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Immunology

Cascade into clarity

Immune mediator molecules such as antimicrobial peptides are crucial for host responses to pathogens. Akirins are the latest identified components of a signalling cascade that leads to these responses in insects and mice.

The availability of powerful genetic tools to study the fruitfly Drosophila melanogaster, and the striking similarities of this insect's immune system to that of mammals, makes Drosophila a valuable organism for researchers interested in innate (nonspecific) immune responses. Indeed, among other advances, the discovery of Toll-like receptors, which are essential mediators of innate immunity in mammals, came about through studies in Drosophila. Reporting in Nature Immunology, Goto et al.1 have used this insect to identify another essential player in the innate immune system that is structurally highly conserved in mammals. This gene, which the authors named Akirin — after the Japanese phrase 'akiraka ni suru', which means 'making things clear' — encodes a nuclear protein that affects the transcription of genes regulated by the transcription factor known as NF-κB, which is found in almost all animal cells.

When an organism suffers a microbial infection, its immune system rapidly mounts a defence characterized by the production of large amounts of cytokines and antimicrobial peptides. This innate response is mediated by pattern-recognition receptors, including Toll-like receptors, that detect evolutionarily conserved structures, such as peptidoglycan subunits, associated with pathogens.

In Drosophila, two main pathways lead to the production of antimicrobial peptides: the Toll pathway and the immune deficiency (Imd) pathway. The Toll pathway responds to Gram-positive bacteria and fungal pathogens2,3, whereas the Imd pathway, in which Akirin plays a crucial part, is turned on in response to infections with Gram-negative bacteria4,5,6.

The Imd signalling cascade culminates in the activation of Relish, an NF-κB-like transcription factor7 (Fig. 1a). Initially, the binding of peptidoglycan subunits of Gram-negative bacteria to the Drosophila peptidoglycan-recognition proteins PGRP-LC and PGRP-LE activates the Imd protein. Active Imd recruits the 'death-related proteins' Fadd and Dredd, which in turn activate a complex of TAK1 and TAB2 proteins. Further down the pathway, two enzymes, IRD5 (the homologue of mammalian IKK-β, which is involved in NF-κB activation) and Kenny (the homologue of mammalian IKK-γ), are activated. These enzymes add a phosphate group to Relish, thus marking it for cleavage. Relish then moves to the nucleus, where it drives the transcription of genes encoding antimicrobial peptides.

Figure 1: Role of Akirin proteins in producing immune mediators following microbial infection.
figure1

a, In Drosophila, peptidoglycan components of Gram-negative bacteria activate the Imd pathway, which results in the movement of Relish (an NF-κB-like transcription factor) to the nucleus. Relish then mediates transcription of genes that encode antimicrobial peptides. Goto et al.1 identify Akirin, a nuclear factor that acts late in this signalling cascade and is required for Relish-mediated gene transcription. b, In mammals, the activation of the TNF receptor 1 (TNFR-1), Toll-like receptor (TLR) or interleukin-1 receptor (IL-1R) turns on a signalling cascade that results in movement of NF-κB to the nucleus and activation of gene transcription. The authors find that, in mice, a structurally highly conserved homologue of Drosophila Akirin, Akirin2, is required for NF-κB-mediated gene transcription.

Goto and colleagues1 now show that this story is incomplete. Using the technique of RNA interference in Drosophila S2 cells, they show that, in response to infection with Gram-negative bacteria, Akirin is required for the expression of the antimicrobial peptide Attacin, which is an essential end-product of the Imd pathway. This observation is unexpected because, apart from a nuclear-localization signal, Akirin has none of the identifiable structural domains characteristic of signalling molecules.

The authors then used genetic-interaction studies to show that Akirin functions downstream of, or at the same level as, Relish (Fig. 1a). Moreover, they found that Akirin deficiency does not affect the Toll pathway, suggesting that this protein is involved in the production of antimicrobial peptides only through the Imd pathway. Consistent with these in vitro findings, reducing Akirin levels in live flies using RNA interference increased the flies' susceptibility to infection with Gram-negative bacteria. These findings clearly establish Akirin's role in the Imd signalling pathway. But this protein probably has other functions too. Goto et al. show that mutant flies lacking the Akirin gene are not viable, implying a crucial role in Drosophila embryonic development.

Does Akirin have a similar function in mammals? In looking at this question, the authors find that structurally highly conserved Akirin is present in mice as two homologues (Akirin1 and Akirin2). To investigate the function of mammalian Akirins, they generated mice deficient in either Akirin1 or Akirin2. Neither Akirin1-deficient mice nor cells derived from these animals have any obvious unusual characteristics. However, the function of Akirin1 could be hidden through functional redundancy in the presence of Akirin2, a point that requires further investigation.

Like Akirin in Drosophila, Akirin2 is required for embryonic development, and Goto et al. found that mice lacking this gene die by embryonic day 9.5. Fibroblast cells derived from Akirin2-deficient mouse embryos showed selective defects in NF-κB-dependent gene expression following stimulation through pathways involving the Toll-like receptor, interleukin-1 receptor or TNF receptor. All of these pathways converge on the activation of the mammalian TAB2–TAK1 complex, which in turn activates the IKK complex. Through phosphorylation, the active IKK complex causes the degradation of the NF-κB inhibitor Iκ-B, allowing NF-κB to enter the nucleus (Fig. 1b). The authors postulate that, like Drosophila Akirin, which acts downstream of Relish, Akirin2 functions downstream of NF-κB.

How do Akirins regulate gene transcription in the nucleus? Although preliminary studies failed to show a direct interaction of Akirins with DNA or with Relish, it is possible that they interact with an intermediary molecule that then engages with DNA and/or Relish, or is otherwise involved in transcription. It is also likely that Akirins are involved in regulating transcription factors other than NF-κB. The fact that Akirin is a potential modulator of the Wnt–Wingless developmental pathway in Drosophila8 suggests that it might regulate the associated β-catenin transcription factor. Similarly, Akirin could be involved in regulating the GATA transcription factor, as it interacts with the GATA-related protein pannier, which is essential for thorax development in Drosophila9.

A clear picture emerges: the functions of Akirins probably extend beyond the immune system, as do those of many other genes involved in immunity, and which also have roles in development. The toll gene, for example, which is essential for innate immune responses in Drosophila, was first identified as a developmental gene. So the results of Goto et al. have opened avenues of research that not only may help to unravel the complexities of the inflammatory signalling pathway in which Akirins function, but also may aid our understanding of the function of these molecules in embryonic development.

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Sutterwala, F., Flavell, R. Cascade into clarity. Nature 451, 254–255 (2008). https://doi.org/10.1038/451254a

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