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MicroRNA Editing Facilitates Immune Elimination of HCMV Infected Cells


The human cytomegalovirus (HCMV) is extremely prevalent in the human population. Infection by HCMV is life threatening in immune compromised individuals and in immune competent individuals it can cause severe birth defects, developmental retardation and is even associated with tumor development. While numerous mechanisms were developed by HCMV to interfere with immune cell activity, much less is known about cellular mechanisms that operate in response to HCMV infection. Here we demonstrate that in response to HCMV infection, the expression of the short form of the RNA editing enzyme ADAR1 (ADAR1-p110) is induced. We identified the specific promoter region responsible for this induction and we show that ADAR1-p110 can edit miR-376a. Accordingly, we demonstrate that the levels of the edited-miR-376a (miR-376a(e)) increase during HCMV infection. Importantly, we show that miR-376a(e) downregulates the immune modulating molecule HLA-E and that this consequently renders HCMV infected cells susceptible to elimination by NK cells.


Vyšlo v časopise: MicroRNA Editing Facilitates Immune Elimination of HCMV Infected Cells. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003963
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003963

Souhrn

The human cytomegalovirus (HCMV) is extremely prevalent in the human population. Infection by HCMV is life threatening in immune compromised individuals and in immune competent individuals it can cause severe birth defects, developmental retardation and is even associated with tumor development. While numerous mechanisms were developed by HCMV to interfere with immune cell activity, much less is known about cellular mechanisms that operate in response to HCMV infection. Here we demonstrate that in response to HCMV infection, the expression of the short form of the RNA editing enzyme ADAR1 (ADAR1-p110) is induced. We identified the specific promoter region responsible for this induction and we show that ADAR1-p110 can edit miR-376a. Accordingly, we demonstrate that the levels of the edited-miR-376a (miR-376a(e)) increase during HCMV infection. Importantly, we show that miR-376a(e) downregulates the immune modulating molecule HLA-E and that this consequently renders HCMV infected cells susceptible to elimination by NK cells.


Zdroje

1. MocarskiESJr (2002) Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol 10: 332–339.

2. WilkinsonGW, TomasecP, StantonRJ, ArmstrongM, Prod'hommeV, et al. (2008) Modulation of natural killer cells by human cytomegalovirus. J Clin Virol 41: 206–212.

3. ParkB, SpoonerE, HouserBL, StromingerJL, PloeghHL (2010) The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation. J Exp Med 207: 2033–2041.

4. FurmanMH, DeyN, TortorellaD, PloeghHL (2002) The human cytomegalovirus US10 gene product delays trafficking of major histocompatibility complex class I molecules. J Virol 76: 11753–11756.

5. TomasecP, BraudVM, RickardsC, PowellMB, McSharryBP, et al. (2000) Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287: 1031.

6. UlbrechtM, MartinozziS, GrzeschikM, HengelH, EllwartJW, et al. (2000) Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J Immunol 164: 5019–5022.

7. ArnonTI, MarkelG, MandelboimO (2006) Tumor and viral recognition by natural killer cells receptors. Semin Cancer Biol 16: 348–358.

8. LongEO, Sik KimH, LiuD, PetersonME, RajagopalanS (2013) Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol 31: 227–258.

9. MorettaA, BottinoC, VitaleM, PendeD, CantoniC, et al. (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19: 197–223.

10. SeidelE, GlasnerA, MandelboimO (2012) Virus-mediated inhibition of natural cytotoxicity receptor recognition. Cell Mol Life Sci [epub ahead of print].

11. LjunggrenHG, KarreK (1985) Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism. J Exp Med 162: 1745–1759.

12. RauletDH (2006) Missing self recognition and self tolerance of natural killer (NK) cells. Semin Immunol 18: 145–150.

13. O'CallaghanCA (2000) Molecular basis of human natural killer cell recognition of HLA-E (human leucocyte antigen-E) and its relevance to clearance of pathogen-infected and tumour cells. Clin Sci (Lond) 99: 9–17.

14. O'CallaghanCA (2000) Natural killer cell surveillance of intracellular antigen processing pathways mediated by recognition of HLA-E and Qa-1b by CD94/NKG2 receptors. Microbes Infect 2: 371–380.

15. BraudVM, AllanDS, O'CallaghanCA, SoderstromK, D'AndreaA, et al. (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391: 795–799.

16. GumaM, AnguloA, VilchesC, Gomez-LozanoN, MalatsN, et al. (2004) Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104: 3664–3671.

17. RauletDH, GasserS, GowenBG, DengW, JungH (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31: 413–441.

18. RauletDH (2003) Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3: 781–790.

19. NachmaniD, LankryD, WolfDG, MandelboimO (2010) The human cytomegalovirus microRNA miR-UL112 acts synergistically with a cellular microRNA to escape immune elimination. Nat Immunol 11: 806–813.

20. Stern-GinossarN, GurC, BitonM, HorwitzE, ElboimM, et al. (2008) Human microRNAs regulate stress-induced immune responses mediated by the receptor NKG2D. Nat Immunol 9: 1065–1073.

21. TsukermanP, Stern-GinossarN, GurC, GlasnerA, NachmaniD, et al. (2012) MiR-10b downregulates the stress-induced cell surface molecule MICB, a critical ligand for cancer cell recognition by natural killer cells. Cancer Res 72: 5463–5472.

22. KawaharaY, ZinshteynB, SethupathyP, IizasaH, HatzigeorgiouAG, et al. (2007) Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315: 1137–1140.

23. FarajollahiS, MaasS (2010) Molecular diversity through RNA editing: a balancing act. Trends Genet 26: 221–230.

24. NishikuraK (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79: 321–349.

25. PattersonJB, SamuelCE (1995) Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol Cell Biol 15: 5376–5388.

26. GeorgeCX, SamuelCE (1999) Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc Natl Acad Sci U S A 96: 4621–4626.

27. GeorgeCX, SamuelCE (1999) Characterization of the 5′-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter. Gene 229: 203–213.

28. KawakuboK, SamuelCE (2000) Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 258: 165–172.

29. HartnerJC, SchmittwolfC, KispertA, MullerAM, HiguchiM, et al. (2004) Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem 279: 4894–4902.

30. WangQ, MiyakodaM, YangW, KhillanJ, StachuraDL, et al. (2004) Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem 279: 4952–4961.

31. XuFengR, BoyerMJ, ShenH, LiY, YuH, et al. (2009) ADAR1 is required for hematopoietic progenitor cell survival via RNA editing. Proc Natl Acad Sci U S A 106: 17763–17768.

32. HiguchiM, MaasS, SingleFN, HartnerJ, RozovA, et al. (2000) Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406: 78–81.

33. SamuelCE (2012) ADARs: viruses and innate immunity. Curr Top Microbiol Immunol 353: 163–195.

34. TenoeverBR, NgSL, ChuaMA, McWhirterSM, Garcia-SastreA, et al. (2007) Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science 315: 1274–1278.

35. TaylorDR, PuigM, DarnellME, MihalikK, FeinstoneSM (2005) New antiviral pathway that mediates hepatitis C virus replicon interferon sensitivity through ADAR1. J Virol 79: 6291–6298.

36. SuspeneR, RenardM, HenryM, GuetardD, Puyraimond-ZemmourD, et al. (2008) Inversing the natural hydrogen bonding rule to selectively amplify GC-rich ADAR-edited RNAs. Nucleic Acids Res 36: e72.

37. ChambersP, RimaBK, DuprexWP (2009) Molecular differences between two Jeryl Lynn mumps virus vaccine component strains, JL5 and JL2. J Gen Virol 90: 2973–2981.

38. BaumanY, NachmaniD, VitenshteinA, TsukermanP, DraymanN, et al. (2011) An identical miRNA of the human JC and BK polyoma viruses targets the stress-induced ligand ULBP3 to escape immune elimination. Cell Host Microbe 9: 93–102.

39. BartelDP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

40. EbertMS, NeilsonJR, SharpPA (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4: 721–726.

41. BorregoF, UlbrechtM, WeissEH, ColiganJE, BrooksAG (1998) Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med 187: 813–818.

42. HouchinsJP, LanierLL, NiemiEC, PhillipsJH, RyanJC (1997) Natural killer cell cytolytic activity is inhibited by NKG2-A and activated by NKG2-C. J Immunol 158: 3603–3609.

43. LeeN, LlanoM, CarreteroM, IshitaniA, NavarroF, et al. (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci U S A 95: 5199–5204.

44. WeisblumY, PanetA, Zakay-RonesZ, Haimov-KochmanR, Goldman-WohlD, et al. (2011) Modeling of human cytomegalovirus maternal-fetal transmission in a novel decidual organ culture. J Virol 85: 13204–13213.

45. SkalskyRL, CullenBR (2010) Viruses, microRNAs, and host interactions. Annu Rev Microbiol 64: 123–141.

46. LiT, ChenJ, CristeaIM (2013) Human Cytomegalovirus Tegument Protein pUL83 Inhibits IFI16-Mediated DNA Sensing for Immune Evasion. Cell Host Microbe 14: 591–599.

47. BeziatV, HervierB, AchourA, BoutolleauD, Marfain-KokaA, et al. (2011) Human NKG2A overrides NKG2C effector functions to prevent autoreactivity of NK cells. Blood 117: 4394–4396.

48. MagriG, MuntasellA, RomoN, Saez-BorderiasA, PendeD, et al. (2011) NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 117: 848–856.

49. BjorkstromNK, LindgrenT, StoltzM, FauriatC, BraunM, et al. (2011) Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 208: 13–21.

50. Stern-GinossarN, ElefantN, ZimmermannA, WolfDG, SalehN, et al. (2007) Host immune system gene targeting by a viral miRNA. Science 317: 376–381.

51. KozomaraA, Griffiths-JonesS (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39: D152–157.

52. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760.

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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