The Subolesin/Akirin constitutes a good model for the study of functional evolution because these proteins have been conserved throughout the metazoan and play a role in the regulation of different biological processes. Here, we investigated the evolutionary history of Subolesin/Akirin with recent results on their structure, protein-protein interactions and function in different species to provide insights into the functional evolution of these regulatory proteins, and their potential as vaccine antigens for the control of ectoparasite infestations and pathogen infection. The results suggest that Subolesin/Akirin evolved conserving not only its sequence and structure, but also its function and role in cell interactome and regulome in response to pathogen infection and other biological processes. This functional conservation provides a platform for further characterization of the function of these regulatory proteins, and how their evolution can meet species-specific demands. Furthermore, the conserved functional evolution of Subolesin/Akirin correlates with the protective capacity shown by these proteins in vaccine formulations for the control of different arthropod and pathogen species. These results encourage further research to characterize the structure and function of these proteins, and to develop new vaccine formulations by combining Subolesin/Akirin with interacting proteins for the control of multiple ectoparasite infestations and pathogen infection.

Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State University Stillwater OK United States

Department of Virology Veterinary Research Institute Brno Czechia

Facultad de Veterinaria Universidad de Zaragoza Zaragoza Spain

Faculty of Science University of South Bohemia České Budějovice Czechia

Institute of Parasitology Biology Centre Czech Academy of Sciences České Budějovice Czechia

SaBio Instituto de Investigación en Recursos Cinegéticos Ciudad Real Spain

UMR BIPAR INRA ANSES Ecole Nationale Vétérinaire d'Alfort Université Paris Est Paris France

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Adipietro K. A., Mainland J. D., Matsunami H. (2012). Functional evolution of mammalian odorant receptors. PLoS Genet. 8:e1002821. 10.1371/journal.pgen.1002821 PubMed DOI PMC

Almazán C., Blas-Machado U., Kocan K. M., Yoshioka J. H., Blouin E. F., Mangold A. J., et al. (2005). Characterization of three Ixodes scapularis cDNAs protective against tick infestations. Vaccine 23 4403–4416. 10.1016/j.vaccine.2005.04.012 PubMed DOI

Almazán C., Kocan K. M., Bergman D. K., Garcia-Garcia J. C., Blouin E. F., de la Fuente J. (2003). Identification of protective antigens for the control of Ixodes scapularis infestations using cDNA expression library immunization. Vaccine 21 1492–1501. 10.1016/S0264-410X(02)00683-7 PubMed DOI

Almazán C., Lagunes R., Villar M., Canales M., Rosario-Cruz R., Jongejan F., et al. (2010). Identification and characterization of Rhipicephalus (Boophilus) microplus candidate protective antigens for the control of cattle tick infestations. Parasitol. Res. 106 471–479. 10.1007/s00436-009-1689-1 PubMed DOI PMC

Almazán C., Moreno-Cantú O., Moreno-Cid J. A., Galindo R. C., Canales M., Villar M., et al. (2012). Control of tick infestations in cattle vaccinated with bacterial membranes containing surface-exposed tick protective antigens. Vaccine 30 265–272. 10.1016/j.vaccine.2011.10.102 PubMed DOI

Andersson S. G., Kurland C. G. (1998). Reductive evolution of resident genomes. Trends Microbiol. 6 263–268. 10.1016/S0966-842X(98)01312-2 PubMed DOI

Antunes S., Merino O., Mosqueda J., Moreno-Cid J. A., Bell-Sakyi L., Fragkoudis R., et al. (2014). Tick capillary feeding for the study of proteins involved in tick-pathogen interactions as potential antigens for the control of tick infestation and pathogen infection. Parasit. Vectors 7:42. 10.1186/1756-3305-7-42 PubMed DOI PMC

Ayllón N., Villar M., Galindo R. C., Kocan K. M., Šíma R., López J. A., et al. (2015). Systems biology of tissue-specific response to Anaplasma phagocytophilum reveals differentiated apoptosis in the tick vector Ixodes scapularis. PLoS Genet. 11:e1005120. 10.1371/journal.pgen.1005120 PubMed DOI PMC

Bensaci M., Bhattacharya D., Clark R., Hu L. T. (2012). Oral vaccination with Vaccinia virus expressing the tick antigen subolesin inhibits tick feeding and transmission of Borrelia burgdorferi. Vaccine 30 6040–6046. 10.1016/j.vaccine.2012.07.053 PubMed DOI PMC

Beutler B., Moresco E. M. (2008). Akirins versus infection. Nat. Immunol. 9 7–9. 10.1038/ni0108-7 PubMed DOI

Bonnay F., Nguyen X. H., Cohen-Berros E., Troxler L., Batsche E., Camonis J., et al. (2014). Akirin specifies NF-κB selectivity of Drosophila innate immune response via chromatin remodeling. EMBO J. 33 2349–2362. 10.15252/embj.201488456 PubMed DOI PMC

Brown C. J., Johnson A. K., Dunker A. K., Daughdrill G. W. (2011). Evolution and disorder. Curr. Opin. Struct. Biol. 21 441–446. 10.1016/j.sbi.2011.02.005 PubMed DOI PMC

Busby A. T., Ayllón N., Kocan K. M., Blouin E. F., de la Fuente G., Galindo R. C., et al. (2012). Expression of heat-shock proteins and subolesin affects stress responses, Anaplasma phagocytophilum infection and questing behavior in the tick, Ixodes scapularis. Med. Vet. Entomol. 26 92–102. 10.1111/j.1365-2915.2011.00973.x PubMed DOI

Canales M., Naranjo V., Almazán C., Molina R., Tsuruta S. A., Szabó M. P. J., et al. (2009). Conservation and immunogenicity of the mosquito ortholog of the tick protective antigen, subolesin. Parasitol. Res. 105 97–111. 10.1007/s00436-009-1368-2 PubMed DOI

Carpio Y., Basabe L., Acosta J., Rodríguez A., Mendoza A., Lisperger A., et al. (2011). Novel gene isolated from Caligus rogercresseyi: a promising target for vaccine development against sea lice. Vaccine 29 2810–2820. 10.1016/j.vaccine.2011.01.109 PubMed DOI

Carpio Y., García C., Pons T., Haussmann D., Rodríguez-Ramos T., Basabe L., et al. (2013). Akirins in sea lice: first steps toward a deeper understanding. Exp. Parasitol. 135 188–199. 10.1016/j.exppara.2013.06.018 PubMed DOI

Carreón D., Pérez de la Lastra J. M., Almazán C., Canales M., Ruiz-Fons F., Boadella M., et al. (2012). Vaccination with BM86, subolesin and akirin protective antigens for the control of tick infestations in white tailed deer and red deer. Vaccine 30 273–279. 10.1016/j.vaccine.2011.10.099 PubMed DOI

Clemons A. M., Brockway H. M., Yin Y., Kasinathan B., Butterfield Y. S., Jones S. J., et al. (2013). Akirin is required for diakinesis bivalent structure and synaptonemal complex disassembly at meiotic prophase I. Mol. Biol. Cell. 24 1053–1067. 10.1091/mbc.E12-11-0841 PubMed DOI PMC

Contreras M., de la Fuente J. (2016a). Control of Ixodes ricinus and Dermacentor reticulatus tick infestations in rabbits vaccinated with the Q38 Subolesin/Akirin chimera. Vaccine 34 3010–3013. 10.1016/j.vaccine.2016.04.092 PubMed DOI

Contreras M., de la Fuente J. (2016b). Vaccinomics approach to the development of vaccines for the control of multiple ectoparasite infestations. Nova Acta Leopold. 411 185–200. 10.1186/1471-2164-12-105 PubMed DOI PMC

Contreras M., Moreno-Cid J. A., Domingos A., Canales M., Díez-Delgado I., Pérez de la Lastra J. M., et al. (2015). Bacterial membranes enhance the immunogenicity and protective capacity of the surface exposed tick Subolesin-Anaplasma marginale MSP1a chimeric antigen. Ticks Tick Borne Dis. 6 820–828. 10.1016/j.ttbdis.2015.07.010 PubMed DOI

da Costa M., Pinheiro-Silva R., Antunes S., Moreno-Cid J. A., Villar M., de la Fuente J., et al. (2014). Mosquito Akirin as a potential antigen for malaria control. Malar. J. 13:470. 10.1186/1475-2875-13-470 PubMed DOI PMC

DasGupta R., Kaykas A., Moon R. T., Perrimon N. (2005). Functional genomic analysis of the Wnt-wingless signaling pathway. Science 308 826–833. 10.1126/science.1109374 PubMed DOI

de la Fuente J. (2018). Controlling ticks and tick-borne diseases…looking forward. Ticks Tick Borne Dis. 9 1354–1357. 10.1016/j.ttbdis.2018.04.001 PubMed DOI

de la Fuente J., Almazaìn C., Blas-Machado U., Naranjo V., Mangold A. J., Blouin E. F., et al. (2006a). The tick protective antigen, 4D8, is a conserved protein involved in modulation of tick blood ingestion and reproduction. Vaccine 24 4082–4095. PubMed

de la Fuente J., Almazán C., Blouin E. F., Naranjo V., Kocan K. M. (2006b). Reduction of tick infections with Anaplasma marginale and A. phagocytophilum by targeting the tick protective antigen subolesin. Parasitol. Res. 100 85–91. PubMed

de la Fuente J., Antunes S., Bonnet S., Cabezas-Cruz A., Domingos A., Estrada-Peña A., et al. (2017a). Tick-pathogen interactions and vector competence: identification of molecular drivers for tick-borne diseases. Front. Cell. Infect. Microbiol. 7:114. 10.3389/fcimb.2017.00114 PubMed DOI PMC

de la Fuente J., Contreras M., Estrada-Peña A., Cabezas-Cruz A. (2017b). Targeting a global health problem: vaccine design and challenges for the control of tick-borne diseases. Vaccine 35 5089–5094. 10.1016/j.vaccine.2017.07.097 PubMed DOI

de la Fuente J., Contreras M. (2015). Tick vaccines: current status and future directions. Expert Rev. Vaccines 14 1367–1376. 10.1586/14760584.2015.1076339 PubMed DOI

de la Fuente J., Kocan K. M. (2006). Strategies for development of vaccines for control of ixodid tick species. Parasite Immunol. 28 275–283. 10.1111/j.1365-3024.2006.00828.x PubMed DOI

de la Fuente J., Kocan K. M. (2014). “Development of vaccines for control of tick infestations and interruption of pathogen transmission,” in Biology of Ticks, 2nd Edn, eds Sonenshine D. E., Roe R. M. (New York, NY: Oxford University Press; ), 333–352.

de la Fuente J., Manzano-Roman R., Naranjo V., Kocan K. M., Zivkovic Z., Blouin E. F., et al. (2010). Identification of protective antigens by RNA interference for control of the lone star tick, Amblyomma americanum. Vaccine 28 1786–1795. 10.1016/j.vaccine.2009.12.007 PubMed DOI

de la Fuente J., Maritz-Olivier C., Naranjo V., Ayoubi P., Nijhof A. M., Almazán C., et al. (2008). Evidence of the role of tick subolesin in gene expression. BMC Genomics 9:372. 10.1186/1471-2164-9-372 PubMed DOI PMC

de la Fuente J., Moreno-Cid J. A., Canales M., Villar M., Pérez de la Lastra J. M., Kocan K. M., et al. (2011). Targeting arthropod subolesin/akirin for the development of a universal vaccine for control of vector infestations and pathogen transmission. Vet. Parasitol. 181 17–22. 10.1016/j.vetpar.2011.04.018 PubMed DOI

de la Fuente J., Moreno-Cid J. A., Galindo R. C., Almazán C., Kocan K. M., Merino O., et al. (2013). Subolesin/Akirin vaccines for the control of arthropod vectors and vector-borne pathogens. Transbound. Emerg. Dis. 60(Suppl. 2), 172–178. 10.1111/tbed.12146 PubMed DOI

de la Fuente J., Villar M., Cabezas-Cruz A., Estrada-Peña A., Ayllón N., Alberdi P. (2016). Tick-host-pathogen interactions: conflict and cooperation. PLoS Pathog. 12:e1005488. 10.1371/journal.ppat.1005488 PubMed DOI PMC

Dingwall C., Robbins J., Dilworth S. M., Roberts B., Richardson W. D. (1988). The nucleoplasmin nuclear location sequence is larger and more complex than that of SV-40 large T antigen. J. Cell Biol. 107 841–849. 10.1083/jcb.107.3.841 PubMed DOI PMC

Driscoll T. P., Verhoeve V. I., Guillotte M. L., Lehman S. S., Rennoll S. A., Beier-Sexton M., et al. (2017). Wholly Rickettsia! Reconstructed metabolic profile of the quintessential bacterial parasite of eukaryotic cells. mBio 8:e859-17. 10.1128/mBio.00859-17 PubMed DOI PMC

Ehrenberg M., Kurland C. G. (1984). Costs of accuracy determined by a maximal growth rate constraint. Q. Rev. Biophys. 17 45–82. 10.1017/S0033583500005254 PubMed DOI

Estrada-Peña A., Villar M., Artigas-Jerónimo S., López V., Alberdi P., Cabezas-Cruz A., et al. (2018). Use of graph theory to characterize human and arthropod vector cell protein response to infection. Front. Cell. Infect. Microbiol. 8:265. 10.3389/fcimb.2018.00265 PubMed DOI PMC

Felsenstein J. (1985). Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39 783–791. 10.1111/j.1558-5646.1985.tb00420.x PubMed DOI

Galindo R. C., Doncel-Pérez E., Zivkovic Z., Naranjo V., Gortazar C., Mangold A. J., et al. (2009). Tick subolesin is an ortholog of the akirins described in insects and vertebrates. Dev. Comp. Immunol. 33 612–617. 10.1016/j.dci.2008.11.002 PubMed DOI

Giraldo-Calderón G. I., Emrich S. J., MacCallum R. M., Maslen G., Dialynas E., Topalis P., et al. (2015). VectorBase: an updated bioinformatics resource for invertebrate vectors and other organisms related with human diseases. Nucleic Acids Res. 43 D707–D713. 10.1093/nar/gku1117 PubMed DOI PMC

Gonzalez K., Baylies M. (2005). “bhringi: A novel Twist co-regulator”, in Proceedings of the Program and Abstracts 46th Annual Drosophila Research Conference, San Diego, CA, 46:320B.

Goto A., Fukuyama H., Imler J. L., Hoffmann J. A. (2014). The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response. J. Biol. Chem. 289 20470–20476. 10.1074/jbc.C114.553719 PubMed DOI PMC

Goto A., Matsushita K., Gesellchen V., El Chamy L., Kuttenkeuler D., Takeuchi O., et al. (2008). Akirins are highly conserved nuclear proteins required for NF-kappaB-dependent gene expression in Drosophila and mice. Nat. Immunol. 9 97–104. 10.1038/ni1543 PubMed DOI PMC

Gregory T. R. (2005). Animal Genome Size Database. Avilable at: http://www.genomesize.com

Gulia-Nuss M., Nuss A. B., Meyer J. M., Sonenshine D. E., Roe R. M., Waterhouse R. M., et al. (2016). Genomic insights into the Ixodes scapularis tick vector of Lyme disease. Nat. Commun. 7:10507. 10.1038/ncomms10507 PubMed DOI PMC

Hajdušek O., Šíma R., Ayllón N., Jalovecká M., Perner J., de la Fuente J., et al. (2013). Interaction of the tick immune system with transmitted pathogens. Front. Cell. Infect. Microbiol. 3:26. 10.3389/fcimb.2013.00026 PubMed DOI PMC

Harrington D., Canales M., de la Fuente J., de Luna C., Robinson K., Guy J., et al. (2009). Immunisation with recombinant proteins subolesin and Bm86 for the control of Dermanyssus gallinae in poultry. Vaccine 27 4056–4063. 10.1016/j.vaccine.2009.04.014 PubMed DOI

Holm L., Laakso L. M. (2016). Dali server update. Nucleic Acids Res. 44 W351–W355. 10.1093/nar/gkw357 PubMed DOI PMC

Hoogstraal H. (1956). African Ixodoidea. I. Ticks of the Sudan (with Special Reference to Equatoria Province and with Preliminary Reviews of the Genera Boophilus, Margaropus and Hyalomma). Washington, DC: Department of the Navy, 1101.

Horak I. G., Heyne H., Williams R., Gallivan G. J., Spickett A. M., Bezuidenhout J. D., et al. (2018). The Ixodid Ticks (Acari: Ixodidae) of Southern Africa. Hamburg: Springer, 675. 10.1007/978-3-319-70642-9 DOI

Hou F., Wang X., Qian Z., Liu Q., Liu Y., He S., et al. (2013). Identification and functional studies of Akirin, a potential positive nuclear factor of NF-κB signaling pathways in the Pacific white shrimp, Litopenaeus vannamei. Dev. Comp. Immunol. 41 703–714. 10.1016/j.dci.2013.08.005 PubMed DOI

Ivics Z., Hackett P. B., Plasterk R. H., Izsvak Z. (1997). Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91 501–510. 10.1016/S0092-8674(00)80436-5 PubMed DOI

Kasthuri S. R., Umasuthan N., Whang I., Wan Q., Lim B. S., Jung H. B., et al. (2013). Akirin2 homologues from rock bream, Oplegnathus fasciatus: genomic and molecular characterization and transcriptional expression analysis. Fish Shellfish Immunol. 35 740–747. 10.1016/j.fsi.2013.06.006 PubMed DOI

Katoh K., Rozewicki J., Yamada K. D. (2017). MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization. Brief. Bioinform. 10.1093/bib/bbx108 [Epub ahead of print]. PubMed DOI PMC

Katoh K., Standley D. M. (2013). MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol. Biol. Evol. 30 772–780. 10.1093/molbev/mst010 PubMed DOI PMC

Kim H., Lee S. K., Hong M. W., Park S. R., Lee Y. S., Kim J. W., et al. (2013). Association of a single nucleotide polymorphism in the akirin 2 gene with economically important traits in Korean native cattle. Anim. Genet. 44 750–753. 10.1111/age.12055 PubMed DOI

Komiya Y., Kurabe N., Katagiri K., Ogawa M., Sugiyama A., Kawasaki Y., et al. (2008). A novel binding factor of 14-3-3beta functions as a transcriptional repressor and promotes anchorage-independent growth, tumorigenicity, and metastasis. J. Biol. Chem. 283 18753–18764. 10.1074/jbc.M802530200 PubMed DOI

Koonin E. V. (2005). Orthologs, paralogs, and evolutionary genomics. Annu. Rev. Genet. 39 309–338. 10.1371/journal.pgen.1002821 PubMed DOI

Krossa S., Schmitt A. D., Hattermann K., Fritsch J., Scheidig A. J., Mehdorn H. M., et al. (2015). Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1. Oncotarget 6 21029–21045. 10.18632/oncotarget.3763 PubMed DOI PMC

Kumar B., Manjunathachar H. V., Nagar G., Ravikumar G., de la Fuente J., Saravanan B. C., et al. (2017). Functional characterization of candidate antigens of Hyalomma anatolicum and evaluation of its cross-protective efficacy against Rhipicephalus microplus. Vaccine 35 5682–5692. 10.1016/j.vaccine.2017.08.049 PubMed DOI

Kumar S., Stecher G., Tamura K. (2016). MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol. Biol. Evol. 33 1870–1874. 10.1093/molbev/msw054 PubMed DOI PMC

Kurland C. G., Canbäck B., Berg O. G. (2007). The origins of modern proteomes. Biochimie 89 1454–1463. 10.1016/j.biochi.2007.09.004 PubMed DOI

Law M. J., Linde M. E., Chambers E. J., Oubridge C., Katsamba P. S., Nilsson L., et al. (2006). The role of positively charged amino acids and electrostatic interactions in the complex of U1A protein and U1 hairpin II RNA. Nucleic Acids Res. 34 275–285. 10.1093/nar/gkj436 PubMed DOI PMC

Leung S. W., Harreman M. T., Hodel M. R., Hodel A. E., Corbett A. H. (2003). Dissection of the karyopherin alpha nuclear localization signal (NLS)-binding groove: functional requirements for NLS binding. J. Biol. Chem. 278 41947–41953. 10.1074/jbc.M307162200 PubMed DOI

Liu N., Wang X. W., Sun J. J., Wang L., Zhang H. W., Zhao X. F., et al. (2016). Akirin interacts with Bap60 and 14-3-3 proteins to regulate the expression of antimicrobial peptides in the kuruma shrimp (Marsupenaeus japonicus). Dev. Comp. Immunol. 55 80–89. 10.1016/j.dci.2015.10.015 PubMed DOI

Liu T., Gao Y., Xu T. (2015). Evolution of akirin family in gene and genome levels and coexpressed patterns among family members and rel gene in croaker. Dev. Comp. Immunol. 52 17–25. 10.1016/j.dci.2015.04.010 PubMed DOI

Liu X., Xia Y., Tang J., Ma L., Li C., Ma P., et al. (2017). Dual roles of Akirin2 protein during Xenopus neural development. J. Biol. Chem. 292 5676–5684. 10.1074/jbc.M117.777110 PubMed DOI PMC

Liu Y., Song L., Sun Y., Liu T., Hou F., Liu X. (2016). Comparison of immune response in Pacific white shrimp, Litopenaeus vannamei, after knock down of Toll and IMD gene in vivo. Dev. Comp. Immunol. 60 41–52. 10.1016/j.dci.2016.02.004 PubMed DOI

Lu P., Zhou Y., Yu Y., Cao J., Zhang H., Gong H., et al. (2016). RNA interference and the vaccine effect of a subolesin homolog from the tick Rhipicephalus haemaphysaloides. Exp. Appl. Acarol. 68 113–126. 10.1007/s10493-015-9987-z PubMed DOI

Macqueen D. (2009). Commentary on Galindo et al. [Dev. Comp. Immunol. 33(4) (2009) 612-617]. Dev. Comp. Immunol. 33 877; authorrely 878–879. 10.1016/j.dci.2009.02.011 PubMed DOI

Macqueen D. J., Johnston I. A. (2009). Evolution of the multifaceted eukaryotic akirin gene family. BMC Evol. Biol. 9:34. 10.1186/1471-2148-9-34 PubMed DOI PMC

Macqueen D. J., Bower N. I., Johnston I. A. (2010a). Positioning the expanded akirin gene family of Atlantic salmon within the transcriptional networks of myogenesis. Biochem. Biophys. Res. Commun. 200 599–605. 10.1016/j.bbrc.2010.08.110 PubMed DOI

Macqueen D. J., Kristjánsson B. K., Johnston I. A. (2010b). Salmonid genomes have a remarkably expanded akirin family, coexpressed with genes from conserved pathways governing skeletal muscle growth and catabolism. Physiol. Genomics 42 134–148. 10.1152/physiolgenomics.00045.2010 PubMed DOI PMC

Maeda I., Kohara Y., Yamamoto M., Sugimoto A. (2001). Large-scale analysis of gene function in Caenorhabditis elegans by high-throughput RNAi. Curr. Biol. 11 171–176. 10.1016/S0960-9822(01)00052-5 PubMed DOI

Makkerh J. P., Dingwall C., Laskey R. A. (1996). Comparative mutagenesis of nuclear localization signals reveals the importance of neutral and acidic amino acids. Curr. Biol. 6 1025–1027. 10.1016/S0960-9822(02)00648-6 PubMed DOI

Mans B. J., De Castro M. H., Pienaar R., De Klerk D., Gaven P., Genu S., et al. (2016). Ancestral reconstruction of tick lineages. Ticks Tick Borne Dis. 7 509–535. 10.1016/j.ttbdis.2016.02.002 PubMed DOI

Manzano-Román R., Díaz-Martín V., Oleaga A., Pérez-Sánchez R. (2015). Identification of protective linear B-cell epitopes on the subolesin/akirin orthologues of Ornithodoros spp. soft ticks. Vaccine 33 1046–1055. 10.1016/j.vaccine.2015.01.015 PubMed DOI

Manzano-Román R., Díaz-Martín V., Oleaga A., Siles-Lucas M., Pérez-Sánchez R. (2012). Subolesin/akirin orthologs from Ornithodoros spp. soft ticks: cloning, RNAi gene silencing and protective effect of the recombinant proteins. Vet. Parasitol. 185 248–259. 10.1016/j.vetpar.2011.10.032 PubMed DOI

Marshall A., Salerno M. S., Thomas M., Davies T., Berry C., Dyer K., et al. (2008). Mighty is a novel promyogenic factor in skeletal myogenesis. Exp. Cell Res. 314 1013–1029. 10.1016/j.yexcr.2008.01.004 PubMed DOI

Medzhitov R., Janeway C. A., Jr. (1997). Innate immunity: impact on the adaptive immune response. Curr. Opin. Immunol. 9 4–9. 10.1016/S0952-7915(97)80152-5 PubMed DOI

Merino O., Alberdi P., Pérez de la Lastra J. M., de la Fuente J. (2013a). Tick vaccines and the control of tick-borne pathogens. Front. Cell. Infect. Microbiol. 3:30 10.3389/fcimb.2013.00030 PubMed DOI PMC

Merino O., Antunes S., Mosqueda J., Moreno-Cid J. A., Pérez de la Lastra J. M., Rosario-Cruz R., et al. (2013b). Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection. Vaccine 31 5889–5896. 10.1016/j.vaccine.2013.09.037 PubMed DOI

Merino O., Almazán C., Canales M., Villar M., Moreno-Cid J. A., Estrada-Peña A., et al. (2011a). Control of Rhipicephalus (Boophilus) microplus infestations by the combination of subolesin vaccination and tick autocidal control after subolesin gene knockdown in ticks fed on cattle. Vaccine 29 2248–2254. 10.1016/j.vaccine.2011.01.050 PubMed DOI

Merino O., Almazán C., Canales M., Villar M., Moreno-Cid J. A., Galindo R. C., et al. (2011b). Targeting the tick protective antigen subolesin reduces vector infestations and pathogen infection by Anaplasma marginale and Babesia bigemina. Vaccine 29 8575–8579. 10.1016/j.vaccine.2011.09.023 PubMed DOI

Mobley C. B., Fox C. D., Ferguson B. S., Amin R. H., Dalbo V. J., Baier S., et al. (2014). L-leucine, beta-hydroxy-beta-methylbutyric acid (HMB) and creatine monohydrate prevent myostatin-induced Akirin-1/Mighty mRNA down-regulation and myotube atrophy. J. Int. Soc. Sports Nutr. 11:38. 10.1186/1550-2783-11-38 PubMed DOI PMC

Morel P. C. (2003). Les Tiques d’Afrique et du Bassin Meìditerraneìen (1965–1995). Can Tho: CIRAD-EMVT, 1342.

Moreno-Cid J. A., Jiménez M., Cornelie S., Molina R., Alarcón P., Lacroix M.-N., et al. (2011). Characterization of Aedes albopictus akirin for the control of mosquito and sand fly infestations. Vaccine 29 77–82. 10.1016/j.vaccine.2010.10.011 PubMed DOI

Moreno-Cid J. A., Pérez de la Lastra J. M., Villar M., Jiménez M., Pinal R., Estrada-Peña A., et al. (2013). Control of multiple arthropod vector infestations with subolesin/akirin vaccines. Vaccine 31 1187–1196. 10.1016/j.vaccine.2012.12.073 PubMed DOI

Naranjo N., Ayllón N., Pérez de la Lastra J. M., Galindo R. C., Kocan K. M., Blouin E. F., et al. (2013). Reciprocal regulation of NF-kB (Relish) and Subolesin in the tick vector, Ixodes scapularis. PLoS One 8:e65915. 10.1371/journal.pone.0065915 PubMed DOI PMC

Nowak S. J., Aihara H., Gonzalez K., Nibu Y., Baylies M. K. (2012). Akirin links twist-regulated transcription with the Brahma chromatin remodeling complex during embryogenesis. PLoS Genet. 8:e1002547. 10.1371/journal.pgen.1002547 PubMed DOI PMC

Nowak S. J., Baylies M. K. (2012). Akirin: a context-dependent link between transcription and chromatin remodeling. Bioarchitecture 2 209–213. 10.4161/bioa.22907 PubMed DOI PMC

Olds C. L., Mwaura S., Odongo D. O., Scoles G. A., Bishop R., Daubenberger C. (2016). Induction of humoral immune response to multiple recombinant Rhipicephalus appendiculatus antigens and their effect on tick feeding success and pathogen transmission. Parasit. Vectors 9:484. 10.1186/s13071-016-1774-0 PubMed DOI PMC

Orengo C. A., Thornton J. M. (2005). Protein families and their evolution-a structural perspective. Annu. Rev. Biochem. 74 867–900. 10.1146/annurev.biochem.74.082803.133029 PubMed DOI

Pavithiran A., Bathige S. D. N. K., Kugapreethan R., Priyathilaka T. T., Yang H., Kim M. J., et al. (2018). A comparative study of three akirin genes from big belly seahorse Hippocampus abdominalis: molecular, transcriptional and functional characterization. Fish Shellfish Immunol. 74 584–592. 10.1016/j.fsi.2018.01.025 PubMed DOI

Peña-Rangel M. T., Rodriguez I., Riesgo-Escovar J. R. (2002). A misexpression study examining dorsal thorax formation in Drosophila melanogaster. Genetics 160 1035–1050. PubMed PMC

Prudencio C. R., Pérez de la Lastra J. M., Canales M., Villar M., de la Fuente J. (2010). Mapping protective epitopes in the tick and mosquito subolesin ortholog proteins. Vaccine 28 5398–5406. 10.1016/j.vaccine.2010.06.021 PubMed DOI

Qu F., Xiang Z., Zhang Y., Li J., Zhang Y., Yu Z. (2014). The identification of the first molluscan Akirin2 with immune defense function in the Hong Kong oyster Crassostrea hongkongensis. Fish Shellfish Immunol. 41 455–465. 10.1016/j.fsi.2014.09.029 PubMed DOI

Rahman M. K., Saiful Islam M., You M. (2018). Impact of subolesin and cystatin knockdown by RNA interference in adult female Haemaphysalis longicornis (Acari: Ixodidae) on blood engorgement and reproduction. Insects 9:E39. 10.3390/insects9020039 PubMed DOI PMC

Richardson J. M., Colloms S. D., Finnegan D. J., Walkinshaw M. D. (2009). Molecular architecture of the Mos1 paired-end complex: the structural basis of DNA transposition in a eukaryote. Cell 138 1096–1108. 10.1016/j.cell.2009.07.012 PubMed DOI PMC

Rioualen C., Da Costa Q., Chetrit B., Charafe-Jauffret E., Ginestier C., Bidaut G. (2017). HTS-Net: an integrated regulome-interactome approach for establishing network regulation models in high-throughput screenings. PLoS One 12:e0185400. 10.1371/journal.pone.0185400 PubMed DOI PMC

Salerno M. S., Dyer K., Bracegirdle J., Platt L., Thomas M., Siriett V., et al. (2009). Akirin1 (Mighty), a novel promyogenic factor regulates muscle regeneration and cell chemotaxis. Exp. Cell Res. 315 2012–2021. 10.1016/j.yexcr.2009.04.014 PubMed DOI

Sasaki M., Akiyama-Oda Y., Oda H. (2017). Evolutionary origin of type IV classical cadherins in arthropods. BMC Evol. Biol. 17:142. 10.1186/s12862-017-0991-2 PubMed DOI PMC

Sasaki S., Yamada T., Sukegawa S., Miyake T., Fujita T., Morita M., et al. (2009). Association of a single nucleotide polymorphism in akirin 2 gene with marbling in Japanese Black beef cattle. BMC Res. Notes 2:131. 10.1186/1756-0500-2-131 PubMed DOI PMC

Schetters T., Bishop R., Crampton M., Kopáčk P., Lew-Tabor A., Maritz-Olivier C., et al. (2016). Cattle tick vaccine researchers join forces in CATVAC. Parasit. Vectors 9:105. 10.1186/s13071-016-1386-8 PubMed DOI PMC

Shakya M., Kumar B., Nagar G., de la Fuente J., Ghosh S. (2014). Subolesin: a candidate vaccine antigen for the control of cattle tick infestations in Indian situation. Vaccine 32 3488–3494. 10.1016/j.vaccine.2014.04.053 PubMed DOI

Shaw D. K., Wang X., Brown L. J., Oliva Chávez A. S., Reif K. E., Smith A. A., et al. (2017). Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nat. Commun. 8:14401. 10.1038/ncomms14401 PubMed DOI PMC

Smith A., Guo X., de la Fuente J., Naranjo N., Kocan K. M., Kaufman W. R. (2009). The impact of RNA interference of the subolesin and voraxin genes in male Amblyomma hebraeum (Acari: Ixodidae) on female engorgement and oviposition. Exp. Appl. Acarol. 47 71–86. 10.1007/s10493-008-9195-1 PubMed DOI

Sonenshine D. E., Kocan K. M., de la Fuente J. (2006). Tick control: further thoughts on a research agenda. Trends Parasitol. 22 550–551. 10.1016/j.pt.2006.09.003 PubMed DOI

Staley J. T. (2017). Domain Cell Theory supports the independent evolution of the Eukarya, Bacteria and Archaea and the Nuclear Compartment Commonality hypothesis. Open Biol. 7:170041. 10.1098/rsob.170041 PubMed DOI PMC

Sun W., Huang H., Ma S., Gan X., Zhu M., Liu H., et al. (2016). Akirin2 could promote the proliferation but not the differentiation of duck myoblasts via the activation of the mTOR/p70S6K signaling pathway. Int. J. Biochem. Cell. Biol. 79 298–307. 10.1016/j.biocel.2016.08.032 PubMed DOI

Tartey S., Matsushita K., Imamura T., Wakabayashi A., Ori D., Mino T., et al. (2015). Essential function for the nuclear protein Akirin2 in B cell activation and humoral immune responses. J. Immunol. 195 519–527. 10.4049/jimmunol.1500373 PubMed DOI

Tartey S., Matsushita K., Vandenbon A., Ori D., Imamura T., Mino T., et al. (2014). Akirin2 is critical for inducing inflammatory genes by bridging IκB-ζ and the SWI/SNF complex. EMBO J. 33 2332–2348. 10.15252/embj.201488447 PubMed DOI PMC

Torina A., Moreno-Cid J. A., Blanda V., Fernández de Mera I. G., Pérez de la Lastra J. M., Scimeca S., et al. (2014). Control of tick infestations and pathogen prevalence in cattle and sheep farms vaccinated with the recombinant Subolesin-Major Surface Protein 1a chimeric antigen. Parasit. Vectors 7:10. 10.1186/1756-3305-7-10 PubMed DOI PMC

Valenzuela-Muñoz V., Gallardo-Escárate C. (2014). TLR and IMD signaling pathways from Caligus rogercresseyi (Crustacea: Copepoda): in silico gene expression and SNPs discovery. Fish Shellfish Immunol. 36 428–434. 10.1016/j.fsi.2013.12.019 PubMed DOI

Villar M., Marina A., de la Fuente J. (2017). Applying proteomics to tick vaccine development: where are we? Expert Rev. Proteomics 14 211–221. 10.1080/14789450.2017.1284590 PubMed DOI

Voigt F., Wiedemann L., Zuliani C., Querques I., Sebe A., Mates L., et al. (2016). Sleeping Beauty transposase structure allows rational design of hyperactive variants for genetic engineering. Nat. Commun. 7:11126. 10.1038/ncomms11126 PubMed DOI PMC

Wan F., Lenardo M. J. (2010). The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives. Cell Res. 20 24–33. 10.1038/cr.2009.137 PubMed DOI PMC

Wang M., Kurland C. G., Caetano-Anollés G. (2011). Reductive evolution of proteomes and protein structures. Proc. Natl. Acad. Sci U.S.A. 108 11954–11958. 10.1073/pnas.1017361108 PubMed DOI PMC

Watanabe N., Satoh Y., Fujita T., Ohta T., Kose H., Muramatsu Y., et al. (2011). Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.∗188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling. BMC Res. Notes 4:10. 10.1186/1756-0500-4-10 PubMed DOI PMC

Wolf Y. I., Koonin E. V. (2013). Genome reduction as the dominant mode of evolution. Bioessays 35 829–837. 10.1002/bies.201300037 PubMed DOI PMC

Xue X., Wang L., Chen Y., Zhang X., Luo H., Li Z., et al. (2014). Identification and molecular characterization of an Akirin2 homolog in Chinese loach (Paramisgurnus dabryanus). Fish Shellfish Immunol. 36 435–443. 10.1016/j.fsi.2013.12.021 PubMed DOI

Yan J., Dong X., Kong Y., Zhang Y., Jing R., Feng L. (2013). Identification and primary immune characteristics of an amphioxus akirin homolog. Fish Shellfish Immunol. 35 564–571. 10.1016/j.fsi.2013.05.020 PubMed DOI

Yang C. G., Wang X. L., Wang L., Zhang B., Chen S. L. (2011). A new Akirin1 gene in turbot (Scophthalmus maximus): molecular cloning, characterization and expression analysis in response to bacterial and viral immunological challenge. Fish Shellfish Immunol 30 1031–1041. 10.1016/j.fsi.2011.01.028 PubMed DOI

Yang C. G., Wang X. L., Zhang B., Sun B., Liu S. S., Chen S. L. (2013). Screening and analysis of PoAkirin1 and two related genes in response to immunological stimulants in the Japanese flounder (Paralichthys olivaceus). BMC Mol. Biol. 14:10. 10.1186/1471-2199-14-10 PubMed DOI PMC

Zanesi N., Balatti V., Riordan J., Burch A., Rizzotto L., Palamarchuk A., et al. (2013). A Sleeping Beauty screen reveals NF-kB activation in CLL mouse model. Blood 121 4355–4358. 10.1182/blood-2013-02-486035 PubMed DOI PMC

Zhang Y. (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40. 10.1186/1471-2105-9-40 PubMed DOI PMC

Zivkovic Z., Esteves E., Almazán C., Daffre S., Nijhof A. M., Kocan K. M., et al. (2010a). Differential expression of genes in salivary glands of male Rhipicephalus (Boophilus) microplus in response to infection with Anaplasma marginale. BMC Genomics 11:186. 10.1186/1471-2164-11-186 PubMed DOI PMC

Zivkovic Z., Torina A., Mitra R., Alongi A., Scimeca S., Kocan K. M., et al. (2010b). Subolesin expression in response to pathogen infection in ticks. BMC Immunol. 11:7. 10.1186/1471-2172-11-7 PubMed DOI PMC

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