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1471-2148-9-34.Pdf BMC Evolutionary Biology BioMed Central Research article Open Access Evolution of the multifaceted eukaryotic akirin gene family Daniel J Macqueen and Ian A Johnston* Address: Gatty Marine Laboratory, School of Biology, University of St Andrews, St Andrews, Fife, KY16 8LB, UK Email: Daniel J Macqueen - [email protected]; Ian A Johnston* - [email protected] * Corresponding author Published: 6 February 2009 Received: 12 September 2008 Accepted: 6 February 2009 BMC Evolutionary Biology 2009, 9:34 doi:10.1186/1471-2148-9-34 This article is available from: http://www.biomedcentral.com/1471-2148/9/34 © 2009 Macqueen and Johnston; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Akirins are nuclear proteins that form part of an innate immune response pathway conserved in Drosophila and mice. This studies aim was to characterise the evolution of akirin gene structure and protein function in the eukaryotes. Results: akirin genes are present throughout the metazoa and arose before the separation of animal, plant and fungi lineages. Using comprehensive phylogenetic analysis, coupled with comparisons of conserved synteny and genomic organisation, we show that the intron-exon structure of metazoan akirin genes was established prior to the bilateria and that a single proto- orthologue duplicated in the vertebrates, before the gnathostome-agnathan separation, producing akirin1 and akirin2. Phylogenetic analyses of seven vertebrate gene families with members in chromosomal proximity to both akirin1 and akirin2 were compatible with a common duplication event affecting the genomic neighbourhood of the akirin proto-orthologue. A further duplication of akirins occurred in the teleost lineage and was followed by lineage-specific patterns of paralogue loss. Remarkably, akirins have been independently characterised by five research groups under different aliases and a comparison of the available literature revealed diverse functions, generally in regulating gene expression. For example, akirin was characterised in arthropods as subolesin, an important growth factor and in Drosophila as bhringi, which has an essential myogenic role. In vertebrates, akirin1 was named mighty in mice and was shown to regulate myogenesis, whereas akirin2 was characterised as FBI1 in rats and promoted carcinogenesis, acting as a transcriptional repressor when bound to a 14-3-3 protein. Both vertebrate Akirins have evolved under comparably strict constraints of purifying selection, although a likelihood ratio test predicted that functional divergence has occurred between paralogues. Bayesian and maximum likelihood tests identified amino-acid positions where the rate of evolution had shifted significantly between paralogues. Interestingly, the highest scoring position was within a conserved, validated binding-site for 14-3-3 proteins. Conclusion: This work offers an evolutionary framework to facilitate future studies of eukaryotic akirins and provides insight into their multifaceted and conserved biochemical functions. Background rial infection [1]. Akirin was strictly localised to the Akirin is a recently discovered protein with an essential nucleus and acted in concert with Relish (a fly homologue function in the Drosophila melanogaster immune deficiency of the vertebrate NF-kB transcription factor) to induce the (Imd) pathway, which responds to gram-negative bacte- expression of a subset of downstream pathway compo- Page 1 of 20 (page number not for citation purposes) BMC Evolutionary Biology 2009, 9:34 http://www.biomedcentral.com/1471-2148/9/34 nents [1]. The knockdown of the fly akirin gene caused a binding IST protein 1 (FBI-1: NP_056982) and as with the lethal embryonic phenotype [1]. akirin is conserved in ver- name 'Mighty' [3] (i.e. akirin1), does not account for evo- tebrates as at least two genes that were named akirin1 and lutionary relationships within the gene family. akirin2 [1]. In mice, akirin2 functions in the toll-like recep- tor (TLR), tumour necrosis factor (TNF) and interleukin The origin of akirin predates the metazoan lineage (IL)-1β signalling pathways, again at the level of/down- An akirin proto-orthologue was not identified in the Bac- stream of NF-kB to induce the transcription of several terial or Archeal genomes examined, which either immune-response genes including the anti-inflammatory excludes a prokaryotic origin, or means that insufficient cytokine interleukin-6 (IL-6) [1]. The knockout of the phylogenetic signal remains to identify these ancient individual mammalian akirin copies produced distinct orthologues. The earliest eukaryotes in which an akirin phenotypes; whereas akirin1-/- mice had no obvious phe- gene was retrieved were the protist taxa Alveolata (in Guil- notype, ablation of the akirin2 gene was embryonic-lethal lardia theta) and Heterolobosea (in Naegleria gruberi) (fig. [1]. Thus, seemingly, the role of invertebrate akirin in 1). The Alveolata and the Euglenozoa (which are phyloge- embryonic development and the innate immune netically closely related to the Heterolobosea, [4]) are response is most strongly conserved in akirin2 and akirin1 thought to have arisen close to 2 billion years ago [5]. This may have diverged in function [1]. While it is clear that places an origin for akirin prior to the split of animal/ vertebrate akirin 1 and 2 are closely related, it is unknown plant/fungi lineages. However, an akirin gene was not whether they form part of a larger gene family related by identified in any plant or fungal genome as previously gene duplication. Further, the exact origin and evolution- noted [1], although it was represented in the Amoebozoa ary relationships of akirin1 and akirin2 are not estab- (in Dictyostelium discoideum) and the choanoflagellate lished. Monosiga brevicollis (fig. 1), which branches as the closest known outgroup to metazoans [6]. The presence of an aki- In this paper we provide a detailed examination of the rin gene was an exception rather than a rule in non-animal evolution of the akirin gene family in eukaryotes. Using an eukaryotic genomes. This is consistent with the independ- exhaustive computational screen including non-model ent non-functionalization of akirin in many eukaryotic species, we show that a single akirin proto-orthologue is lineages, before it obtained a fundamental function in the highly conserved across invertebrate metazoans in terms metazoans. of genomic organisation and coding features and identify orthologues in several more basal eukaryotes. Robust phy- Genomic organisation of eukaryotic akirins logenetic analysis revealed that akirin duplicated in a com- In D. discoideum and N. gruberi, akirin comprises a single mon chordate ancestor before the separation of jawed and exon, whereas M. brevicollis has conserved a 3-exon gene jawless vertebrate lineages. We show that akirin genes (fig. 2a). Choanoflagellates are the closest known living have been characterised independently on several occa- relatives to metazoans and its genes are comparably rich sions, and suggest that a single, simple nomenclature sys- in intronic sequences [6]. Thus, relative to these more tem is employed in future studies. By bringing together basal eukaryotes, it might be expected that certain features the available akirin literature and examining the divergent of the M. brevicollis akirin proto-orthologue would be con- molecular evolution of Akirin1 and 2 coding sequences, served with animal akirins. While the two exon-exon we provide significant insight into the multiple functions boundaries of the choanoflagellate gene are not conserved of this small gene family. A common feature of Akirins is with any metazoans (not shown), a string of 4 codons to regulate gene transcription in several characterised sig- (ATG-GCC-TGC-GCG) 38 nucleotides into the second nalling pathways, seemingly through interactions with exon code the signature residues Met-Ala-Cys-Ala, con- intermediary factors such as 14-3-3 proteins. served at the start region of all invertebrate metazoan Aki- rins (fig. 2a). Additionally, in close downstream Results and Discussion proximity to this motif, a nuclear localization signal akirin nomenclature (NLS) (Pro-Val-Lys-Arg-Arg) is present (fig. 2a), which is Future studies of akirin genes would benefit from a com- conserved in metazoan sequences. These findings suggest mon nomenclature system to aid the dissemination of that the metazoan akirin1/2 coding sequence was derived results between different research groups. Of the current from exons 2 and 3 of a single gene in a common ancestor names utilised, we suggest that the naming system to metazoans and choanoflagellates. employed by Goto et al. [1] is used in future submissions, since it is derived from the most detailed functional anal- A comparison of the genomic organisation of metazoan ysis and suitably describes the evolutionary relationships akirins provides insight into their evolutionary heritage of different orthologues and paralogues. The designation (fig. 2). In all vertebrate species examined (mouse and 'FBI1' [2] (i.e. for akirin2) is also founded on important zebrafish shown), akirin1 and akirin2 are organized as 5 functional data, but is very similar to a gene named factor exons of comparable size and 4 more variable introns (fig. Page
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