PGRPs sense peptidoglycans (PGNs) that derive from bacterial cell walls and stimulate the Drosophila immune deficiency (IMD) pathway, which leads to activation of the nuclear factor-κB-like transcription factor Relish and the expression of antimicrobial genes. It is known that polymeric PGNs, which are only released on bacterial death, induce more efficient resolution of the immune response compared with monomeric PGNs, which are released from live bacteria, but the mechanism involved was unclear. Neyen et al. studied the PGRP-LC locus in detail and identified a potential alternative first exon that might encode a functionally distinct cytoplasmic tail, generating variant forms of the three known PGRP-LC isoforms (PGRP-LCa, PGRP-LCx and PGRP-LCy). To test whether these variants had a role in adjusting immune responses to different ligands, the authors generated mutant Drosophila strains that overexpressed or lacked expression of the variants of PGRP-LC isoforms. Notably, overexpression of the regulatory variant of PGRP-LCx (termed rPGRP-LCx) potently reduced the immune response to polymeric PGN but did not affect the response to monomeric PGN, suggesting that suppression of the response was ligand specific. The response to monomeric PGN was dependent on heterodimers of PGRP-LCx and PGRP-LCa and was not inhibited by their variant forms.
Next, the authors tested whether these regulatory isoforms could curtail immune signalling in the presence of dead bacteria. Flies lacking rPGRP-LCx killed bacteria as efficiently as wild-type flies, but they showed significant delay in resolving the immune response and died earlier (probably due to a dysregulated IMD pathway and induction of apoptosis). Conversely, flies overexpressing rPGRP-LCx showed poor survival after live bacterial infection owing to insufficient IMD activation.
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