"Adventures in Innate Immunity from Flies to Mice"

The Drosophila innate immune response is rapidly and robustly activated by microbial cell walls, especially by peptidoglycans from bacteria. The recognition of peptidoglycan occurs in the extracellular space, at the cell surface, and within the cytosol, depending on the exact chemical nature of the agonist. Cytosolic recognition of peptidoglycan requires a newly characterized family of conserved transport proteins, the SLC46 family, that functions in both flies and mice to enable small fragments of peptidoglycan to access intracellular compartments where it can be sensed by cytosolic innate immune receptors. Regardless of the location, innate immune recognition of peptidoglycan in Drosophila activates one of two NF-kB signaling pathways, either the Toll or Imd pathways. The Imd pathway, in particular, is activated by DAP-peptidoglycan, common to gram-negative bacteria, and drives the activation of the NF-kB precursor protein Relish through a signaling pathway with striking similarity to the TNFR pathway. For signaling through the Imd pathway, the peptidoglycan receptors PGRP-LC or PGRP-LE and the signaling adapter Imd form functional amyloids, that are required for signaling transduction and are highly regulated.