Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-κB Activation

Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the trans...

Full description

Saved in:
Bibliographic Details
Published in:Journal of virology 2017-04, Vol.91 (7), p.e00025-17
Main Authors: Xu, Haiyan, Su, Chenhe, Pearson, Angela, Mody, Christopher H, Zheng, Chunfu
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Animals
Cercopithecus aethiops
Gene Expression Regulation, Viral
HEK293 Cells
HeLa Cells
Herpesviridae
Herpesvirus 1, Human
Herpesvirus 1, Human - physiology
Host-Pathogen Interactions
Humans
Interferon-beta
Interferon-beta - genetics
Interferon-beta - metabolism
Interleukin-6
Interleukin-6 - genetics
Interleukin-6 - metabolism
Life Sciences
Microbiology and Parasitology
NF-kappa B p50 Subunit
NF-kappa B p50 Subunit - physiology
Promoter Regions, Genetic
Protein Binding
Protein Interaction Domains and Motifs
Protein Interaction Maps
Signal Transduction
Transcription Factor RelA
Transcription Factor RelA - physiology
Vero Cells
Viral Proteins
Viral Proteins - physiology
Virology
Virus-Cell Interactions
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cyclic GMP-AMP synthase (cGAS) is a newly identified DNA sensor that recognizes foreign DNA, including the genome of herpes simplex virus 1 (HSV-1). Upon binding of viral DNA, cGAS produces cyclic GMP-AMP, which interacts with and activates stimulator of interferon genes (STING) to trigger the transcription of antiviral genes such as type I interferons (IFNs), and the production of inflammatory cytokines. HSV-1 UL24 is widely conserved among members of the herpesviruses family and is essential for efficient viral replication. In this study, we found that ectopically expressed UL24 could inhibit cGAS-STING-mediated promoter activation of IFN-β and interleukin-6 (IL-6), and UL24 also inhibited interferon-stimulatory DNA-mediated IFN-β and IL-6 production during HSV-1 infection. Furthermore, UL24 selectively blocked nuclear factor κB (NF-κB) but not IFN-regulatory factor 3 promoter activation. Coimmunoprecipitation analysis demonstrated that UL24 bound to the endogenous NF-κB subunits p65 and p50 in HSV-1-infected cells, and UL24 was also found to bind the Rel homology domains (RHDs) of these subunits. Furthermore, UL24 reduced the tumor necrosis factor alpha (TNF-α)-mediated nuclear translocation of p65 and p50. Finally, mutational analysis revealed that the region spanning amino acids (aa) 74 to 134 of UL24 [UL24(74-134)] is responsible for inhibiting cGAS-STING-mediated NF-κB promoter activity. For the first time, UL24 was shown to play an important role in immune evasion during HSV-1 infection. NF-κB is a critical component of the innate immune response and is strongly induced downstream of most pattern recognition receptors (PRRs), leading to the production of IFN-β as well as a number of inflammatory chemokines and interleukins. To establish persistent infection, viruses have evolved various mechanisms to counteract the host NF-κB pathway. In the present study, for the first time, HSV-1 UL24 was demonstrated to inhibit the activation of NF-κB in the DNA sensing signal pathway via binding to the RHDs of the NF-κB subunits p65 and p50 and abolishing their nuclear translocation.
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.00025-17