Abstract
Although ICP4 is the only essential transcription activator of herpes simplex virus 1 (HSV-1), its mechanisms of action are still only partially understood. We and others propose a model in which HSV-1 genomes are chromatinized as a cellular defense to inhibit HSV-1 transcription. To counteract silencing, HSV-1 would have evolved proteins that prevent or destabilize chromatinization to activate transcription. These proteins should act as HSV-1 transcription activators. We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1. We now show that whereas HSV-1 mutants encoding no functional ICP0 or VP16 partially enhanced histone dynamics, mutants encoding no functional ICP4 did so only minimally. Transient expression of ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or HSV-1 DNA. The dynamics of H3.1 were increased in cells expressing ICP4 to a greater extent than those of H3.3. The dynamics of H2B were increased in cells expressing ICP4, whereas those of canonical H2A were not. ICP4 preferentially targets silencing H3.1 and may also target the silencing H2A variants. In infected cells, histone dynamics were increased in the viral replication compartments, where ICP4 localizes. These results suggest a mechanism whereby ICP4 activates transcription by disrupting, or preventing the formation of, stable silencing nucleosomes on HSV-1 genomes.
Highlights
The genes of the nuclear-replicating double stranded DNA virus herpes simplex virus 1 (HSV-1) are expressed in a coordinate manner
We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1
We have shown that histone dynamics are enhanced in HSV-1 lytically infected cells
Summary
The genes of the nuclear-replicating double stranded (ds) DNA virus herpes simplex virus 1 (HSV-1) are expressed in a coordinate manner. VP16, a virion protein, first activates expression of the five immediate early (IE) genes, in part through the recruitment of the histone demethylase LSD1 and histone acetyltransferase CBP/p300 to IE promoters [1,2,3,4,5]. Two IE proteins, ICPO and ICP4, activate transcription of the early (E) genes, which encode proteins required for HSV-1 DNA replication and several other functions [6]. Late (L) genes are transcribed after DNA replication Both ICP0 and ICP4 contribute to the activation of L gene expression. ICP4 binds to specific DNA sequences to inhibit transcription of IE genes [13]. It does not bind to any specific sequences to activate transcription of E or L genes [14]. ICP4 interacts with many components of the mediator complex and may activate transcription by a gene looping mechanism [15], promoting the recycling of RNA polymerase II from the 3’ end of a gene back to the transcription start sites
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
