Fig. 3.24 Drosophila Toll is activated as a result of a proteolytic cascade initiated by pathogen recognition. The peptidoglycan-recognition protein PGRP-SA and the Gram-negative binding protein GNBP1 cooperate in the recognition of bacterial pathogens and activate the first protease in a protease cascade that leads to cleavage of the Drosophila protein Spätzle (first panel). Cleavage alters the conformation of Spätzle, enabling it to bind Toll and induce Toll dimerization (second panel). Toll’s cytoplasmic TIR domains recruit the adaptor protein dMyD88 (third panel), which initiates a signaling pathway very similar to that leading to the release of NFκB from its cytoplasmic inhibitor in mammals. The Drosophila version of NFκB is the transcription factor DIF, which then enters the nucleus and activates the transcription of genes encoding antimicrobial peptides. Fungal recognition also leads to cleavage of Spätzle and the production of antimicrobial peptides by this pathway, although the recognition proteins for fungi are as yet unidentified.
3-14 TLR and NOD genes have undergone extensive diversification in both invertebrates and some primitive chordates.
There are only about a dozen mammalian TLR genes, but some organisms have diversified their repertoire of innate recognition receptors, especially those containing LRR domains, to a much greater degree. The sea urchin Strongylocentrotus purpuratus has an unprecedented 222 different TLR genes, more than 200 NOD-like receptor genes, and more than 200 scavenger receptor genes in its genome. The sea urchin also has an increased number of proteins that are likely to be involved in signaling from these receptors, there being, for example, four genes that are similar to the single mammalian MyD88 gene. However, there is no apparent increase in the number of downstream targets, such as the family of NFκB transcription factors, suggesting that the ultimate outcome of TLR signaling in the sea urchin may be very similar to that in other organisms.
Sea urchin TLR genes fall into two broad categories. One is a small set of 11 divergent genes. The other is a large family of 211 genes, which show a high degree of sequence variation within particular LRR regions; this, together with the large number of pseudogenes in this family, indicates rapid evolutionary turnover, suggesting rapidly changing receptor specificities, in contrast with the few stable mammalian TLRs. Although the pathogen specificity of sea urchin TLRs is unknown, the hypervariability in the LRR domains could be used to generate a highly diversified pathogen-recognition system based on Toll-like receptors. A similar expansion of innate receptors has occurred in some chordates, the phylum to which vertebrates belong. Amphioxus (the lancelet) is a nonvertebrate chordate lacking an adaptive immune system. The amphioxus genome contains 71 TLRs, more than 100 NOD-like receptors, and more than 200 scavenger receptors. As we will see in Chapter 5, a primitive vertebrate lineage—the jawless fish, which lack immunoglobulinand T-cell-based adaptive immunity—uses somatic gene rearrangement of LRR-containing proteins to provide a version of adaptive immunity (see Section 5-18).
Summary.