Abstract
Studies involving miRNAs have opened discussions about their broad participation in viral infections. Regarding the Human gammaherpesvirus 4 or Epstein–Barr virus (EBV), miRNAs are important regulators of viral and cellular gene expression during the infectious process, promoting viral persistence and, in some cases, oncogenic processes. We identified 55 miRNAs of EBV type 2 and inferred the viral mRNA target to self-regulate. This data indicate that gene self-repression is an important strategy for maintenance of the viral latent phase. In addition, a protein network was constructed to establish essential proteins in the self-regulation process. We found ten proteins that work as hubs, highlighting BTRF1 and BSRF1 as the most important proteins in the network. These results open a new way to understand the infection by EBV type 2, where viral genes can be targeted for avoiding oncogenic processes, as well as new therapies to suppress and combat the persistent viral infection.
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References
Lefkowitz EJ, Dempsey DM, Hendrickson RC, Orton RJ, Siddell SG, Smith DB (2018) Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Res 46:D708–D717. https://doi.org/10.1093/nar/gkx932
Cohen JI (2000) Epstein–Barr virus infection. N Engl J Med 343:481–492. https://doi.org/10.1056/NEJM200008173430707
Palser AL, Grayson NE, White RE, Corton C, Correia S, Ba Abdullah MM, Watson SJ, Cotton M, Arrand JR, Murray PG, Allday MJ, Rickinson AB, Young LS, Farrell PJ, Kellam P (2015) Genome diversity of Epstein–Barr virus from multiple tumor types and normal infection. J Virol 89:5222–5237. https://doi.org/10.1128/JVI.03614-14
Houldcroft CJ, Kellam P (2015) Host genetics of Epstein–Barr virus infection, latency and disease: genetics of EBV infection. Rev Med Virol 25:71–84. https://doi.org/10.1002/rmv.1816
Dolan A, Addison C, Gatherer D, Davison AJ, McGeoch DJ (2006) The genome of Epstein–Barr virus type 2 strain AG876. Virology 350:164–170. https://doi.org/10.1016/j.virol.2006.01.015
Buisson M, Morand P, Genoulaz O, Bourgeat M-J, Micoud M, Seigneurin J-M (1994) Changes in the dominant Epstein–Barr virus type during human immunodeficiency virus infection. J Gen Virol 75:431–437. https://doi.org/10.1099/0022-1317-75-2-431
Fruci D, Rota R, Gallo A (2017) The role of HCMV and HIV-1 microRNAs: processing, and mechanisms of action during viral infection. Front Microbiol 8:689. https://doi.org/10.3389/fmicb.2017.00689
Skalsky RL, Cullen BR (2010) Viruses, microRNAs, and host interactions. Annu Rev Microbiol 64:123–141. https://doi.org/10.1146/annurev.micro.112408.134243
Pfeffer S (2004) Identification of virus-encoded microRNAs. Science 304:734–736. https://doi.org/10.1126/science.1096781
Piedade D, Azevedo-Pereira J (2016) The role of microRNAs in the pathogenesis of herpesvirus infection. Viruses 8:156. https://doi.org/10.3390/v8060156
Arias-Carrasco R, Vásquez-Morán Y, Nakaya HI, Maracaja-Coutinho V (2018) StructRNAfinder: an automated pipeline and web server for RNA families prediction. BMC Bioinform. https://doi.org/10.1186/s12859-018-2052-2
Burge SW, Daub J, Eberhardt R, Tate J, Barquist L, Nawrocki EP, Eddy SR, Gardner PP, Bateman A (2013) Rfam 11.0: 10 years of RNA families. Nucleic Acids Res 41:D226–D232. https://doi.org/10.1093/nar/gks1005
Nawrocki EP, Eddy SR (2013) Infernal 1.1: 100-fold faster RNA homology searches. Bioinformatics 29:2933–2935. https://doi.org/10.1093/bioinformatics/btt509
Denman RB (1993) Using RNAFOLD to predict the activity of small catalytic RNAs. Biotechniques 15:1090–1095
Ondov BD, Bergman NH, Phillippy AM (2011) Interactive metagenomic visualization in a web browser. BMC Bioinform 12:385. https://doi.org/10.1186/1471-2105-12-385
Mann M, Wright PR, Backofen R (2017) IntaRNA 2.0: enhanced and customizable prediction of RNA–RNA interactions. Nucleic Acids Res 45:W435–W439. https://doi.org/10.1093/nar/gkx279
Calderone A, Licata L, Cesareni G (2015) VirusMentha: a new resource for virus–host protein interactions. Nucleic Acids Res 43:D588–D592. https://doi.org/10.1093/nar/gku830
Shannon P (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303
Cai X, Schäfer A, Lu S, Bilello JP, Desrosiers RC, Edwards R, Raab-Traub N, Cullen BR (2006) Epstein–Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog 2:e23
Skalsky RL (2017) Analysis of viral and cellular microRNAs in EBV-infected cells. Methods Mol Biol 1532:133–146
Hooykaas MJ, Kruse E, Wiertz EJ, Lebbink RJ (2016) Comprehensive profiling of functional Epstein–Barr virus miRNA expression in human cell lines. BMC Genom 17:644. https://doi.org/10.1186/s12864-016-2978-6
Choy EY-W, Siu K-L, Kok K-H, Lung RW-M, Tsang CM, To K-F, Kwong DL-W, Tsao SW, Jin D-Y (2008) An Epstein–Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med 205:2551–2560. https://doi.org/10.1084/jem.20072581
Barth S, Pfuhl T, Mamiani A, Ehses C, Roemer K, Kremmer E, Jaker C, Hock J, Meister G, Grasser FA (2007) Epstein–Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res 36:666–675. https://doi.org/10.1093/nar/gkm1080
Lei T, Yuen K-S, Xu R, Tsao SW, Chen H, Li M, Kok K-H, Jin D-Y (2013) Targeting of DICE1 tumor suppressor by Epstein–Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma. Int J Cancer 133:79–87. https://doi.org/10.1002/ijc.28007
Kang M-S, Kieff E (2015) Epstein–Barr virus latent genes. Exp Mol Med 47:e131–e131. https://doi.org/10.1038/emm.2014.84
Aubry V, Mure F, Mariame B, Deschamps T, Wyrwicz LS, Manet E, Gruffat H (2014) Epstein–Barr virus late gene transcription depends on the assembly of a virus-specific preinitiation complex. J Virol 88:12825–12838. https://doi.org/10.1128/JVI.02139-14
Hutt-Fletcher LM (2015) EBV glycoproteins: where are we now? Future Virol 10:1155–1162. https://doi.org/10.2217/fvl.15.80
Mackett M, Conway MJ, Arrand JR, Haddad RS, Hutt-Fletcher LM (1990) Characterization and expression of a glycoprotein encoded by the Epstein–Barr virus BamHI I fragment. J Virol 64:2545–2552
Watanabe T, Tsuruoka M, Narita Y, Katsuya R, Goshima F, Kimura H, Murata T (2015) The Epstein–Barr virus BRRF2 gene product is involved in viral progeny production. Virology 484:33–40. https://doi.org/10.1016/j.virol.2015.05.010
Kawashima D, Kanda T, Murata T, Saito S, Sugimoto A, Narita Y, Tsurumi T (2013) Nuclear transport of Epstein–Barr virus DNA polymerase is dependent on the BMRF1 polymerase processivity factor and molecular chaperone Hsp90. J Virol 87:6482–6491. https://doi.org/10.1128/JVI.03428-12
Tycowski KT, Guo YE, Lee N, Moss WN, Vallery TK, Xie M, Steitz JA (2015) Viral noncoding RNAs: more surprises. Genes Dev 29:567–584. https://doi.org/10.1101/gad.259077.115
Barabasi AL, Albert R (1999) Emergence of scaling in random networks. Science 286:509–512. https://doi.org/10.1126/science.286.5439.509
Aittokallio T, Schwikowski B (2006) Graph-based methods for analysing networks in cell biology. Brief Bioinform 7:243–255. https://doi.org/10.1093/bib/bbl022
Nozawa N, Kawaguchi Y, Tanaka M, Kato A, Kato A, Kimura H, Nishiyama Y (2005) Herpes simplex virus type 1 UL51 protein is involved in maturation and egress of virus particles. J Virol 79:6947–6956. https://doi.org/10.1128/JVI.79.11.6947-6956.2005
Do N-V, Ingemar E, Phi P-TP, Jenny A, Chinh T-T, Zeng Y, Hu L (2008) A major EBNA1 variant from Asian EBV isolates shows enhanced transcriptional activity compared to prototype B95.8. Virus Res 132:15–24. https://doi.org/10.1016/j.virusres.2007.10.020
Levitskaya J, Sharipo A, Leonchiks A, Ciechanover A, Masucci MG (1997) Inhibition of ubiquitin/proteasomedependent protein degradation by the Gly-Ala repeat domain of the Epstein–Barr virus nuclear antigen 1. Proc Natl Acad Sci USA 94:12616–12621
Gustafson EA, Chillemi AC, Sage DR, Fingeroth JD (1998) The Epstein–Barr virus thymidine kinase does not phosphorylate ganciclovir or acyclovir and demonstrates a narrow substrate specificity compared to the herpes simplex virus type 1 thymidine kinase. Antimicrob Agents Chemother 42:2923–2931
Boccellato F, Anastasiadou E, Rosato P, Kempkes B, Frati L, Faggioni A, Trivedi P (2007) EBNA2 interferes with the germinal center phenotype by downregulating BCL6 and TCL1 in non-Hodgkin’s lymphoma cells. J Virol 81:2274–2282. https://doi.org/10.1128/JVI.01822-06
Pan S-H, Tai C-C, Lin C-S, Hsu W-B, Chou S-F, Lai C-C, Chen J-Y, Tien H-F, Lee F-Y, Wang W-B (2009) Epstein–Barr virus nuclear antigen 2 disrupts mitotic checkpoint and causes chromosomal instability. Carcinogenesis 30:366–375. https://doi.org/10.1093/carcin/bgn291
Hickabottom M, Parker GA, Freemont P, Crook T, Allday MJ (2002) Two nonconsensus sites in the Epstein–Barr virus oncoprotein EBNA3A cooperate to bind the co-repressor carboxyl-terminal-binding protein (CtBP). J Biol Chem 277:47197–47204. https://doi.org/10.1074/jbc.M208116200
Bhattacharjee S, Ghosh RS, Bose P, Saha A (2016) Role of EBNA-3 family proteins in EBV associated B-cell lymphomagenesis. Front Microbiol. https://doi.org/10.3389/fmicb.2016.00457
Van Gent M, Braem SGE, de Jong A, Delagic N, Peeters JGC, Boer IGJ, Moynagh PN, Kremmer E, Wiertz EJ, Ovaa H, Griffin BD, Ressing ME (2014) Epstein–Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling. PLoS Pathog 10:e1003960. https://doi.org/10.1371/journal.ppat.1003960
Acknowledgements
This work was funded in part by grants from Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), Chile: FONDECYT 10111620, FONDAP 15130011, PAI PAI79170021. ACC received a master degree fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. VSS was a post doctorate fellowship from PNPD/CAPES.
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Serrano-Solis, V., Carlos, A.C., Maracaja-Coutinho, V. et al. Prediction of MicroRNAs in the Epstein–Barr Virus Reveals Potential Targets for the Viral Self-Regulation. Indian J Microbiol 59, 73–80 (2019). https://doi.org/10.1007/s12088-018-0775-4
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DOI: https://doi.org/10.1007/s12088-018-0775-4