Activation of the Drosophila NF‐κB factor Relish by rapid endoproteolytic cleavage

Abstract

The Rel/NF-κB transcription factor Relish plays a key role in the humoral immune response in Drosophila. We now find that activation of this innate immune response is preceded by rapid proteolytic cleavage of Relish into two parts. An Nterminal fragment, containing the DNA-binding Rel homology domain, translocates to the nucleus where it binds to the promoter of the Cecropin A1 gene and probably to the promoters of other antimicrobial peptide genes. The Cterminal IκB-like fragment remains in the cytoplasm. This endoproteolytic cleavage does not involve the proteasome, requires the DREDD caspase, and is different from previously described mechanisms for Rel factor activation.

Stop press: genes that fight infections: what the drosophila genome says about animal immunity

“…The caspase encoding gene dredd, functions in an antibacterial pathway probably with imd and relish 1,2 . This conclusion is supported by results from Stöven et al, who show that Relish processing and activation requires a functional dredd gene 3 . Two members of a Drosophila I B kinase complex, the kinase DmIKK␤ and the structural factor DmIKK␥,`` are required for antibacterial gene induction by LPS, regulate Relish phosphorylation and processing but are not required for Toll-mediated antifungal gene expression 4 .…”

The road to Toll

“…Surprisingly, none of these mutations affect any detectable functions of the Toll pathway. Genetic epistasis studies and molecular analysis of gene function show that imd, Relish and these other genes encode components of a signalling pathway, which is completely distinct from the Toll pathway and is essential for combating Gram-negative bacterial infection 38,39,42,[44][45][46][47][48] (FIG. 3).…”

Nitric oxide contributes to induction of innate immune responses to gram-negative bacteria inDrosophila

“…Although there are uncertainties regarding its specificity, PGRP-LC has attributes of a PAMP and it acts upstream of the death-domain-containing protein Immune deficiency (Imd). Imd signaling proceeds through the MAP kinase kinase kinase homolog, dTAK1, the caspase, dredd, and an I--kinase to culminate in the proteolytic activation of the NF-B family member Relish (Rel; Lemaitre et al 1995a;Dushay et al 1996;Wu and Anderson 1998;Hedengren et al 1999;Kim et al 2000;Silverman et al 2000;Stoven et al 2000;Georgel et al 2001;Lu et al 2001;Vidal et al 2001). Mutants lacking Rel are highly sensitive to infection with gram-negative bacteria (Hedengren et al 1999).…”