Virologica Sinica

, Volume 32, Issue 5, pp 431–439 | Cite as

Human cytomegalovirus miR-US5-1 inhibits viral replication by targeting Geminin mRNA

  • Shujuan Jiang
  • Yujing Huang
  • Ying Qi
  • Rong He
  • Zhongyang Liu
  • Yanping Ma
  • Xin Guo
  • Yaozhong Shao
  • Zhengrong Sun
  • Qiang Ruan
Research Article

Abstract

Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. MicroRNAs (miRNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus (HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin (GMNN) was identified to be a direct target of hcmv-miR-US5-1. Overexpression of hcmv-miR-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-miR-US5-1 or GMNN specific siRNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-miR-US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-miR-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection.

Keywords

Human cytomegalovirus (HCMV) hcmv-miR-US5-1 Geminin (GMNN) DNA replication cell cycle 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

12250_2017_4064_MOESM1_ESM.pdf (115 kb)
Human cytomegalovirus miR-US5-1 inhibits viral replication by targeting Geminin mRNA

References

  1. Babu SG, Pandeya A, Verma N, Shukla N, Kumar RV, Saxena S. 2014. Role of HCMV miR-UL70-3p and miR-UL148D in overcoming the cellular apoptosis. Mol Cell Biochem, 393: 89–98.CrossRefPubMedGoogle Scholar
  2. Ballabeni A, Zamponi R, Moore JK, Helin K, Kirschner MW. 2013. Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication. Proc Natl Acad Sci U S A, 110: E2848–E2853.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Barry KA, Schultz KM, Payne CJ, McGarry TJ. 2012. Geminin is required for mitotic proliferation of spermatogonia. Dev Biol, 371: 35–46.CrossRefPubMedGoogle Scholar
  4. Biswas N, Sanchez V, Spector DH. 2003. Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication. J Virol, 77: 2369–2376.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Caffarelli N, Fehr AR, Yu D. 2013. Cyclin A degradation by primate cytomegalovirus protein pUL21a counters its innate restriction of virus replication. PLoS Pathog, 9: e1003825.CrossRefPubMedPubMedCentralGoogle Scholar
  6. de Renty C, Kaneko KJ, Depamphilis ML. 2014. The dual roles of geminin during trophoblast proliferation and differentiation. Dev Biol, 387: 49–63.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Einsele H, Hebart H. 1999. Cytomegalovirus infection following stem cell transplantation. Haematologica, 84 Suppl EHA-4: 46–49.PubMedGoogle Scholar
  8. Fehr AR, Yu D. 2013. Control the host cell cycle: viral regulation of the anaphase-promoting complex. J Virol, 87: 8818–8825.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fu M, Gao Y, Zhou Q, Zhang Q, Peng Y, Tian K. 2014. Human cytomegalovirus latent infection alters the expression of cellular and viral microRNA. Gene, 536: 272–278.CrossRefPubMedGoogle Scholar
  10. Gottwein E, Cullen BR. 2008. Viral and cellular microRNAs as determinants of viral pathogenesis and immunity. Cell Host Microbe, 3: 375–387.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Grey F, Meyers H, White EA, Spector DH, Nelson J. 2007. A human cytomegalovirus-encoded microRNA regulates expression of multiple viral genes involved in replication. PLoS Pathog, 3: e163.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Grey F, Tirabassi R, Meyers H, Wu G, McWeeney S, Hook L. 2010. A viral microRNA down-regulates multiple cell cycle genes through mRNA 5'UTRs. PLoS Pathog, 6: e1000967.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Guo X, Qi Y, Huang Y, Liu Z, Ma Y, Shao Y. 2015. Human cytomegalovirus miR-US33-5p inhibits viral DNA synthesis and viral replication by down-regulating expression of the host Syntaxin3. Febs Lett, 589: 440–446.CrossRefPubMedGoogle Scholar
  14. Hook LM, Grey F, Grabski R, Tirabassi R, Doyle T, Hancock M. 2014. Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe, 15: 363–373.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Huang Y, Qi Y, Ruan Q, Ma Y, He R, Ji Y. 2011. A rapid method to screen putative mRNA targets of any known microRNA. Virol J, 8: 8.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Huang Y, Chen D, He J, Cai J, Shen K, Liu X. 2014. Hcmv-miRUL112 attenuates NK cell activity by inhibition type I interferon secretion. Immunol Lett, 163: 151–156.CrossRefPubMedGoogle Scholar
  17. Khoshnevis M, Tyring SK. 2002. Cytomegalovirus infections. Dermatol Clin, 20: 291–299.CrossRefPubMedGoogle Scholar
  18. Kim S, Lee S, Shin J, Kim Y, Evnouchidou I, Kim D. 2011. Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol, 12: 984–991.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kloosterman WP, Plasterk RH. 2006. The diverse functions of microRNAs in animal development and disease. Dev Cell, 11: 441–450.CrossRefPubMedGoogle Scholar
  20. Klotz-Noack K, McIntosh D, Schurch N, Pratt N, Blow JJ. 2012. Re-replication induced by geminin depletion occurs from G2 and is enhanced by checkpoint activation. J Cell Sci, 125: 2436–2445.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Schmittgen TD, Lee EJ, Jiang J, Sarkar A, Yang L, Elton TS. 2008. Real-time PCR quantification of precursor and mature microRNA. Methods, 44: 31–38.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Shen ZZ, Pan X, Miao LF, Ye HQ, Chavanas S, Davrinche C. 2014. Comprehensive analysis of human cytomegalovirus microRNA expression during lytic and quiescent infection. PLoS One, 9: e88531.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Shreeram S, Sparks A, Lane DP, Blow JJ. 2002. Cell type-specific responses of human cells to inhibition of replication licensing. Oncogene, 21: 6624–6632.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Stark TJ, Amold JD, Spector DH, Yeo GW. 2012. High-resolution profiling and analysis of viral and host small RNAs during human cytomegalovirus infection. J Virol, 86: 226–235.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Stern-Ginossar N, Elefant N, Zimmermann A, Wolf DG, Saleh N, Biton M. 2007. Host immune system gene targeting by a viral miRNA. Science, 317: 376–381.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Stern-Ginossar N, Saleh N, Goldberg MD, Prichard M, Wolf DG, Mandelboim O. 2009. Analysis of human cytomegalovirus-encoded microRNA activity during infection. J Virol, 83: 10684–10693.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Tada S. 2007. Cdt1 and geminin: role during cell cycle progression and DNA damage in higher eukaryotes. Front Biosci, 12: 1629–1641.CrossRefPubMedGoogle Scholar
  28. Tirabassi R, Hook L, Landais I, Grey F, Meyers H, Hewitt H. 2011. Human cytomegalovirus US7 is regulated synergistically by two virally encoded microRNAs and by two distinct mechanisms. J Virol, 85: 11938–11944.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Qi M, Qi Y, Ma Y, He R, Ji Y, Sun Z. 2013. Over-expression of human cytomegalovirus miR-US25-2-3p downregulates eIF4A1 and inhibits HCMV replication. Febs Lett, 587: 2266–2271.CrossRefPubMedGoogle Scholar
  30. Wohlschlegel JA, Kutok JL, Weng AP, Dutta A. 2002. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Am J Pathol, 161: 267–273.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Wu M, Lu W, Santos RE, Frattini MG, Kelly TJ. 2014. Geminin inhibits a late step in the formation of human pre-replicative complexes. J Biol Chem, 289: 30810–30821.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Yoshida K, Oyaizu N, Dutta A, Inoue I. 2004. The destruction box of human Geminin is critical for proliferation and tumor growth in human colon cancer cells. Oncogene, 23: 58–70.CrossRefPubMedGoogle Scholar
  33. Zhao Y, Srivastava D. 2007. A developmental view of microRNA function. Trends Biochem Sci, 32: 189–197.CrossRefPubMedGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Virus Laboratory, the Affiliated Shengjing HospitalChina Medical UniversityShenyangChina
  2. 2.Clinical Genetics, the Affiliated Shengjing HospitalChina Medical UniversityShenyangChina

Personalised recommendations