In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 19, No. 6 ( 2023-6-15), p. e1010761-
Abstract:
The mechanisms by which the innate immune system senses damage have been extensively explored in multicellular organisms. In Drosophila , various types of tissue damage, including epidermal injury, tumor formation, cell competition, and apoptosis deficiency, induce sterile activation of the Toll pathway, a process that requires the use of extracellular serine protease (SP) cascades. Upon infection, the SP Spätzle (Spz)-processing enzyme (SPE) cleaves and activates the Toll ligand Spz downstream of two paralogous SPs, Hayan and Persephone (Psh). However, upon tissue damage, it is not fully understood which SPs establish Spz activation cascades nor what damage-associated molecules can activate SPs. In this study, using newly generated uncleavable spz mutant flies, we revealed that Spz cleavage is required for the sterile activation of the Toll pathway, which is induced by apoptosis-deficient damage of wing epidermal cells in adult Drosophila . Proteomic analysis of hemolymph, followed by experiments with Drosophila Schneider 2 (S2) cells, revealed that among hemolymph SPs, both SPE and Melanization Protease 1 (MP1) have high capacities to cleave Spz. Additionally, in S2 cells, MP1 acts downstream of Hayan and Psh in a similar manner to SPE. Using genetic analysis, we found that the upstream SPs Hayan and Psh contributes to the sterile activation of the Toll pathway. While SPE / MP1 double mutants show more impairment of Toll activation upon infection than SPE single mutants, Toll activation is not eliminated in these apoptosis-deficient flies. This suggests that Hayan and Psh sense necrotic damage, inducing Spz cleavage by SPs other than SPE and MP1. Furthermore, hydrogen peroxide, a representative damage-associated molecule, activates the Psh-Spz cascade in S2 cells overexpressing Psh. Considering that reactive oxygen species (ROS) were detected in apoptosis-deficient wings, our findings highlight the importance of ROS as signaling molecules that induce the activation of SPs such as Psh in response to damage.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010761
DOI:
10.1371/journal.pgen.1010761.g001
DOI:
10.1371/journal.pgen.1010761.g002
DOI:
10.1371/journal.pgen.1010761.g003
DOI:
10.1371/journal.pgen.1010761.g004
DOI:
10.1371/journal.pgen.1010761.g005
DOI:
10.1371/journal.pgen.1010761.g006
DOI:
10.1371/journal.pgen.1010761.g007
DOI:
10.1371/journal.pgen.1010761.s001
DOI:
10.1371/journal.pgen.1010761.s002
DOI:
10.1371/journal.pgen.1010761.s003
DOI:
10.1371/journal.pgen.1010761.s004
DOI:
10.1371/journal.pgen.1010761.s005
DOI:
10.1371/journal.pgen.1010761.s006
DOI:
10.1371/journal.pgen.1010761.s007
DOI:
10.1371/journal.pgen.1010761.s008
DOI:
10.1371/journal.pgen.1010761.s009
DOI:
10.1371/journal.pgen.1010761.s010
DOI:
10.1371/journal.pgen.1010761.s011
DOI:
10.1371/journal.pgen.1010761.s012
DOI:
10.1371/journal.pgen.1010761.s013
DOI:
10.1371/journal.pgen.1010761.s014
DOI:
10.1371/journal.pgen.1010761.s015
DOI:
10.1371/journal.pgen.1010761.s016
DOI:
10.1371/journal.pgen.1010761.s017
DOI:
10.1371/journal.pgen.1010761.s018
DOI:
10.1371/journal.pgen.1010761.s019
DOI:
10.1371/journal.pgen.1010761.s020
DOI:
10.1371/journal.pgen.1010761.s021
DOI:
10.1371/journal.pgen.1010761.r001
DOI:
10.1371/journal.pgen.1010761.r002
DOI:
10.1371/journal.pgen.1010761.r003
DOI:
10.1371/journal.pgen.1010761.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2186725-2
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