Disease relevance of Rel

• In Relish mutants, the Cecropin A gene was induced by the G(+) bacteria Micrococcus luteus and Staphylococcus aureus, but not by other G(+) or G(-) bacteria [1].
• Differential activation of the NF-kappaB-like factors Relish and Dif in Drosophila melanogaster by fungi and Gram-positive bacteria [1].
• PG extracted from M. luteus induced Cecropin A in Relish mutants, whereas PGs from the G(+) bacteria Bacillus megaterium and Bacillus subtilis did not, suggesting that the Drosophila immune system can distinguish PGs from various G(+) bacteria [1].
• The Rel/NF-kappa B transcription factor Relish performs a central role in the acute-phase response to microbial challenge by activating immune antibacterial peptides [2].
• Our data show that Drosophila IKK gamma is required for the Relish-dependent immune induction of the genes encoding antibacterial peptides and for resistance to infections by Escherichia coli [3].

High impact information on Rel

• A novel Rel-containing gene in Drosophila, Dif (dorsal-related immunity factor), provides a potential link between these seemingly disparate processes [4].
• Both depend on regulatory factors containing rel domains (dorsal and NF-kappa B) that are controlled at the level of nuclear transport [4].
• These results provide direct evidence for the role of phosphorylation in the in vivo regulation of a rel-like transcription factor [5].
• The dl protein recognizes a sequence motif similar to that of the mammalian transcriptional activator NF-kappa B, which was shown to contain extensive homology with dl and the oncoprotein rel [6].
• In response to infection, two Rel proteins, Dif and Dorsal, translocate from the cytoplasm to the nuclei of larval fat-body cells [7].

Biological context of Rel

• We have identified the first endogenous targets of the mbo nuclear import pathway in the Rel proteins Dorsal and Dif [8].
• These results illustrate how the formation of Rel protein dimers differentially regulate target gene expression [9].
• NF-kappaB/Rel family proteins regulate genes that are critical for many cellular processes including apoptosis, inflammation, immune response, and development [9].
• NF-kappaB/Rel proteins function as homodimers or heterodimers, which recognize specific DNA sequences within target promoters [9].
• Innate immunity and hematopoiesis are regulated by analogous Rel/NF-kappaB-family pathways in mammals [10].

Anatomical context of Rel

• We examined the activity of different Drosophila Rel-related proteins in modulating Drosophila immunity genes by expressing the Rel proteins in stably transfected cell lines [9].
• The lesswright mutation activates Rel-related proteins, leading to overproduction of larval hemocytes in Drosophila melanogaster [11].
• Here we show that mutants that lack the Drosophila Rel/NF-kappaB proteins Dorsal and Dif have very few blood cells, are constitutively infected by opportunistic microbes, and die from infection as larvae [12].
• 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 [13].
• In Drosophila, a coordinate interplay between the Rel transcription factor Dorsal and the basic Helix-Loop-Helix transcription factor Twist initiates mesoderm formation by activating the zygotic expression of mesoderm-determining genes [14].

Associations of Rel with chemical compounds

• We ask here whether parallel pathways might function in Drosophila by determining if Rel/NF-kappa B or AP-1 family members contribute to the steroid-triggered death of larval salivary glands during Drosophila metamorphosis [13].
• In Drosophila, lipopolysaccharide (LPS) signal-induced activation of the Rel/NF-kappaB family transcription factors is an essential step in the transcriptional activation of inducible antimicrobial peptide genes [15].
• Finally, an N-terminal serine-rich region in Relish and the PEST domain were found to negatively regulate Relish activation [16].
• Also within the Rel homology domain, there is a conserved consensus sequence (Arg-Arg-Pro-Ser) for phosphorylation by cyclic AMP-dependent protein kinase (PKA) [17].
• However, deletion constructs of the Factor C promoter harboring different numbers of dorsal-like binding sites upstream of the kappaB motif as well as the electrophoretic mobility shift assay of these motifs with Rel proteins strongly suggest that the up-regulation of Factor C gene expression is attenuated during microbial challenge [18].

Regulatory relationships of Rel

• The current model of immune activation in Drosophila melanogaster suggests that fungi and Gram-positive (G(+)) bacteria activate the Toll/Dif pathway and that Gram-negative (G(-)) bacteria activate the Imd/Relish pathway [1].
• Signaling by Drosophila Toll pathway activates two Rel/NF-kappaB transcription factors, Dorsal (Dl) and Dorsal-related immune factor (Dif) [19].
• This result suggests a functional redundancy between both Rel proteins in the control of drosomycin gene expression in the larvae of Drosophila [20].
• Like the Toll pathway, the IMD pathway regulates antimicrobial peptide gene expression via a Rel/nuclear factor (NF)-kappaB-like transcription factor [21].
• The interaction of Sp1 with NF-kappaB sites thus provides a means to keep an elevated basal expression of NF-kappaB-dependent genes in the absence of activated nuclear NF-kappaB/Rel [22].

Other interactions of Rel

• In addition, we find that the activated DmIKK complex, as well as recombinant DmIKKbeta, can phosphorylate Relish in vitro [23].
• Although the R1 motif was required for Rel protein-mediated CecA1 expression in cotransfection experiments, our data argue against it being a direct target for the Drosophila Rel proteins [24].
• Various fungi stimulated antimicrobial peptides through at least two different pathways requiring Relish and/or Dif [1].
• Induction of Attacin A by Geotrichum candidum required Relish, whereas activation by Beauvaria bassiana required Dif, suggesting that the Drosophila immune system can distinguish between at least these two fungi [1].
• Thus, a yet to be identified IkappaB kinase complex must be required for Rel protein activation via the Toll signaling pathway [23].

Analytical, diagnostic and therapeutic context of Rel

• PCR and Southern blot hybridization analyses show that these three transcripts originated from the same large inducible mRNA encoded by a single Relish gene [2].
• Molecular cloning and characterization of SRAM, a novel insect rel/ankyrin-family protein present in nuclei [25].
• A cDNA encoding a Rel/NF-kappaB homologue was cloned from a beetle, Allomyrina dichotoma, by reverse transcriptase-polymerase chain reactions (RT-PCR) taking advantage of the conserved Rel homology domain (RHD) to synthesize primers [26].
• However, in situ hybridization of rat tissues demonstrated more restricted expression of Rel-N1 mRNA within a subset of neurons of the hippocampus, cortex, and other regions of the gray matter, but not in glial cells or white matter [27].
• Electrophoretic mobility shift assay further confirmed a strong interaction of the limulus kappaB motif with Rel proteins [18].

References