Beyond the NEC: Modulation of Herpes Simplex Virus Nuclear Egress by Viral and Cellular Components
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Purpose of Review
Herpesvirus virions are complex molecular machines that, like most viruses, must be stable in the extracellular environment yet disassemble readily upon receipt of the appropriate molecular cues. While we have learned much about the assembly and composition of these fascinating particles, many central questions remain unanswered.
This review focuses on an early stage in herpesvirus assembly called nuclear egress whereby viral DNA genomes packaged within an icosahedral protein capsid are translocated from the nucleoplasm across both the inner and outer nuclear membranes to reach the cytoplasm where the final stages of virion maturation take place.
Here, I provide an overview of our current understanding of herpes simplex virus nuclear egress, the hurdles that the virus must overcome during nuclear egress, and discuss the literature pointing to the regulation and facilitation of this process by viral and cellular components.
KeywordsHerpes simplex virus Virion assembly Nuclear egress
I thank Jie Gao for the helpful discussions and Renée Finnen for the helpful discussions and critical reading of the manuscript. Work in our laboratory is supported by the Canadian Institutes of Health Research operating grant 93804, Natural Sciences and Engineering Research Council of Canada Discovery grant 418719, and Canada Foundation for Innovation award 16389. I apologize to my many colleagues whose work could not be cited because of length restrictions.
Compliance with Ethical Standards
Conflict of Interest
The author declares that he has no competing interests.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 1.Pellet, P., Roizman, B. Herpesviridae: A Brief Introduction, in Fields Virology, Edn. 5th Edition. (ed. P. Howley) 2480–2499 (Lippincott, Philadelphia; 2007).Google Scholar
- 9.Gibson W, Roizman B. Proteins specified by herpes simplex virus. 8. Characterization and composition of multiple capsid forms of subtypes 1 and 2. J Virol. 1972;10:1044–52.Google Scholar
- 10.Roizman B, Furlong D. The replication of herpesviruses. In: Fraenkel-Conrat H, Wager RR, editors. Comprehensive virology, vol. 3. New York: Plenum Press; 1974. p. 229–403.Google Scholar
- 17.Chang YE, Van Sant C, Krug PW, Sears AE, Roizman B. The null mutant of the U(L)31 gene of herpes simplex virus 1: construction and phenotype in infected cells. J Virol. 1997;71:8307–15.Google Scholar
- 25.Walzer SA, Egerer-Sieber C, Sticht H, Sevvana M, Hohl K, Milbradt J, et al. Crystal structure of the human cytomegalovirus pUL50-pUL53 core nuclear egress complex provides insight into a unique assembly scaffold for virus-host protein interactions. J Biol Chem. 2015;290:27452–8.CrossRefGoogle Scholar
- 29.Bailer, S.M. Venture from the interior-herpesvirus pUL31 escorts capsids from nucleoplasmic replication compartments to sites of primary envelopment at the inner nuclear membrane. Cells 2017;6(4):46.Google Scholar
- 34.Wilkie, A.R., Lawler, J.L. & Coen, D.M. A Role for nuclear F-actin induction in human cytomegalovirus nuclear egress. MBio 2016;7:e01254–16.Google Scholar
- 35.Wilkie, A.R. et al. A role for myosin Va in human cytomegalovirus nuclear egress. J Virol 2018;92:e01849–17.Google Scholar
- 38.Gao, J., Hay, T.J.M. & Banfield, B.W. The product of the herpes simplex virus 2 UL16 gene is critical for the egress of capsids from the nuclei of infected cells. J Virol 2017;91:e00350–17.Google Scholar
- 39.• Gao, J., Yan, X. & Banfield, B.W. Comparative analysis of UL16 mutants derived from multiple strains of herpes simplex virus 2 (HSV-2) and HSV-1 reveals species-specific requirements for the UL16 protein. J Virol 2018;92:e00629–18. This study provides evidence that the viral components required for nuclear egress differ bewteen HSV-1 and HSV-2. Google Scholar
- 41.• Vu A, Poyzer C, Roller R. Extragenic suppression of a mutation in herpes simplex virus 1 UL34 that affects lamina disruption and nuclear egress. J Virol. 2016;90:10738–51 This study brings into the question the importance of overt disruptions of the nuclear lamina in the nuclear egress of HSV-1.CrossRefGoogle Scholar
- 51.Dai, X. & Zhou, Z.H. Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes. Science 2018;360:eaao7298.Google Scholar
- 65.Baines JD, Cunningham C, Nalwanga D, Davison A. The U(L)15 gene of herpes simplex virus type 1 contains within its second exon a novel open reading frame that is translated in frame with the U(L)15 gene product. J Virol. 1997;71:2666–73.Google Scholar
- 67.Tengelsen LA, Pederson NE, Shaver PR, Wathen MW, Homa FL. Herpes simplex virus type 1 DNA cleavage and encapsidation require the product of the UL28 gene: isolation and characterization of two UL28 deletion mutants. J Virol. 1993;67:3470–80.Google Scholar
- 68.Sarfo, A. et al. The UL21 Tegument Protein of Herpes Simplex Virus 1 Is Differentially Required for the Syncytial Phenotype. J Virol 2017;91:e01161–17.Google Scholar
- 69.Finnen, R., Banfield, BW . Unpublished observations. (2018).Google Scholar
- 72.McNab AR, et al. The product of the herpes simplex virus type 1 UL25 gene is required for encapsidation but not for cleavage of replicated viral DNA. J Virol. 1998;72:1060–70.Google Scholar
- 81.Hirohata Y, Arii J, Liu Z, Shindo K, Oyama M, Kozuka-Hata H, et al. Herpes simplex virus 1 recruits CD98 heavy chain and beta1 integrin to the nuclear membrane for viral de-envelopment. J Virol. 2015;89:7799–812.Google Scholar
- 82.Ito Y, et al. Fusion regulation proteins on the cell surface: isolation and characterization of monoclonal antibodies which enhance giant polykaryocyte formation in Newcastle disease virus-infected cell lines of human origin. J Virol. 1992;66:5999–6007.Google Scholar
- 83.Ohgimoto S, et al. Molecular characterization of fusion regulatory protein-1 (FRP-1) that induces multinucleated giant cell formation of monocytes and HIV gp160-mediated cell fusion. FRP-1 and 4F2/CD98 are identical molecules. J Immunol. 1995;155:3585–92.Google Scholar
- 88.Baines JD, Ward PL, Campadelli-Fiume G, Roizman B. The UL20 gene of herpes simplex virus 1 encodes a function necessary for viral egress. J Virol. 1991;65:6414–24.Google Scholar
- 93.• Klupp, B.G. et al. Integrity of the linker of nucleoskeleton and cytoskeleton is required for efficient herpesvirus nuclear egress. J Virol 2017;91:e00330–17. This study provides evidence that the maintanance of the LINC complex is critical for nuclear egress of PRV likely because it keeps primary enveloped virions in the perinuclear space in proximity to the outer nuclear membrane where de-envelopment must take place. Google Scholar