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

Abstract

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-␤ and interleukin-6 (IL-6), and UL24 also inhibited interferon-stimulatory DNAmediated IFN-␤ and IL-6 production during HSV-1 infection. Furthermore, UL24 selectively blocked nuclear factor B (NF-B) but not IFN-regulatory factor 3 promoter activation. Coimmunoprecipitation analysis demonstrated that UL24 bound to the endogenous NF-B 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-␣)-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-B promoter activity. For the first time, UL24 was shown to play an important role in immune evasion during HSV-1 infection.IMPORTANCE NF-B 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-␤ as well as a number of inflammatory chemokines and interleukins. To establish persistent infection, viruses have evolved various mechanisms to counteract the host NF-B pathway. In the present study, for the first time, HSV-1 UL24 was demonstrated to inhibit the activation of NF-B in the DNA sensing signal pathway via binding to the RHDs of the NF-B subunits p65 and p50 and abolishing their nuclear translocation.KEYWORDS HSV-1, DNA sensor, UL24, NF-B, p65 T he innate immune system is the first line of defense against viral infection. The first step in innate immunity is the detection of the invading pathogen. Pathogen recognition receptors (PRRs) recognize pathogen-associated molecular patterns to trigger the production of type I interferons (IFNs) and other antiviral immune responses (1-3). Viral nucleic acids exposed in the cytoplasm are signs of foreign invasion and can be recognized by a subset of host cell PRRs. The membrane-bound Toll-like receptors recognize endosomal nucleic acids, the family of RIG-I-like receptors recognizes viral RNAs, and a broad class of putative DNA sensors recognizes viral DNA (4-6). A number of DNA sensors have been discovered in recent years, including cyclic GMP-AMP

Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

“…To successfully infect and persist in the host, viruses must possess multiple strategies to subvert host immune responses (12)(13)(14). A number of viral proteins that inhibit IFN-I production through modulation of the cGAS-STING DNA-sensing pathway have been identified, including HSV-1 UL41 (15), VP22 (16), VP24 (18), ICP27 (19), UL24 (20), and VP11/12 (35), as well as viral proteins encoded by KSHV (9), human cytomegalovirus (17,36), and murine gammaherpesvirus 68 (37). Nevertheless, to date, the strategies used by chicken DNA viruses to hinder the DNA-sensing pathway in host cells remain unclear.…”

Middle East Respiratory Syndrome Coronavirus-Encoded Accessory Proteins Impair MDA5-and TBK1-Mediated Activation of NF-��B

“…As NF-κB plays a critical role in the induction of innate and adaptive immune responses, a number of viruses have evolved to encode antagonists in their genome to prevent or down-regulate NF-κB activation upon infection [25,[45][46][47][48][49] and the same is true of coronaviruses [26,50,51]. Considering the importance of the roles played by NF-κB in the regulation of the host immune responses, it is still possible that MERS-CoV may encode other NF-κB antagonists than ORF4b [26].…”

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

“…Besides, IRFs are also suppressed by KSHV vIRFs, EBV LF2, KSHV ORF50, and the cellular protein suppressor of cytokine signaling (SOCS) 1 prompted by HTLV‐1 Tax 94a. HSV1 UL24 binds to NF‐κB subunits p65 and p50 and abrogates nuclear translocation during disease, decreasing NF‐κB activity via the cGAS‐STING response 100. Mumps virus (MuV) small hydrophobic protein (SH) decreases NF‐κB stimulation by reducing inhibitor of kappa B (IκB) kinase α (IKKα) and kinase β (IKKβ), and p65 phosphorylation, including nuclear translocation of p65 in diseased cells 101.…”