Disease relevance of Dif

• Dif is normally localized in the cytoplasm of the larval fat body, but quickly accumulates in the nucleus upon bacterial infection or injury [1].
• Differential activation of the NF-kappaB-like factors Relish and Dif in Drosophila melanogaster by fungi and Gram-positive bacteria [2].

High impact information on Dif

• A novel Rel-containing gene in Drosophila, Dif (dorsal-related immunity factor), provides a potential link between these seemingly disparate processes [1].
• Evidence is presented that once in the nucleus, Dif binds to kappa B-like sequence motifs present in promoter regions of immunity genes [1].
• Therefore the two signalling pathways that target Cactus for degradation must discriminate between Cactus-Dorsal and Cactus-Dif complexes [3].
• The Toll signalling pathway, which controls dorsal-ventral patterning during Drosophila embryogenesis, regulates the nuclear import of Dorsal in the immune response, but here we show that the Toll pathway is not required for nuclear import of Dif [3].
• In response to infection, two Rel proteins, Dif and Dorsal, translocate from the cytoplasm to the nuclei of larval fat-body cells [3].

Biological context of Dif

• Dl plays a central role in the establishment of dorsoventral polarity during early embryogenesis, whereas Dif mediates the Toll receptor-dependent antifungal immune response in adult Drosophila [4].
• The absence of a Dif ortholog in mosquito genomes suggests that Dl may play its functional role in the mosquito Toll-mediated innate immune responses [4].
• Mutations in three of these genes prevent nuclear import of Dif in response to infection, and define new components of signalling pathways involving Rel [3].
• Genetic epistasis experiments demonstrate that Dif mediates the Toll-dependent control of the inducibility of the antifungal peptide gene Drosomycin [5].
• The Drosophila Rel/NF-kappaB transcription factors - Dorsal, Dif, and Relish - control several biological processes, including embryonic pattern formation, muscle development, immunity, and hematopoiesis [6].

Anatomical context of Dif

• We propose a new model to account for this immune system complexity, incorporating distinct pattern recognition receptors of the Drosophila immune system, which can distinguish between various fungi and G(+) bacteria, thereby leading to selective induction of antimicrobial peptides via differential activation of Relish and Dif [2].
• These findings demonstrate that the cellular immune response is essential for the ability of Drosophila to survive in their standard laboratory environment, and that Dif and Dorsal control crucial aspects of the cellular immune response, including blood cell survival and the ability to fight off microbial infection [7].
• We show that two of the three Drosophila Rel/NF-kappa B genes are expressed in doomed salivary glands and that one family member, Dif, is induced in a stage-specific manner immediately before the onset of programmed cell death [8].
• Here, we demonstrate that both Dif and Cactus are expressed in the central nervous system (CNS) of Drosophila [9].
• In blastoderm cells and immune competent cells, Cactus inhibits Dorsal and Dif by preventing their nuclear localization [10].

Regulatory relationships of Dif

• We now present evidence that the Dif gene product trans-activates the Drosophila Cecropin A1 gene in co-transfection assays [11].

Other interactions of Dif

• Remarkably, this Drosophila IkappaB kinase complex is not required for the activation of the Rel proteins Dif and Dorsal through the Toll signaling pathway, which is essential for antifungal immunity and dorsoventral patterning during early development [12].
• We have examined the requirement of Dorsal and DIF for drosomycin expression in larval fat body cells, the predominant immune-responsive tissue, using the yeast site-specific flp/FRT recombination system to generate cell clones homozygous for a deficiency uncovering both the dorsal and the dif genes [13].
• In mbo mutants the upstream signaling events leading to the degradation of the IkappaB homolog Cactus are functional, but Dorsal and Dif remain cytoplasmic and the larval immune response is not activated in response to infection [14].
• The morphogen dorsal (dl) can also activate the Cecropin A1 promoter, but to a lesser extent and in a less sequence-specific manner than Dif [11].
• Signal-induced transcriptional activation by Dif requires the dTRAP80 mediator module [15].

References