Negative regulation of immune responses on the fly.

NF-jB-dependent immune responses are tightly controlled so as to avoid runaway inflammation. One easy model to study the negative regulation of these pathways is provided by the Drosophila melanogaster immune deficiency (IMD) pathway, which regulates both systemic and epithelial immune responses against bacteria. Ragab et al (2011) report in this issue of the EMBO Journal that the Ras/ MAPK pathway negatively regulates the IMD pathway when activated by the PDGF/VEGF receptor (PVR), a process mediated by the PIRK/Rudra/PIMS inhibitor. This study raises interesting questions regarding the biological significance of IMD negative regulation in diverse settings. The immune deficiency (IMD) pathway is triggered upon the binding of peptidoglycan (PGN) to the PGRP-LC receptor, which further signals intracellularly through the deathdomain containing adapters IMD, FADD, and the DREDD apical caspase (see Figure 1). DREDD cleaves IMD, thus allowing its K63-linked polyubiquitination by the Uev1A, Bendless, Effete, and DIAP2 complex. Polyubiquitinated IMD is then thought to recruit the TAK1/TAB2 and the IRD5/Kenny (IKKb and NEMO fly homologues) kinase complexes, the latter of which ultimately activates the Rel transcriptional factor Relish. Relish is likely directly cleaved by DREDD, thus allowing the nuclear uptake of its N-terminal domain. This process thus leads to the induction of the expression of