Peptidoglycan recognition protein (PGRP)-LE and PGRP-LC act synergistically in Drosophila immunity

Abstract

In innate immunity, pattern recognition molecules recognize cell wall components of microorganisms and activate subsequent immune responses, such as the induction of antimicrobial peptides and melanization in Drosophila. The diaminopimelic acid (DAP)-type peptidoglycan potently activates imd-dependent induction of antibacterial peptides. Peptidoglycan recognition protein (PGRP) family members act as pattern recognition molecules. PGRP-LC loss-of-function mutations affect the imd-dependent induction of antibacterial peptides and resistance to Gramnegative bacteria, whereas PGRP-LE binds to the DAPtype peptidoglycan, and a gain-of-function mutation induces constitutive activation of both the imd pathway and melanization. Here, we generated PGRP-LE null mutants and report that PGRP-LE functions synergistically with PGRP-LC in producing resistance to Escherichia coli and Bacillus megaterium infections, which have the DAP-type peptidoglycan. Consistent with this, PGRP-LE acts both upstream and in parallel with PGRP-LC in the imd pathway, and is required for infection-dependent activation of melanization in Drosophila. A role for PGRP-LE in the epithelial induction of antimicrobial peptides is also suggested.

Peptidoglycan recognition proteins (PGRPs)

“…It is a transmembrane protein and has three alternative splice forms (LC-A, LC-B, and LC-C), which differ in the extracellular PGRP domains; they probably cooperate with each other and have somewhat different recognition specificities [25,29,[32][33][34]. PGRP-LC activates the Imd pathway in cooperation with PGRP-LE [35] and also probably with another, as yet unidentified co-receptor (Figure 4b). Drosophila PGRP-LC may also have a role in phagocytosis of Gram-negative bacteria, because inhibition of PGRP-LC expression in Drosophila S-2 cells diminishes phagocytosis of Escherichia coli, but not of Staphylococcus aureus [31]; the mechanism of this phenomenon is still unclear, however.…”

“…This generates antimicrobial products, such as melanin and reactive oxygen species, surrounds the infection site with melanin, and contains the infection. Drosophila PGRP-LE [35] and beetle (Holotrichia diomphalia) PGRP-1 [38] (and probably other PGRPs) also activate the prophenol-oxidase cascade, but H. diomphalia PGRP-1 responds to 1,3-␤-D-glucan, a common constituent of fungal cell walls.…”

Induction of autophagy via innate bacterial recognition

“…PGRP-LE, first reported by our group to be an extracellular bacteria recognition protein, exists in both the hemolymph and inside hemocytes, the immune reactive cells, and can activate immune signaling in response to a bacterial component inside cultured cells. [13][14][15] These findings led us to examine the function of PGRP-LE as a recognition receptor for intracellular bacteria, and to further study PGRP-LE mediated innate immune responses against intracellular bacteria.…”

The peptidoglycan recognition protein PGRP-SC1a is essential for Toll signaling and phagocytosis of Staphylococcus aureus in Drosophila

“…Gram ϩ PGN and Gram Ϫ PGN differ in the stem peptide portion; typical Gram ϩ bacteria have a lysine as the third amino acid, whereas Gram Ϫ bacteria and the Gram ϩ Bacillus have a diaminopimelic acid (DAP) in that position (22). Two other noncatalytic PGRPs, PGRP-LE and PGRP-SD, also play a role in activation of the Imd and Toll pathways, respectively (23,24). PGRP-LC, PGRP-LE double mutants show a more dramatic phenotype to Bacillus and Gram Ϫ bacterial infection than either mutation alone, suggesting that PGRP-LE acts with PGRP-LC in the recognition of Gram Ϫ DAP-type peptidoglycan for the activation of the Imd pathway (24).…”

“…Two other noncatalytic PGRPs, PGRP-LE and PGRP-SD, also play a role in activation of the Imd and Toll pathways, respectively (23,24). PGRP-LC, PGRP-LE double mutants show a more dramatic phenotype to Bacillus and Gram Ϫ bacterial infection than either mutation alone, suggesting that PGRP-LE acts with PGRP-LC in the recognition of Gram Ϫ DAP-type peptidoglycan for the activation of the Imd pathway (24). PGRP-SD may be playing a similar role with PGRP-SA for activation of the Gram ϩ ͞Toll pathway (23).…”