NF-κB and Akirin protein interactions

NF-kB: Akirin

NF-kB Akirin: A "Novel Nuclear Factor"

Statement of Topic Significance

Genetic engineering and experimentation hold enormous promise for eradicating many of the diseases that currently plague mankind, and researchers may even be able extend the human lifespan to unprecedented levels in the future. More importantly, perhaps, ongoing research into the human innate immune systems also suggests that such increased lifespans will be healthier and devoid of many of the physical and cognitive problems that currently go hand in hand with the aging process. In the tradition of "standing on the shoulders of giants," scientists today continue to expanding the ever-growing body of knowledge using newly discovered methods and tools that promise to yield these important research outcomes and one such tool has been the recent discovery of protein, which has been termed "Akirin." This paper provides a review of the relevant literature to determine what current scientific researchers have found concerning Akirins and what future potential this nuclear factor holds for improving the human condition. An overview of the literature review approach is followed by an analysis and critique of a series of recent articles concerning Akirins, followed by a summary of key findings.

Overview of Literature Review

Because the most recent research concerning NF-kB: Akirin has not had time to find its way into the peer-reviewed and scholarly literature, the study relies on comparable online resources from reputable providers. These recent resources are reviewed for content and relevance and are critiqued below.

Review and Analysis

Akirins vs. infection" by Buetler and Moresco (2008). In this recent study, Beutler and Moresco provide a useful description of the mechanisms involved in using Akirins proteins in various genetic experiments. These authors also note that the term, "Akirins," is taken from the Japanese akiraka ni suru, which means "making things clear"; they also note that Akirins.".. do indeed make things clear (or at least clearer) while raising new questions at the same time" (Beutler & Moresco, p. 7). Some of the new questions that have emerged since the discovery of the Akirins nuclear factor involve how different species react to various deprivations of genetic material to determine if an analogous response could be expected in humans in an effort to identify culprits for human diseases and potential cures. Therefore, by identifying species that posses the same genetic "stuff" at the nuclear level, scientists can conduct experiments that were simply not possible even in recent years. In this regard, the authors report, "This so-called 'Akirin' gene provides a wonderful example of what genetics can do. The function of the protein it encodes could never have been guessed from its predicted domain structure and, as far as is known, could not have been found by any but a forward genetic approach" (p. 7).

Today, though, researchers have been able to use these proteins to investigate a wide range of "what-if" type scenarios using various animals and insects as test subjects. As Beutler and Moresco point out, "Over 20 years have passed since the discovery of NF-?B and its signaling pathways, yet additional participants continue to be identified. The highly conserved protein Akirin is such an example" (p. 7). The Akirins are useful in helping researchers better understand the role various genes in the etiology of various disease process. In this regard, Beutler and Moresco report, "Among the Akirin2- and NF-?B-dependent genes are those encoding the inflammatory chemokines RANTES, IP-10 and IL-6 and the proto-oncogene Bcl3, and some are affected more severely than others"; they also caution, though, that there are a number of other factors involved that must be taken into account: "Of course, most of these genes are dependent on more types of signaling input than NF-?B alone" (Beutler & Moresco, p. 8). The authors provide a number of graphics to help illustrate the fundamental biological processes involved at the nuclear level and cite eight peer-reviewed journal articles, including the by Goto et al. (2008) which they suggest will be cited as the demarcation point in genetic research by future scientists as background and in support of their findings.

The authors also sprinkle their report with definite statements of what has been established by other researchers together with a sufficient number of provisos concerning the need for additional research in various areas as well. They clearly state what is known and unknown throughout their study (i.e., "It is certain that drosophila Akirin, and Akirin2 in vertebrates, do more than assist in the function of NF-?B. The lethality resulting from gene knockout alone indicates that this is the case, more so because not all NF-?B dependent genes seem Akirin2 dependent," p. 9), but the authors are not reluctant to posit potential explanations and interpretations of these findings either. For example, a representative sampling of commentary by Beutler and Moresco in this regard includes: (a) Activation of TNF receptor 1 (TNFR1), the IL-1R or Toll-like receptor by their cognate ligands leads to signaling that ultimately impinges on NF-?B. The pathways converge on the TAB2-TAK1 complex, which probably interacts with the NF-?B modulator IKK?; and (b) "How it contributes to the regulation of such genes is unknown but may involve DNA-binding or chromatin-remodeling proteins" (emphasis added) (pp. 8, 9). The several strengths of this study included its timeliness, the number of recent peer-reviewed sources cited (seven within the last three years), the fact that the authors provided clear explanations of what has been scientifically determined together with what remains unknown, and their use of colorful graphics to help illustrate the complex process they are describing.

Akirins clarify NF-B signaling" by Gough (2008, January). This article reviews the preceding study by Beutler and Moresco and cite the study by Goto et al. (2008) that performed a genome-wide RNA interference (RNAi) screen in cultured Drosophila S2 cells for those genes required for NF-B-dependent gene expression. Goto and his colleagues determined that the gene CG8580 (which these researchers termed "Akirin" for the reasons noted above), can be used for genetic research using Drosophila to identify analogous responses in humans. The author also provides a useful explanation of all how the different types of Akirin genes in Drosophila require the use of Akirin 2 for such research. By and large, this article is a recapitulation and summary of the recent research but does not add much of anything further beyond that except the observation that, "These results suggest that in mice, as in the fly, Akirin2 acts at the same level as NF-B, and it will be interesting to see whether these two proteins form a complex, as has been recently reported for ribosomal protein S3 and NF-B" (p. 6).

Shared principles in NF-?B signaling" Hayden and Ghosh (2008, February). Following a brief introduction concerning recent studies and a "shoulder of giants" reference, Hayden and Ghosh cite the growing interest in and use of various techniques to further research into the key principles governing NF-?B signaling. These authors emphasize that researchers from a number of disciplines are interested in this research because these findings are important in understanding how humans respond at the cellular levels in response to various environmental, mechanical, chemical, and microbiological stresses. According to Hayden and Ghosh, "The inducible regulation of gene expression is a central element of normal physiology and is the key to the ability of multicellular organisms Owing to its amenability to experimentation and its importance in disease, NF-?B has served as a model of cell, tissue, and organism level responses that are orchestrated through inducible transcription factors" (p. 344).

One of the best features of this review of the recent relevant literature concerns the authors' careful explanation of the underlying physiological process fulfilled by NF-?B and how researchers have used this information in an effort to determine how molecules regulate signaling to NF-?B in all pathways and how discrete inputs provide customized transcriptional responses to particular tissues and organs with the same limited set of regulators. The authors also incorporate a number of useful original graphics to illustrate these concepts (e.g., an illustration of the NF-?B Signaling Pathways, the members of the NF-?B, I-B, and IKK protein families, a putative model for IKK Activation, and regulation of NF-?B transcriptional activity). The strengths of this study included the use of these graphics as well as the comprehensive nature of their review of the literature that provided a valuable compilation of the research to date (171 peer-reviewed studies!) and there were no discernible weaknesses.

Innate immunity: NF-B is not alone" by Marta Tufet (2008). In this brief account of a recent experiment using knockout mice using Akirin-1 and Akirin-2, the author According to Tufet, "Akirin is a novel nuclear factor that functions in parallel with NF-B to regulate innate immune responses in mice and flies" (p. 1). The Akirin protein is also a needed component for innate immune responses, Tufet advises, and the Akirin nuclear factor is also highly conserved in mice and flies thereby making it highly useful in genetic experimentation involving potential analogous responses in humans. In this regard, Tufet advises, "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" (pp. 1-2). Based on previous research that found that Akirin proteins were ubiquitous in flies and humans and strictly nuclear, Tufet sought to determine if the Akirin homologues had a similar function in mice. While the experiment using Akirin-1 failed to produce any meaningful results, the tests using Akirin-2 showed that it acts in tandem with or downstream of NF-B in the regulation of TLR- and IL-1-inducible gene expression (Tufet).