Imd pathway

The Imd pathway bears a number of similarities to mammalian TNFR signalling, though many of the intracellular regulatory proteins of Imd signalling also bear homology to different signalling cascades of human Toll-like receptors. • Imd: human orthologue = RIP1 • Tak1: human orthologue = Tak1 • TAB2: human orthologue = TAB2 • Dredd: human orthologue = caspase-8 • FADD: human orthologue = FADD • Key/Ikkγ: human orthologue = NEMO • Ird5: human orthologue = IKK2 • Relish: human orthologues = p65/p50 and IκB • Iap2: human orthologue = cIAP2 • UEV1a: human orthologue = UEV1a • bend: human orthologue = UBC13 == In Drosophila ==

While the exact epistasis of Imd pathway signalling components is continually scrutinized, the mechanistic order of many key components of the pathway is well-established. The following sections discuss Imd signalling as it is found in Drosophila melanogaster, where it is exceptionally well-characterized. Intracellular signalling components infected by GFP-producing bacteria. Red-eyed flies lacking antimicrobial peptide genes are susceptible to infection, while white-eyed flies have a wild-type immune response. The principle intracellular signalling protein is Imd, a death domain-containing protein that binds with FADD and Dredd to form a complex. Dredd is activated following ubiquitination by the Iap2 complex (involving Iap2, UEV1a, bend, and eff), which allows Dredd to cleave the 30 residue N-terminus of Imd, allowing it to also be ubiquitinated by Iap2. The antimicrobial response Imd signalling regulates a number of effector peptides and proteins that are produced en masse following immune challenge. This includes many of the major antimicrobial peptide genes of Drosophila, particularly: Diptericin, Attacin, Drosocin, Cecropin, and Defensin. The Imd pathway regulates hundreds of genes after infection, however the antimicrobial peptides play one of the most essential roles of Imd signalling in defence. Flies lacking multiple antimicrobial peptide genes succumb to infections by a broad suite of Gram-negative bacteria. Classical thinking suggested that antimicrobial peptides worked as a generalist cocktail in defence, where each peptide provided a small and somewhat redundant contribution.). A second specificity is encoded by Diptericin B, which defends flies against Acetobacter bacteria of the fly microbiome. A third specificity is encoded by the gene Drosocin. Flies lacking Drosocin are highly susceptible to Enterobacter cloacae infection. The Drosocin gene itself encodes two peptides (named Drosocin and Buletin), wherein it is specifically the Drosocin peptide that is responsible for defence against E. cloacae, while the Buletin peptide instead mediates a specific defence against another bacterium, Providencia burhodogranariea. This work on Drosophila immune antimicrobial peptides and effectors has greatly revised the former view that such peptides are generalist molecules. The modern interpretation is now that specific molecules might provide a somewhat redundant layer of defence, but also single peptides can have critical importance, individually, against relevant microbes. == Conservation in insects ==

The Imd pathway appears to have evolved in the last common ancestor of centipedes and insects. It has also been suggested that antimicrobial peptides, the downstream components of Imd signalling, may be detrimental to fitness and lost by insects with exclusively plant-feeding ecologies. Crosstalk between the Imd and Toll signalling pathways While the Toll and Imd signalling pathways of Drosophila are commonly depicted as independent for explanatory purposes, the underlying complexity of Imd signalling involves a number of likely mechanisms wherein Imd signalling interacts with other signalling pathways including Toll and JNK. Insects and arthropods lacking Imd signalling • The pea aphid Acyrthosiphon pisum • The mite Tetranychus urticae == References ==