EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival
One important innate immune response to viral infection is apoptosis, also called programmed cell death, whereby the infected cells commit suicide rather than serve as factories for virus production. As a result, many viruses have developed strategies to inhibit apoptosis. Here, we demonstrate that five of the Epstein-Barr virus (EBV) miR-BART microRNAs that are expressed in EBV-transformed epithelial cell tumors display anti-apoptotic activity. We have identified ten cellular mRNAs that are bound and downregulated by one of these five anti-apoptotic microRNAs and show that this downregulation can explain the observed reduction in apoptosis in miR-BART-expressing cells. Together, these data demonstrate that the EBV miR-BARTs can help sustain latently EBV-infected cells in the face of pro-apoptotic innate immune signals and this may explain the resistance to DNA damaging agents, including chemotherapeutics and radiation, seen in a subset of EBV-induced epithelial tumors.
Vyšlo v časopise:
EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004979
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004979
Souhrn
One important innate immune response to viral infection is apoptosis, also called programmed cell death, whereby the infected cells commit suicide rather than serve as factories for virus production. As a result, many viruses have developed strategies to inhibit apoptosis. Here, we demonstrate that five of the Epstein-Barr virus (EBV) miR-BART microRNAs that are expressed in EBV-transformed epithelial cell tumors display anti-apoptotic activity. We have identified ten cellular mRNAs that are bound and downregulated by one of these five anti-apoptotic microRNAs and show that this downregulation can explain the observed reduction in apoptosis in miR-BART-expressing cells. Together, these data demonstrate that the EBV miR-BARTs can help sustain latently EBV-infected cells in the face of pro-apoptotic innate immune signals and this may explain the resistance to DNA damaging agents, including chemotherapeutics and radiation, seen in a subset of EBV-induced epithelial tumors.
Zdroje
1. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297. 14744438
2. Grundhoff A, Sullivan CS. Virus-encoded microRNAs. Virology. 2011;411:325–343. doi: 10.1016/j.virol.2011.01.002 21277611
3. Skalsky RL, Cullen BR. Viruses, microRNAs, and host interactions. Annu Rev Microbiol. 2010;64:123–141. doi: 10.1146/annurev.micro.112408.134243 20477536
4. Cullen BR. Transcription and processing of human microRNA precursors. Mol Cell. 2004;16:861–865. 15610730
5. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233. doi: 10.1016/j.cell.2009.01.002 19167326
6. Schirle NT, Sheu-Gruttadauria J, MacRae IJ. Structural basis for microRNA targeting. Science. 2014;346:608–613. doi: 10.1126/science.1258040 25359968
7. Cai X, Schäfer A, Lu S, Bilello JP, Desrosiers RC, Edwards R, et al. Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog. 2006;2:e23. 16557291
8. Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, et al. Identification of virus-encoded microRNAs. Science. 2004;304:734–736. 15118162
9. Zhu JY, Pfuhl T, Motsch N, Barth S, Nicholls J, Grasser F, et al. Identification of novel Epstein-Barr virus microRNA genes from nasopharyngeal carcinomas. J Virol. 2009;83:3333–3341. doi: 10.1128/JVI.01689-08 19144710
10. Cosmopoulos K, Pegtel M, Hawkins J, Moffett H, Novina C, Middeldorp J, et al. Comprehensive profiling of Epstein-Barr virus microRNAs in nasopharyngeal carcinoma. J Virol. 2009;83:2357–2367. doi: 10.1128/JVI.02104-08 19091858
11. Skalsky RL, Corcoran DL, Gottwein E, Frank CL, Kang D, Hafner M, et al. The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathog. 2012;8:e1002484. doi: 10.1371/journal.ppat.1002484 22291592
12. Feederle R, Linnstaedt SD, Bannert H, Lips H, Bencun M, Cullen BR, et al. A viral microRNA cluster strongly potentiates the transforming properties of a human herpesvirus. PLoS Pathog. 2011;7:e1001294. doi: 10.1371/journal.ppat.1001294 21379335
13. Seto E, Moosmann A, Gromminger S, Walz N, Grundhoff A, Hammerschmidt W. Micro RNAs of Epstein-Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog. 2010;6:e1001063. doi: 10.1371/journal.ppat.1001063 20808852
14. Vereide DT, Seto E, Chiu YF, Hayes M, Tagawa T, Grundhoff A, et al. Epstein-Barr virus maintains lymphomas via its miRNAs. Oncogene. 2014;33:1258–1264. doi: 10.1038/onc.2013.71 23503461
15. Kanda T, Miyata M, Kano M, Kondo S, Yoshizaki T, Iizasa H. Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor. J Virol. 2015;89:2684–2697. doi: 10.1128/JVI.03189-14 25520514
16. Marquitz AR, Mathur A, Chugh PE, Dittmer DP, Raab-Traub N. Expression profile of microRNAs in Epstein-Barr virus-infected AGS gastric carcinoma cells. J Virol. 2014;88:1389–1393. doi: 10.1128/JVI.02662-13 24227849
17. Kim DN, Chae HS, Oh ST, Kang JH, Park CH, Park WS, et al. Expression of viral microRNAs in Epstein-Barr virus-associated gastric carcinoma. J Virol. 2007;81:1033–1036. 17079300
18. Marquitz AR, Mathur A, Shair KH, Raab-Traub N. Infection of Epstein-Barr virus in a gastric carcinoma cell line induces anchorage independence and global changes in gene expression. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:9593–9598. doi: 10.1073/pnas.1202910109 22647604
19. Kassis J, Maeda A, Teramoto N, Takada K, Wu C, Klein G, et al. EBV-expressing AGS gastric carcinoma cell sublines present increased motility and invasiveness. Int J Cancer. 2002;99:644–651. 12115496
20. Marquitz AR, Mathur A, Nam CS, Raab-Traub N. The Epstein-Barr Virus BART microRNAs target the pro-apoptotic protein Bim. Virology. 2011;412:392–400. doi: 10.1016/j.virol.2011.01.028 21333317
21. Shinozaki-Ushiku A, Kunita A, Isogai M, Hibiya T, Ushiku T, Takada K, et al. Profiling of virus-encoded microRNAs in Epstein-Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. J Virol. 2015;in press.
22. Choy EY, Siu KL, Kok KH, Lung RW, Tsang CM, To KF, et al. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med. 2008;205:2551–2560. doi: 10.1084/jem.20072581 18838543
23. Lei T, Yuen KS, Xu R, Tsao SW, Chen H, Li M, et al. Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma. Int J Cancer. 2013;133:79–87. doi: 10.1002/ijc.28007 23280823
24. Cai LM, Lyu XM, Luo WR, Cui XF, Ye YF, Yuan CC, et al. EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene. 2014.
25. Qiu J, Smith P, Leahy L, Thorley-Lawson DA. The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo. PLoS Pathog. 2015;11:e1004561. doi: 10.1371/journal.ppat.1004561 25590614
26. Upton JW, Chan FK. Staying alive: cell death in antiviral immunity. Mol Cell. 2014;54:273–280. doi: 10.1016/j.molcel.2014.01.027 24766891
27. Liang C, Oh BH, Jung JU. Novel functions of viral anti-apoptotic factors. Nat Rev Microbiol. 2015;13:7–12. doi: 10.1038/nrmicro3369 25363821
28. Mullokandov G, Baccarini A, Ruzo A, Jayaprakash AD, Tung N, Israelow B, et al. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nat Methods. 2012;9:840–846. doi: 10.1038/nmeth.2078 22751203
29. Gottwein E, Cullen BR. A human herpesvirus microRNA inhibits p21 expression and attenuates p21-mediated cell cycle arrest. J Virol. 2010;84:5229–5237. doi: 10.1128/JVI.00202-10 20219912
30. Skalsky RL, Kang D, Linnstaedt SD, Cullen BR. Evolutionary conservation of primate lymphocryptovirus microRNA targets. J Virol. 2014;88:1617–1635. doi: 10.1128/JVI.02071-13 24257599
31. Iizasa H, Wulff BE, Alla NR, Maragkakis M, Megraw M, Hatzigeorgiou A, et al. Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency. J Biol Chem. 2010;285:33358–33370. doi: 10.1074/jbc.M110.138362 20716523
32. Dölken L, Malterer G, Erhard F, Kothe S, Friedel CC, Suffert G, et al. Systematic analysis of viral and cellular microRNA targets in cells latently infected with human gamma-herpesviruses by RISC immunoprecipitation assay. Cell Host Microbe. 2010;7:324–334. doi: 10.1016/j.chom.2010.03.008 20413099
33. Huang WT, Lin CW. EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-gamma-STAT1 pathway associated with disease progression in nasal NK-cell lymphoma. Am J Pathol. 2014;184:1185–1197. doi: 10.1016/j.ajpath.2013.12.024 24655378
34. Suffert G, Malterer G, Hausser J, Viiliainen J, Fender A, Contrant M, et al. Kaposi's sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis. PLoS Pathog. 2011;7:e1002405. doi: 10.1371/journal.ppat.1002405 22174674
35. Bellot G, Cartron PF, Er E, Oliver L, Juin P, Armstrong LC, et al. TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax. Cell Death Differ. 2007;14:785–794. 17096026
36. Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell. 2010;141:129–141. doi: 10.1016/j.cell.2010.03.009 20371350
37. Gottwein E, Corcoran DL, Mukherjee N, Skalsky RL, Hafner M, Nusbaum JD, et al. Viral microRNA targetome of KSHV-infected primary effusion lymphoma cell lines. Cell Host Microbe. 2011;10:515–526. doi: 10.1016/j.chom.2011.09.012 22100165
38. Corcoran DL, Georgiev S, Mukherjee N, Gottwein E, Skalsky RL, Keene JD, et al. PARalyzer: definition of RNA binding sites from PAR-CLIP short-read sequence data. Genome Biol. 2011;12:R79. doi: 10.1186/gb-2011-12-8-r79 21851591
39. Liu Z, Naranjo A, Thiele CJ. CASZ1b, the short isoform of CASZ1 gene, coexpresses with CASZ1a during neurogenesis and suppresses neuroblastoma cell growth. PLoS ONE. 2011;6:e18557. doi: 10.1371/journal.pone.0018557 21490919
40. Bazzini AA, Lee MT, Giraldez AJ. Ribosome profiling shows that miR-430 reduces translation before causing mRNA decay in zebrafish. Science. 2012;336:233–237. doi: 10.1126/science.1215704 22422859
41. Djuranovic S, Nahvi A, Green R. miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay. Science. 2012;336:237–240. doi: 10.1126/science.1215691 22499947
42. Zeng Y, Wagner EJ, Cullen BR. Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. Mol Cell. 2002;9:1327–1333. 12086629
43. Hsu CY, Yi YH, Chang KP, Chang YS, Chen SJ, Chen HC. The Epstein-Barr virus-encoded microRNA MiR-BART9 promotes tumor metastasis by targeting E-cadherin in nasopharyngeal carcinoma. PLoS Pathog. 2014;10:e1003974. doi: 10.1371/journal.ppat.1003974 24586173
44. Ross N, Gandhi MK, Nourse JP. The Epstein-Barr virus microRNA BART11-5p targets the early B-cell transcription factor EBF1. Am J Blood Res. 2013;3:210–224. 23997984
45. Chijioke O, Azzi T, Nadal D, Munz C. Innate immune responses against Epstein Barr virus infection. J Leukoc Biol. 2013;94:1185–1190. doi: 10.1189/jlb.0313173 23812328
46. Liu SC, Tsang NM, Chiang WC, Chang KP, Hsueh C, Liang Y, et al. Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance. J Clin Invest. 2013;123:5269–5283. doi: 10.1172/JCI63428 24270418
47. Yang GD, Huang TJ, Peng LX, Yang CF, Liu RY, Huang HB, et al. Epstein-Barr Virus_Encoded LMP1 upregulates microRNA-21 to promote the resistance of nasopharyngeal carcinoma cells to cisplatin-induced Apoptosis by suppressing PDCD4 and Fas-L. PLoS ONE. 2013;8:e78355. doi: 10.1371/journal.pone.0078355 24194922
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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