Cell Surface; D017386:Sequence Homology, Amino Acid; D051193:Toll-Like Receptors
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D002352:Carrier Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; C118897:peptidoglycan recognition protein; C091227:DRS protein, Drosophila