Work

Glucocorticoid receptor and specificity protein 1 (Sp1) or Sp3 transactivate HSV-1 ICP0 promoter sequences but a GC-rich binding antibiotic, Mithramycin A, impairs reactivation from latency

Year: 2024

Type: article

Abstract: • Specificity protein 1 (Sp1) and Sp3 cooperate with glucocorticoid receptor (GR) to transactivate cis-regulatory modules (CRMs) in the HSV-1 ICP0 promoter. • Mutation of C-rich and/or G-rich consensus Sp1 binding sites were important for GR and Sp1 or Sp3 mediated transactivation. • Sp1 or Sp3 over-expression enhances GR binding to ICP0 CRMs. • The antibiotic Mithramycin, which selectively interacts with GC-rich DNA impairs HSV-1 replication and reactivation from latency. Glucocorticoid receptor (GR) activation enhances Human alpha-herpes virus 1 (HSV-1) replication and explant-induced reactivation from latency. Furthermore, GR and Krüppel-like factor 15 (KLF15) cooperatively transactivate cis-regulatory modules (CRMs) that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. KLF and specificity protein (Sp) family members bind GC-rich or C-rich sequences and belong to the same super-family of transcription factors. Based on these observations, we hypothesized CRMs spanning the ICP0 promoter are transactivated by GR and Sp1 or Sp3. CRM-A (-800 to -635), CRM-B (-485 to -635), and CRM-D (-232 to -24), but not CRM-C, were significantly transactivated by GR, DEX, and Sp1 or Sp3 in mouse neuroblastoma cells (Neuro-2A). Mutagenesis of Sp1/Sp3 binding sites were important for transactivation of CRM-A and CRM-B. Chromatin immunoprecipitation studies revealed significantly higher levels of GR occupied ICP0 promoter sequences when Sp1 or Sp3 was over-expressed suggesting these transcriptions factors recruit GR to ICP0 CRM sequences. Mithramycin A, an antibiotic that preferentially binds GC-rich DNA and impairs Sp1/Sp3 dependent transactivation and reduced virus shedding during reactivation from latency in mice latently infected with HSV-1. These studies indicate GR and certain stress-induced cellular transcription factors preferentially bind GC rich DNA, which stimulates HSV-1 gene expression and reactivation from latency in trigeminal ganglia of latently infected mice.

Source: Virus Research

DOI: 10.1016/j.virusres.2024.199487

Authors: Vanessa Claire Santos, Nishani Wijesekera, Fouad S. El-Mayet, Clinton Jones

Institutions: Oklahoma State University, Benha University

Language: English

Topic: Herpesvirus Infections and Treatments

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,830