# Glucocorticoid Receptor and Cell Cycle Regulator (E2F2) Cooperatively Transactivate a Cis-Regulatory Module in the HSV-1 Infected Cell Protein 0 (ICP0) Promoter

## TL;DR

The paper shows how the glucocorticoid receptor and E2F2 work together to activate a specific region of the HSV-1 ICP0 promoter, potentially boosting viral replication.

## Contribution

The novel finding is that GR and E2F2 cooperatively transactivate the ICP0 CRM-C, which was not previously known.

## Key findings

- GR and E2F2, but not other E2F variants, cooperatively transactivate the ICP0 CRM-C promoter region.
- Mutating the GRE or E2F binding sites in CRM-C reduces transactivation by GR and E2F2.
- E2F2 binds to the CRM-C region during productive HSV-1 infection.

## Abstract

Human alpha-herpesvirus 1 (HSV-1) acute infection culminates in life-long latency in sensory neurons in trigeminal ganglia and certain neurons in the central nervous system. Previously, E2F family members and glucocorticoid receptor (GR) were shown to stimulate HSV-1 and bovine herpesvirus 1 (BoHV-1) replication. Consequently, we hypothesized GR and E2F family members activate certain HSV-l promoters. To test this hypothesis, we determined if four HSV-1 ICP0 cis-regulatory modules (CRM) upstream of the ICP0 promoter were activated by E2F. GR and E2F2, but not E2F1, E2F3a, or E2F3b, cooperatively transactivate the ICP0 CRM-C, but not CRM-A, -B, or -D fragments upstream of a minimal promoter in a luciferase reporter construct. CRM-C sequences contain two E2F consensus binding sites, a GC-rich motif that E2F2 can bind, and a consensus ½ GR response element (GRE) adjacent to the consensus E2F #2 binding site. Mutating the ½ GRE or the 3 E2F binding sites significantly reduced GR- and E2F2-mediated transactivation. Chromatin immunoprecipitation studies revealed E2F2 occupied ICP0 CRM-C sequences during productive infection and mutating the E2F binding sites prevented E2F2 binding. These studies reveal GR and E2F2 transactivate ICP0-promoter activity, which may enhance viral replication in certain cell types.