Akirins are highly conserved nuclear proteins required for NF-κB-dependent gene expression in drosophila and mice

Abstract

During a genome-wide RNAi screen, we isolated CG8580 as a gene involved in the innate immune response of Drosophila. CG8580, which we named Akirin, acts in parallel with the NF-κB transcription factor downstream of the Imd pathway and was required for defense against Gram-negative bacteria. Akirin is highly conserved and the human genome contains two homologues, one of which was able to rescue the loss of function phenotype in Drosophila cells. Akirins had a strict nuclear localization. Knockout of both Akirin homologues in mice revealed that one had an essential function downstream of Toll-like receptor, tumor necrosis factor and interleukin 1-β (IL-1β) signaling pathways leading to the production of IL-6. Thus, Akirin is a conserved nuclear factor required for innate immune responses.The innate immune system shields all metazoans against invading microorganisms. This well conserved defense mechanism relies on host-pathogen interactions between nonclonally distributed pattern recognition receptors in the host and pathogen-associated molecular patterns in microbes (reviewed in1-4). In contrast, the acquired immune system, based on selection of lymphocytes and their antigen-specific receptors, is specific to vertebrates. Drosophila has become an attractive model organism for the study of the innate immune system due to its well-established genetics, the absence of an acquired immune system and the striking conservation between its immune system and many mammalian Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to J-MR (e-mail: JM.Reichhart@ibmc.u-strasbg.fr). 4 current address, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki Aoba-ku, Sendai, 980-8578, Japan 5 AG and KM contributed equally to this work. AUTHOR CONTRIBUTIONS A.G., V.G., L.E.-C., and D.K. did the Drosophila experiments. K.M. and O.T. did the mouse experiments. S.A., M.B., O.T. and JM.R. conceived and directed the experiments, A.G., O.T., JA.H. and JM.R. wrote the paper. All authors contributed to manuscript criticism. Despite more than ten years of research since the initial discovery of the Imd mutation, the pathway that took its name is still not fully understood. We undertook a functional genome- (Fig. 1). The conservation is highest for the putative C and N-terminal domains. All sequences show a clear nuclear localization signal (NLS) located between residues 24 and 29 at the N-terminus ( Supplementary Fig. 1 online). We renamed the gene Akirin (Akirin1 and Akirin2 in the case of vertebrates) from the japanese `akiraka ni suru', which means `making things clear'. HHS Public Access RESULTS Identification of Drosophila and mice Akirin homologues Akirins are ubiquitously expressed nuclear proteinsMicroarray data in Flybase35 indicate that DmAkirin expression is ubiquitous. Similarly, an an...

Negative Feedback Regulation of NF-κB Action by CITED2 in the Nucleus

“…For example, p300/CBP is an essential coactivator for NF-kB, which simultaneously serves as a scaffold protein for the NF-kB enhanceosome and catalyzes the acetylation of p65 (22). In addition, the nuclear proteins UXT (21), CARM1 (40), protein kinase C bΙΙ (41), Akirin2 (20), and so on are essential for NF-kB to induce a subset of target genes.…”

“…Some proteins have been shown to play dual roles in development and immunity (20,33). As CITED2 is essential for development, we wondered if it could play a role in immunity.…”

“…For example, Akirin2 (20) and UXT (21) were recently demonstrated to function as essential coactivators in the NF-kB enhanceosome. Importantly, the transcriptional coactivator p300/CBP not only serves as a scaffold for the NF-kB enhanceosome but also directly acetylates both p65 and histones simultaneously (22).…”

NF-κB in Renal Inflammation

“…8 The newly described nuclear protein Akirin-2 binds to nuclear NF-B complexes and is required for the transcription of a subset of NF-B-dependent genes such as IL-6, CXCL10, and CCL5. 26 The dynamics of classical NF-B activation influence gene transcription. 27 Waves of NF-B activity encode temporal molecular profiles with distinct functions.…”

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“…, Dif 1 , Cg-Gal4, and YP1-Gal4 constructs have been previously described (17,21,25 . Septic injury was carried out by puncturing the animals with a sharp tungsten needle that had been dipped in bacteria.…”