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Review
. 2019 Sep 7;8(9):1408.
doi: 10.3390/jcm8091408.

Early Nuclear Events after Herpesviral Infection

Florian Full  1 , Armin Ensser  2
Affiliations
Review

Early Nuclear Events after Herpesviral Infection

Florian Full et al. J Clin Med. .

Abstract

Herpesviruses are important pathogens that can cause significant morbidity and mortality in the human population. Herpesviruses have a double-stranded DNA genome, and viral genome replication takes place inside the nucleus. Upon entering the nucleus, herpesviruses have to overcome the obstacle of cellular proteins in order to enable viral gene expression and genome replication. In this review, we want to highlight cellular proteins that sense incoming viral genomes of the DNA-damage repair (DDR) pathway and of PML-nuclear bodies (PML-NBs) that all can act as antiviral restriction factors within the first hours after the viral genome is released into the nucleus. We show the function and significance of both nuclear DNA sensors, the DDR and PML-NBs, and demonstrate for three human herpesviruses of the alpha-, beta- and gamma-subfamilies, HSV-1, HCMV and KSHV respectively, how viral tegument proteins antagonize these pathways.

Keywords: ATRX; CMV; DAXX; DNA-damage repair; DNA-damage response; HHV-6; HR; HSV-1; Herpes simplex virus; Herpesviruses; ICP-0; IE-1; KSHV; Kaposi’s sarcoma-associated herpesvirus; ND10; NHEJ; ORF75; PML; PML nuclear bodies; SP100; cytomegalovirus; double strand break; double-stranded DNA virus; homology repair; infection; non-homologous end joining; nuclear DNA sensors; restriction factors; virus; virus-host interaction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Herpesviral antagonism of the ATM- and DNA-PK-branch of the DDR directly after infection. After infection of target cells, the herpesviral capsid is transported to the nuclear membrane and the viral DNA released into the nucleus through nuclear pores. We propose that the cellular DDR complexes recognize the viral linear DNA by MRN- and KU70/KU80-complex binding to double-strand break resembling ends of the linear viral DNA. This results in activation of kinases ATM and DNA-PK respectively, followed by phosphorylation of H2AX (γH2AX) and CHK1/2 and activation of downstream proteins including the cell cycle regulator p53. HSV-1, HCMV and KSHV have been shown to counteract this activation as indicated in the graph, however, the viral effector proteins and mechanisms are not identified. Depletion of proteins depicted in red font has been shown to enhance herpesviral replication, indicating an inhibiting role on herpesviral replication. ? indicates an unknown mechanism.
Figure 2
Figure 2
Herpesviral antagonism of PML-nuclear bodies. After the infection of target cells, the herpesviral capsid is transported to the nuclear membrane and the viral DNA released into the nucleus through nuclear pores. The genome rapidly associates with PML nuclear bodies (PML-NBs). PML-NBs are considered as antiviral nuclear organelles that restrict gene expression from viral genomes, and PML-NB components PML, SP100, DAXX and ATRX as well as the transiently associated proteins IFI16 and HIRA have been shown to mediate this restriction. PML is an essential structural component of PML-NBs and depletion of PML disrupts PML-NBs. Herpesviruses in contrast have evolved mechanisms to counteract this restriction, in particular viral tegument and immediate-early proteins as depicted in the graph. ? Indicates hypothetical mode of interference.
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