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HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation


Autoři: Iliyana Mikell aff001;  Lindsey B. Crawford aff001;  Meaghan H. Hancock aff001;  Jennifer Mitchell aff001;  Jason Buehler aff002;  Felicia Goodrum aff002;  Jay A. Nelson aff001
Působiště autorů: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America aff001;  Department of Immunobiology, BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America aff002
Vyšlo v časopise: HCMV miR-US22 down-regulation of EGR-1 regulates CD34+ hematopoietic progenitor cell proliferation and viral reactivation. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1007854
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007854

Souhrn

Reactivation of latent Human Cytomegalovirus (HCMV) in CD34+ hematopoietic progenitor cells (HPCs) is closely linked to hematopoiesis. Viral latency requires maintenance of the progenitor cell quiescence, while reactivation initiates following mobilization of HPCs to the periphery and differentiation into CD14+ macrophages. Early growth response gene 1 (EGR-1) is a transcription factor activated by Epidermal growth factor receptor (EGFR) signaling that is essential for the maintenance of CD34+ HPC self-renewal in the bone marrow niche. Down-regulation of EGR-1 results in mobilization and differentiation of CD34+ HPC from the bone marrow to the periphery. In the current study we demonstrate that the transcription factor EGR-1 is directly targeted for down-regulation by HCMV miR-US22 that results in decreased proliferation of CD34+ HPCs and a decrease in total hematopoietic colony formation. We also show that an HCMV miR-US22 mutant fails to reactivate in CD34+ HPCs, indicating that expression of EGR-1 inhibits viral reactivation. Since EGR-1 promotes CD34+ HPC self-renewal in the bone marrow niche, HCMV miR-US22 down-regulation of EGR-1 is a necessary step to block HPC self-renewal and proliferation to induce a cellular differentiation pathway necessary to promote reactivation of virus.

Klíčová slova:

Bone marrow cells – Cell differentiation – Human cytomegalovirus – MicroRNAs – Stem cells – Transcription factors – Viral persistence and latency – Viral replication


Zdroje

1. Aguado JM, Navarro D, San Juan R, Caston JJ. Cytomegalovirus infection in solid organ transplantation. Enfermedades infecciosas y microbiologia clinica. 2012;30 Suppl 2:57–62. Epub 2012/05/11. doi: 10.1016/S0213-005X(12)70083-6 22542036.

2. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am. 2011;25(1):151–69. Epub 2011/01/18. doi: 10.1016/j.hoc.2010.11.011 21236396.

3. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infection & chemotherapy. 2013;45(3):260–71. Epub 2014/01/08. doi: 10.3947/ic.2013.45.3.260 24396627.

4. Smith MS, Goldman DC, Bailey AS, Pfaffle DL, Kreklywich CN, Spencer DB, et al. Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. Cell Host Microbe. 2010;8(3):284–91. Epub 2010/09/14. doi: 10.1016/j.chom.2010.08.001 20833379.

5. Goodrum FD, Jordan CT, High K, Shenk T. Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(25):16255–60. Epub 2002/11/29. doi: 10.1073/pnas.252630899 12456880.

6. Collins-McMillen D, Buehler J, Peppenelli M, Goodrum F. Molecular Determinants and the Regulation of Human Cytomegalovirus Latency and Reactivation. Viruses. 2018;10(8). doi: 10.3390/v10080444 30127257.

7. Elder E, Sinclair J. HCMV latency: what regulates the regulators? Medical microbiology and immunology. 2019. doi: 10.1007/s00430-019-00581-1 30761409.

8. Cheng S, Caviness K, Buehler J, Smithey M, Nikolich-Zugich J, Goodrum F. Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(49):E10586–E95. Epub 2017/11/22. doi: 10.1073/pnas.1710522114 29158406.

9. Soderberg-Naucler C, Fish KN, Nelson JA. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell. 1997;91(1):119–26. Epub 1997/10/23. doi: 10.1016/s0092-8674(01)80014-3 9335340.

10. Soderberg-Naucler C, Streblow DN, Fish KN, Allan-Yorke J, Smith PP, Nelson JA. Reactivation of latent human cytomegalovirus in CD14(+) monocytes is differentiation dependent. Journal of virology. 2001;75(16):7543–54. Epub 2001/07/20. doi: 10.1128/JVI.75.16.7543-7554.2001 11462026.

11. Taylor-Wiedeman J, Sissons P, Sinclair J. Induction of endogenous human cytomegalovirus gene expression after differentiation of monocytes from healthy carriers. Journal of virology. 1994;68(3):1597–604. Epub 1994/03/01. 8107221.

12. Goodrum F. Human Cytomegalovirus Latency: Approaching the Gordian Knot. Annu Rev Virol. 2016;3(1):333–57. Epub 2016/08/09. doi: 10.1146/annurev-virology-110615-042422 27501258.

13. Sukhatme VP, Kartha S, Toback FG, Taub R, Hoover RG, Tsai-Morris CH. A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. Oncogene research. 1987;1(4):343–55. Epub 1987/09/01. 3130602.

14. Lim RW, Varnum BC, Herschman HR. Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene. 1987;1(3):263–70. Epub 1987/01/01. 3330774.

15. Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987;238(4828):797–9. Epub 1987/11/06. doi: 10.1126/science.3672127 3672127.

16. Christy BA, Lau LF, Nathans D. A gene activated in mouse 3T3 cells by serum growth factors encodes a protein with "zinc finger" sequences. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(21):7857–61. Epub 1988/11/01. doi: 10.1073/pnas.85.21.7857 3141919.

17. Thiel G, Cibelli G. Regulation of life and death by the zinc finger transcription factor Egr-1. Journal of cellular physiology. 2002;193(3):287–92. Epub 2002/10/18. doi: 10.1002/jcp.10178 12384981.

18. Min IM, Pietramaggiori G, Kim FS, Passegue E, Stevenson KE, Wagers AJ. The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell. 2008;2(4):380–91. Epub 2008/04/10. doi: 10.1016/j.stem.2008.01.015 18397757.

19. Liu C, Yao J, de Belle I, Huang RP, Adamson E, Mercola D. The transcription factor EGR-1 suppresses transformation of human fibrosarcoma HT1080 cells by coordinated induction of transforming growth factor-beta1, fibronectin, and plasminogen activator inhibitor-1. The Journal of biological chemistry. 1999;274(7):4400–11. Epub 1999/02/06. doi: 10.1074/jbc.274.7.4400 9933644.

20. Krishnaraju K, Hoffman B, Liebermann DA. Early growth response gene 1 stimulates development of hematopoietic progenitor cells along the macrophage lineage at the expense of the granulocyte and erythroid lineages. Blood. 2001;97(5):1298–305. Epub 2001/02/27. doi: 10.1182/blood.v97.5.1298 11222373.

21. Nguyen HQ, Hoffman-Liebermann B, Liebermann DA. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell. 1993;72(2):197–209. Epub 1993/01/29. doi: 10.1016/0092-8674(93)90660-i 7678779.

22. Buehler J, Zeltzer S, Reitsma J, Petrucelli A, Umashankar M, Rak M, et al. Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. PLoS pathogens. 2016;12(5):e1005655. Epub 2016/05/25. doi: 10.1371/journal.ppat.1005655 27218650.

23. Kim JH, Collins-McMillen D, Buehler JC, Goodrum FD, Yurochko AD. Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34(+) Human Progenitor Cells. Journal of virology. 2017;91(5). Epub 2016/12/16. doi: 10.1128/JVI.01206-16 27974567.

24. Rak MA, Buehler J, Zeltzer S, Reitsma J, Molina B, Terhune S, et al. Human Cytomegalovirus UL135 Interacts with Host Adaptor Proteins To Regulate Epidermal Growth Factor Receptor and Reactivation from Latency. Journal of virology. 2018;92(20). Epub 2018/08/10. doi: 10.1128/JVI.00919-18 30089695.

25. Stark TJ, Arnold JD, Spector DH, Yeo GW. High-resolution profiling and analysis of viral and host small RNAs during human cytomegalovirus infection. Journal of virology. 2012;86(1):226–35. Epub 2011/10/21. doi: 10.1128/JVI.05903-11 22013051.

26. Grey F, Antoniewicz A, Allen E, Saugstad J, McShea A, Carrington JC, et al. Identification and characterization of human cytomegalovirus-encoded microRNAs. Journal of virology. 2005;79(18):12095–9. Epub 2005/09/06. doi: 10.1128/JVI.79.18.12095-12099.2005 16140786.

27. Diggins NL, Hancock MH. HCMV miRNA Targets Reveal Important Cellular Pathways for Viral Replication, Latency, and Reactivation. Noncoding RNA. 2018;4(4). Epub 2018/10/27. doi: 10.3390/ncrna4040029 30360396.

28. Grey F, Meyers H, White EA, Spector DH, Nelson J. A human cytomegalovirus-encoded microRNA regulates expression of multiple viral genes involved in replication. PLoS pathogens. 2007;3(11):e163. Epub 2007/11/07. doi: 10.1371/journal.ppat.0030163 17983268.

29. Murphy E, Vanicek J, Robins H, Shenk T, Levine AJ. Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: implications for latency. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(14):5453–8. Epub 2008/04/02. doi: 10.1073/pnas.0711910105 18378902.

30. Hook LM, Grey F, Grabski R, Tirabassi R, Doyle T, Hancock M, et al. Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe. 2014;15(3):363–73. Epub 2014/03/19. doi: 10.1016/j.chom.2014.02.004 24629342.

31. Hancock MH, Hook LM, Mitchell J, Nelson JA. Human Cytomegalovirus MicroRNAs miR-US5–1 and miR-UL112–3p Block Proinflammatory Cytokine Production in Response to NF-kappaB-Activating Factors through Direct Downregulation of IKKalpha and IKKbeta. MBio. 2017;8(2). Epub 2017/03/09. doi: 10.1128/mBio.00109-17 28270578.

32. Kim Y, Lee S, Kim S, Kim D, Ahn JH, Ahn K. Human cytomegalovirus clinical strain-specific microRNA miR-UL148D targets the human chemokine RANTES during infection. PLoS pathogens. 2012;8(3):e1002577. Epub 2012/03/14. doi: 10.1371/journal.ppat.1002577 22412377.

33. Landais I, Pelton C, Streblow D, DeFilippis V, McWeeney S, Nelson JA. Human Cytomegalovirus miR-UL112–3p Targets TLR2 and Modulates the TLR2/IRAK1/NFkappaB Signaling Pathway. PLoS pathogens. 2015;11(5):e1004881. Epub 2015/05/09. doi: 10.1371/journal.ppat.1004881 25955717.

34. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M, et al. Host immune system gene targeting by a viral miRNA. Science. 2007;317(5836):376–81. Epub 2007/07/21. doi: 10.1126/science.1140956 17641203.

35. Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O. Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe. 2009;5(4):376–85. Epub 2009/04/22. doi: 10.1016/j.chom.2009.03.003 19380116.

36. Babu SG, Pandeya A, Verma N, Shukla N, Kumar RV, Saxena S. Role of HCMV miR-UL70–3p and miR-UL148D in overcoming the cellular apoptosis. Mol Cell Biochem. 2014;393(1–2):89–98. Epub 2014/04/17. doi: 10.1007/s11010-014-2049-8 24737391.

37. Pan D, Flores O, Umbach JL, Pesola JM, Bentley P, Rosato PC, et al. A neuron-specific host microRNA targets herpes simplex virus-1 ICP0 expression and promotes latency. Cell Host Microbe. 2014;15(4):446–56. Epub 2014/04/12. doi: 10.1016/j.chom.2014.03.004 24721573.

38. Ellis-Connell AL, Iempridee T, Xu I, Mertz JE. Cellular microRNAs 200b and 429 regulate the Epstein-Barr virus switch between latency and lytic replication. Journal of virology. 2010;84(19):10329–43. Epub 2010/07/30. doi: 10.1128/JVI.00923-10 20668090.

39. Grey F, Tirabassi R, Meyers H, Wu G, McWeeney S, Hook L, et al. A viral microRNA down-regulates multiple cell cycle genes through mRNA 5'UTRs. PLoS pathogens. 2010;6(6):e1000967. Epub 2010/06/30. doi: 10.1371/journal.ppat.1000967 20585629.

40. Qi M, Qi Y, Ma Y, He R, Ji Y, Sun Z, et al. Over-expression of human cytomegalovirus miR-US25-2-3p downregulates eIF4A1 and inhibits HCMV replication. FEBS Lett. 2013;587(14):2266–71. Epub 2013/06/12. doi: 10.1016/j.febslet.2013.05.057 23747307.

41. Stern-Ginossar N, Saleh N, Goldberg MD, Prichard M, Wolf DG, Mandelboim O. Analysis of human cytomegalovirus-encoded microRNA activity during infection. Journal of virology. 2009;83(20):10684–93. Epub 2009/08/07. doi: 10.1128/JVI.01292-09 19656885.

42. Umashankar M, Goodrum F. Hematopoietic long-term culture (hLTC) for human cytomegalovirus latency and reactivation. Methods Mol Biol. 2014;1119:99–112. Epub 2014/03/19. doi: 10.1007/978-1-62703-788-4_7 24639220.

43. Crawford LB, Kim JH, Collins-McMillen D, Lee BJ, Landais I, Held C, et al. Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation. MBio. 2018;9(2). Epub 2018/04/25. doi: 10.1128/mBio.00682-18 29691342.

44. Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nature reviews Genetics. 2008;9(2):115–28. Epub 2008/01/19. doi: 10.1038/nrg2269 18202695.

45. Martinez-Agosto JA, Mikkola HK, Hartenstein V, Banerjee U. The hematopoietic stem cell and its niche: a comparative view. Genes Dev. 2007;21(23):3044–60. Epub 2007/12/07. doi: 10.1101/gad.1602607 18056420.

46. Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nature reviews Molecular cell biology. 2009;10(2):116–25. doi: 10.1038/nrm2621 19165214.

47. Georgantas RW 3rd, Hildreth R, Morisot S, Alder J, Liu CG, Heimfeld S, et al. CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(8):2750–5. Epub 2007/02/13. doi: 10.1073/pnas.0610983104 17293455.

48. Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell. 2006;126(4):755–66. Epub 2006/08/23. doi: 10.1016/j.cell.2006.06.052 16923394.

49. Pritchard MT, Malinak RN, Nagy LE. Early growth response (EGR)-1 is required for timely cell-cycle entry and progression in hepatocytes after acute carbon tetrachloride exposure in mice. American journal of physiology Gastrointestinal and liver physiology. 2011;300(6):G1124–31. Epub 2011/03/19. doi: 10.1152/ajpgi.00544.2010 21415413.

50. Buehler J, Carpenter E, Zeltzer S, Igarashi S, Rak M, Mikell I, et al. EGR1 transcriptional control of human cytomegalovirus latency. bioRxiv. 2019:648543.

51. Bellare P, Ganem D. Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe. 2009;6(6):570–5. Epub 2009/12/17. doi: 10.1016/j.chom.2009.11.008 20006845.

52. Pan C, Zhu D, Wang Y, Li L, Li D, Liu F, et al. Human Cytomegalovirus miR-UL148D Facilitates Latent Viral Infection by Targeting Host Cell Immediate Early Response Gene 5. PLoS pathogens. 2016;12(11):e1006007. Epub 2016/11/09. doi: 10.1371/journal.ppat.1006007 27824944.

53. Kennedy GA, Kay TD, Johnson DW, Hawley CM, Campbell SB, Isbel NM, et al. Neutrophil dysplasia characterised by a pseudo-Pelger-Huet anomaly occurring with the use of mycophenolate mofetil and ganciclovir following renal transplantation: a report of five cases. Pathology. 2002;34(3):263–6. Epub 2002/07/12. doi: 10.1080/0031302022013136 12109788.

54. Chen Y, Fachko D, Ivanov NS, Skinner CM, Skalsky RL. Epstein-Barr virus microRNAs regulate B cell receptor signal transduction and lytic reactivation. PLoS pathogens. 2019;15(1):e1007535. Epub 2019/01/08. doi: 10.1371/journal.ppat.1007535 30615681.

55. Crawford LB, Tempel R, Streblow DN, Kreklywich C, Smith P, Picker LJ, et al. Human Cytomegalovirus Induces Cellular and Humoral Virus-specific Immune Responses in Humanized BLT Mice. Sci Rep. 2017;7(1):937. Epub 2017/04/22. doi: 10.1038/s41598-017-01051-5 28428537.

56. Caviness K, Bughio F, Crawford LB, Streblow DN, Nelson JA, Caposio P, et al. Complex Interplay of the UL136 Isoforms Balances Cytomegalovirus Replication and Latency. MBio. 2016;7(2):e01986. Epub 2016/03/05. doi: 10.1128/mBio.01986-15 26933055.

57. Sinzger C, Hahn G, Digel M, Katona R, Sampaio KL, Messerle M, et al. Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. The Journal of general virology. 2008;89(Pt 2):359–68. Epub 2008/01/17. doi: 10.1099/vir.0.83286-0 18198366.

58. Umashankar M, Petrucelli A, Cicchini L, Caposio P, Kreklywich CN, Rak M, et al. A novel human cytomegalovirus locus modulates cell type-specific outcomes of infection. PLoS pathogens. 2011;7(12):e1002444. Epub 2012/01/14. doi: 10.1371/journal.ppat.1002444 22241980.

59. Fellmann C, Hoffmann T, Sridhar V, Hopfgartner B, Muhar M, Roth M, et al. An optimized microRNA backbone for effective single-copy RNAi. Cell Rep. 2013;5(6):1704–13. Epub 2013/12/18. doi: 10.1016/j.celrep.2013.11.020 24332856.

60. Miller CL, Eaves CJ. Long-term culture-initiating cell assays for human and murine cells. In: Klug CA, Jordan CT, editors. Hematopoietic Stem Cell Protocols. Methods in Molecular Medicine. Totowa: Humana Press; 2002. p. 123–41.

61. Goodrum F, Reeves M, Sinclair J, High K, Shenk T. Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro. Blood. 2007;110(3):937–45. Epub 2007/04/19. doi: 10.1182/blood-2007-01-070078 17440050.

62. Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. Journal of immunological methods. 2009;347(1–2):70–8. Epub 2009/07/02. doi: 10.1016/j.jim.2009.06.008 19567251.

63. Nissen-Druey C, Tichelli A, Meyer-Monard S. Human Hematopoietic Colonies in Health and Disease. Karger; 2005.

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