Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll

Abstract

In drosophila, fungal and Gram-positive bacterial molecular determinants are detected by circulating pattern recognition receptors (PRRs). Previous findings suggest that these PRRs activate yet unidentified serine protease cascades culminating in the cleavage of Spaetzle, the endogenous Toll receptor ligand, and triggering the immune response. We demonstrate here that the Grass protease defines a common activation cascade for PRR-mediated fungal and Gram-positive bacterial detection. The serine protease Persephone, previously shown to be specific for fungal detection in a cascade activated by secreted fungal proteases, was also required for sensing of proteases elicited by bacteria in the hemolymph. Hence, Persephone defines a parallel proteolytic cascade activated by danger signals such as abnormal proteolytic activities.

Persephone/Spätzle Pathogen Sensors Mediate the Activation of Toll Receptor Signaling in Response to Endogenous Danger Signals in Apoptosis-deficient Drosophila

“…The pattern recognition receptor-dependent pathway consists of a set of circulating receptors, including peptidoglycan recognition proteins and Gram-negative bacteria-binding proteins, capable of discriminating between bacterial and fungal determinants (55), the recognition of which triggers a subsequent proteolytic cascade leading to Spz activation. The parallel path-way is activated when Psh senses virulence factors secreted from filamentous fungi (41) or Gram-positive bacteria (40). Although the molecular mechanism of how these enzymes are detected by Psh is currently unknown, Psh has been implicated as a key factor in the "danger signal-dependent extracellular pathway" ever since the recognition of its ability to detect abnormal protease activity (40).…”

“…The parallel path-way is activated when Psh senses virulence factors secreted from filamentous fungi (41) or Gram-positive bacteria (40). Although the molecular mechanism of how these enzymes are detected by Psh is currently unknown, Psh has been implicated as a key factor in the "danger signal-dependent extracellular pathway" ever since the recognition of its ability to detect abnormal protease activity (40). Our findings extend this theory by showing that Psh is responsible for endogenous DAMP-mediated systemic activation of Toll signaling.…”

“…Drosophila Toll activation involves the activation of two distinct, but parallel pathways, namely a pattern recognition receptor-dependent pathway and a Psh-dependent pathway (40), that converge on the proteolytic cleavage of Spz (54). The pattern recognition receptor-dependent pathway consists of a set of circulating receptors, including peptidoglycan recognition proteins and Gram-negative bacteria-binding proteins, capable of discriminating between bacterial and fungal determinants (55), the recognition of which triggers a subsequent proteolytic cascade leading to Spz activation.…”

“…Persephone (Psh) is an extracellular CLIP domain serine protease that activates Spz, through a proteolytic cascade that is partly independent of proteoglycan sensing (40). The proteolytic maturation of Psh can be triggered by virulent proteases secreted by fungi or Gram-positive bacteria (40,41).…”

“…The proteolytic maturation of Psh can be triggered by virulent proteases secreted by fungi or Gram-positive bacteria (40,41). To test whether Psh was involved in the DAMP-mediated Toll activation, we replaced the wild-type psh allele in dronc ⌬A8 with a loss of function allele psh 1 , which encodes a Psh protein with impaired catalytic activity (16), and assessed Drs expression in the double mutants.…”