Document Type : Review Article


1 Department of Pathology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran

2 Academy of Medical Sciences of I.R. Iran, Tehran, Iran

3 Department of Pathology, Pathology and Stem cells Research Center, Afzalipour Medical School, Kerman University of Medical Sciences, Kerman, Iran

4 Tehran University of Medical Sciences, Tehran, Iran


The nucleolus is a subcellular membraneless structure of eukaryotic cells. In 1965, in a world’s southern summer summit in Uruguay, the role of the nucleolus as the site of ribosome synthesis, biogenesis, and processing of tRNA was conclusively established. Today, accumulating evidence confirm the multiple functions of the nucleolus, including tRNA precursor processing, cell stress sensing, as well as being influential in gene silencing, senescence, lifespan, DNA damage response (DDR), and cell cycle regulation. Therefore, nucleolopathy is observed in various human diseases. Modern advances have provided fundamental insights concerning how and why the nucleolus is targeted by different pathogenic organisms. Viruses are major organisms that disrupt the normal function of the nucleus and produce nucleoli proteins for facilitating the replication of viruses causing viral infections. In this review, we focus on the possible role of nucleoli upon coronavirus infections, in particular coronavirus disease 2019.


Main Subjects

  1. Pederson T. The nucleolus. Cold Spring Harbor perspectives in biology. 2011;3(3):a000638. [DOI:10.1101/cshperspect.a000638] [PMID] [PMCID]
  2. Bahadori M, Azizi MH, Dabiri S. Recent Advances on Nucleolar Functions in Health and Disease. Arch Iran Med. 2018;21(12):600-7.
  3. Montgomery Jr TS. Comparative cytological studies, with especial regard to the morphology of the nucleolus. J Morphol. 1898;15(2):265-582. [DOI:10.1002/jmor.1050150204]
  4. Pianese G. Beitrag zur histologie und aetiologie des carcinoms: G. Fischer; 1896.
  5. Pederson T. The nucleolus. Cold Spring Harb Perspect Biol 3: a000638. 2011. [PMID] [PMCID] [DOI:10.1101/cshperspect.a000638]
  6. Raska I, Shaw PJ, Cmarko D. New insights into nucleolar architecture and activity. Int Rev Cytol. 2006;255:177-235. [DOI:10.1016/S0074-7696(06)55004-1]
  7. Lam YW, Trinkle-Mulcahy L. New insights into nucleolar structure and function. F1000prime reports. 2015;7:48. [DOI:10.12703/P7-48] [PMID] [PMCID]
  8. Hiscox JA. RNA viruses: hijacking the dynamic nucleolus. Nat Rev Microbiol. 2007;5(2):119-27. [DOI:10.1038/nrmicro1597] [PMID] [PMCID]
  9. Emmott E, Hiscox JA. Nucleolar targeting: the hub of the matter. EMBO Rep. 2009;10(3):231-8. [DOI:10.1038/embor.2009.14] [PMID] [PMCID]
  10. Hiscox JA, Whitehouse A, Matthews DA. Nucleolar proteomics and viral infection. Proteomics. 2010;10(22):4077-86. [PMID] [PMCID] [DOI:10.1002/pmic.201000251]


  1. Tiku V, Antebi A. Nucleolar Function in Lifespan Regulation. Trends Cell Biol. 2018;28(8):662-72. [DOI:10.1016/j.tcb.2018.03.007] [PMID]
  2. Swovick K, Firsanov D, Welle KA, Hryhorenko JR, Wise JP, Sr., George C, et al. Interspecies Differences in Proteome Turnover Kinetics Are Correlated With Life Spans and Energetic Demands. Mol Cell Proteomics. 2021;20:100041. [PMID] [PMCID] [DOI:10.1074/mcp.RA120.002301]
  3. Pederson T, Tsai RYL. In search of nonribosomal nucleolar protein function and regulation. The Journal of cell biology. 2009;184(6):771-6. [DOI:10.1083/jcb.200812014] [PMID] [PMCID]
  4. Correll CC, Bartek J, Dundr M. The Nucleolus: A Multiphase Condensate Balancing Ribosome Synthesis and Translational Capacity in Health, Aging and Ribosomopathies. Cells. 2019;8(8). [DOI:10.3390/cells8080869] [PMID] [PMCID]
  5. Salvetti A, Greco A. Viruses and the nucleolus: the fatal attraction. Biochim Biophys Acta. 2014;1842(6):840-7. [PMID] [PMCID] [DOI:10.1016/j.bbadis.2013.12.010]
  6. Greco A. Involvement of the nucleolus in replication of human viruses. Rev Med Virol. 2009;19(4):201-14. [DOI:10.1002/rmv.614] [PMID] [PMCID]
  7. Chen H, Wurm T, Britton P, Brooks G, Hiscox JA. Interaction of the coronavirus nucleoprotein with nucleolar antigens and the host cell. J Virol. 2002;76(10):5233-50. [PMID] [PMCID] [DOI:10.1128/JVI.76.10.5233-5250.2002]
  8. Cawood R, Harrison SM, Dove BK, Reed ML, Hiscox JA. Cell cycle dependent nucleolar localization of the coronavirus nucleocapsid protein. Cell Cycle. 2007;6(7):863-7. [DOI:10.4161/cc.6.7.4032] [PMID]
  9. Korsholm LM, Gál Z, Nieto B, Quevedo O, Boukoura S, Lund CC, et al. Recent advances in the nucleolar responses to DNA double-strand breaks. Nucleic Acids Res. 2020;48(17):9449-61. [DOI:10.1093/nar/gkaa713] [PMID] [PMCID]
  10. Stochaj U, Weber SC. Nucleolar Organization and Functions in Health and Disease. Cells. 2020;9(3):526. [DOI:10.3390/cells9030526] [PMID] [PMCID]
  11. Hernandez-Verdun D. Assembly and disassembly of the nucleolus during the cell cycle. Nucleus (Austin, Tex). 2011;2(3):189-94. [DOI:10.4161/nucl.2.3.16246] [PMID] [PMCID]
  12. Matthews D, Emmott E, Hiscox J. Viruses and the Nucleolus. The Nucleolus. 2011;15:321-45. [DOI:10.1007/978-1-4614-0514-6_14] [PMCID]
  13. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433. [PMID] [PMCID] [DOI:10.1016/j.jaut.2020.102433]
  14. Simabuco FM, Tamura RE, Pavan ICB, Morale MG, Ventura AM. Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses. Genet Mol Biol. 2020;44(1 Suppl 1) :e20200212. [PMID] [PMCID] [DOI:10.1590/1678-4685-gmb-2020-0212]
  15. Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol. 2015;1282:1-23. [DOI:10.1007/978-1-4939-2438-7_1] [PMID] [PMCID]
  16. Rawlinson SM, Moseley GW. The nucleolar interface of RNA viruses. Cell Microbiol. 2015;17(8):1108-20. [DOI:10.1111/cmi.12465] [PMID]
  17. Bahadori M, Dabiri S, Javadi A, Shamsi Meymandi S, Movahedinia S, Shamsi Meymandi M, et al. Pathogenesis of COVID-19; Acute Auto-inflammatory Disease (Endotheliopathica & Leukocytoclastica COVIDicus). Arch Iran Med. 2021;24(5):419-26. [DOI:10.34172/aim.2021.60] [PMID]
  18. Ouassou H, Kharchoufa L, Bouhrim M, Daoudi NE, Imtara H, Bencheikh N, et al. The Pathogenesis of Coronavirus Disease 2019 (COVID-19): Evaluation and Prevention. J Immunol Res. 2020;2020:1357983. [DOI:10.1155/2020/1357983] [PMID] [PMCID]
  19. Maier HJ, Bickerton E, Britton P. Coronaviruses. Methods and protocols. 2015. [DOI:10.1007/978-1-4939-2438-7]
  20. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92(4):418-23. [DOI:10.1002/jmv.25681] [PMID] [PMCID]
  21. Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, Meydan C, et al. The spatial landscape of lung pathology during COVID-19 progression. Nature. 2021;593(7860):564-9. [DOI:10.1038/s41586-021-03475-6] [PMID]
  22. Bastard P, Gervais A, Le Voyer T, Rosain J, Philippot Q, Manry J, et al. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. Sci Immunol. 2021;6(62).
  23. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses. 2020;12(4). [DOI:10.3390/v12040372] [PMID] [PMCID]
  24. Huertas A, Montani D, Savale L, Pichon J, Tu L, Parent F, et al. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? European Respiratory Journal. 2020;56(1):2001634. [PMID] [PMCID] DOI:10.1183/13993003.01634-2020]
  25. Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol. 2019;17(3):181-92. [DOI:10.1038/s41579-018-0118-9] [PMID] [PMCID]
  26. McBride R, van Zyl M, Fielding BC. The coronavirus nucleocapsid is a multifunctional protein. Viruses. 2014;6(8):2991-3018. [DOI:10.3390/v6082991] [PMID] [PMCID]
  27. Su S, Wong G, Shi W, Liu J, Lai ACK, Zhou J, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses. Trends Microbiol. 2016;24(6):490-502. [PMID] [PMCID] [DOI:10.1016/j.tim.2016.03.003]
  28. Zeng H, Pappas C, Belser JA, Houser KV, Zhong W, Wadford DA, et al. Human pulmonary microvascular endothelial cells support productive replication of highly pathogenic avian influenza viruses: possible involvement in the pathogenesis of human H5N1 virus infection. J Virol. 2012;86(2):667-78. [DOI:10.1128/JVI.06348-11] [PMID] [PMCID]
  29. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-68. [DOI:10.1038/s41586-020-2286-9] [PMID] [PMCID]
  30. Zhang K, Miorin L, Makio T, Dehghan I, Gao S, Xie Y, et al. Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression. Sci Adv. 2021;7(6). [DOI:10.1126/sciadv.abe7386] [PMID] [PMCID]
  31. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. The Lancet. 2020;395(10234):1417-8. [DOI:10.1016/S0140-6736(20)30937-5]
  32. Nägele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020;314:58-62. [DOI:10.1016/j.atherosclerosis.2020.10.014] [PMID] [PMCID]
  33. Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. European Heart Journal. 2020;41(32):3038-44. [PMID] [PMCID] [DOI:10.1093/eurheartj/ehaa623]
  34. Oprinca GC, Muja LA. Postmortem examination of three SARS-CoV-2-positive autopsies including histopathologic and immunohi-stochemical analysis. Int J Legal Med. 2021;135 (1):329-39. [DOI:10.1007/s00414-020-02406-w] [PMID] [PMCID]
  35. Bernard I, Limonta D, Mahal LK, Hobman TC. Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19. Viruses. 2020;13(1). [DOI:10.3390/v13010029] [PMID] [PMCID]
  36. Calabretta E, Moraleda JM, Iacobelli M, Jara R, Vlodavsky I, O'Gorman P, et al. COVID-19-induced endotheliitis: emerging evidence and possible therapeutic strategies. British J Haematol. 2021;193(1):43-51. [DOI:10.1111/bjh.17240] [PMID] [PMCID]
  37. Hiscox JA. The nucleolus--a gateway to viral infection? Arch Virol. 2002;147(6):1077-89. [DOI:10.1007/s00705-001-0792-0] [PMID] [PMCID].