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Akirin is a novel nuclear factor that functions in parallel with NF-
B to regulate innate immune responses in mice and flies.
A new nuclear factor has been discovered that is required for innate immune responses and is highly conserved in mice and flies. The new molecule, Akirin, functions in parallel with the transcription factor NF-B (nuclear factor-B) downstream of the immune deficiency (IMD) pathway in Drosophila melanogaster, and has an essential role downstream of the Toll-like receptor (TLR), tumour-necrosis factor (TNF) and interleukin-1
(IL-1) signalling pathways that lead to the production of IL-6 in mice.
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Following immune challenge, D. melanogaster generates antimicrobial peptides as a defence response. The transcription of genes that encode these peptides is mediated by two pathways, the Toll pathway (which has parallels with the mammalian TLR signalling pathways) and the IMD pathway (which has similarities with the mammalian TNF signalling pathway). To identify new components of the IMD pathway, the authors carried out a high-throughput genome-wide RNAi screen of D. melanogaster and identified Akirin, which was found to have two highly conserved homologues in mammals (Akirin-1 and Akirin-2).
Expression of Akirin proteins was shown to be ubiquitous in flies and humans, and strictly nuclear. Further analysis in vitro and in vivo revealed that Akirin is involved in the IMD pathway but not in the Toll pathway. More specifically Akirin was shown to function downstream of IMD and, in keeping with its nuclear localization, downstream of or at the same level as Relish (a member of the NF-B family).
In view of these results, could the Akirin homologues have a similar function in mice? Akirin-1-knockout mice developed with no obvious phenotype, but Akirin-2 was shown to be essential for embryogenesis. In response to stimulation with TLR ligands, IL-1 or TNF, Akirin-1-deficient mouse embryonic fibroblasts (MEFs) produced similar amounts of IL-6 to their wild-type counterparts. By contrast, Akirin-2-deficient MEFs produced significantly lower amounts of IL-6 in response to the same stimuli. Further analysis showed that Akirin-2 was crucial for the regulation of only a specific set of lipopolysaccharide (LPS)- and IL-1-inducible genes. The degradation of IB
(inhibitor of NF-B ) and the DNA-binding activity of NF-B after stimulation with IL-1 and LPS were not affected in Akirin-2-deficient cells, indicating that, similar to D. melanogaster Akirin, Akirin-2 acts in parallel with or downstream of NF-B in the regulation of TLR- and IL-1-inducible gene expression.
This study has identified a previously unknown nuclear factor that, together with or downstream of NF-B, can regulate innate immune responses. Further studies will be needed to determine precisely how Akirin proteins control gene expression.
Marta Tufet
B-dependent gene expression in Drosophila and mice. Nature Immunol. 9, 97–104 (2008) | Article | PubMed |
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