NF-kappaB in the immune response of Drosophila

Abstract

The nuclear factor kappaB (NF-kappaB) pathways play a major role in Drosophila host defense. Two recognition and signaling cascades control this immune response. The Toll pathway is activated by Gram-positive bacteria and by fungi, whereas the immune deficiency (Imd) pathway responds to Gram-negative bacterial infection. The basic mechanisms of recognition of these various types of microbial infections by the adult fly are now globally understood. Even though some elements are missing in the intracellular pathways, numerous proteins and interactions have been identified. In this article, we present a general picture of the immune functions of NF-kappaB in Drosophila with all the partners involved in recognition and in the signaling cascades.

Figure 1.

The NF-κB and IκB proteins in Drosophila. The length in amino acids is indicated by numbers. REL, Rel-homology domain; NLS, nuclear localization sequence; PEST, proline, glutamic acid, serine, and threonine-rich segment; Ac, acidic domain.

Figure 2.

(A) The 13 PGRPs of Drosophila melanogaster. (B) Simplified representation of the various activities of PGRPs versus PGN. (Top) PGRP with an amidase activity cleaves PGN (SC1, arrow). (Bottom) PGRPs that have lost their amidase activities serve as recognition proteins for Lys-type PGN (PGRP-SA) or DAP-type PGN (PGRP-LC).

Figure 3.

GNBP1 and GNBP3.

Figure 4.

Induction of Toll and Imd pathway by pathogens. Gram-positive bacteria are recognized by PGRP-SA with the cooperation of GNBP1 and PGRP-SD. This recognition results in activation of a proteolytic cascade culminating in the cleavage of Spaetzle via the serine protease Spaetzle Processing Enzyme (SPE). Dimeric cleaved Spaetzle binds to the Toll receptor, activating the intracellular signaling cascade shown in Figure 6. Fungi are recognized by GNBP3 and induce a proteolytic cascade, which also activates SPE. Entomopathogenic fungi have been shown to also activate the Toll pathway through secreted proteases, which activate the circulating zymogen Persephone (virulence factor). Gram-negative bacteria are directly detected by the transmembrane receptor PGRP-LC, which recognizes the DAP-type peptidoglycan. The amidase PGRP-LB and PGRP-SC degrade PGN to nonimmunogenic moieties (Fig. 2).

Figure 5.

Representatives of the Toll and the TLR families.

Figure 6.

Toll pathway in adult Drosophila melanogaster. Signaling through Toll involves the receptor/adaptor complex, composed of three death-domain-containing proteins, MyD88, Tube, and Pelle. The trimeric complex assembles around the bipartite DD of Tube. It is unclear how the signal is transduced from the complex to Cactus, a homolog of IkB. Phosphorylated Cactus is degraded after polyubiquitination by the proteasome. The liberated DIF is translocated to the nucleus and binds to NF-κB response elements, inducing the expression of hundreds of genes, namely those encoding antimicrobial peptides, such as drosomycin.

Figure 7.

Imd pathway in adult Drosophila melanogaster. The transmembrane protein PGRP-LC senses the presence of DAP-type PGN and activates the Imd pathway Imd has an essential role in controlling the phosphorylation of Relish through the activation of TAK1 and the IKK signalosome. Cleavage of phosphorylated Relish is dependent on the caspase Dredd. The activation of TAK1 and the IKK signalosome requires several proteins, including FADD and Dredd. Cleaved Relish is translocated in the nucleus and binds to NF-κB response elements, inducing the expression of numerous genes encoding immune response proteins, namely antimicrobial peptides such as Diptericin. In addition to phosphorylating the IKK complex, TAK1 also acts as a JNK kinase and activates the JNK pathway.