title: 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-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.IMPORTANCENF-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.
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China.
authors.forename: Chenhe
authors.initials: C
authors.lastname: Su
authors.affiliation: Université INRS, INRS-Institut Armand-Frappier, Laval, Québec, Canada.
authors.forename: Angela
authors.initials: A
authors.lastname: Pearson
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
authors.forename: Christopher H
authors.identifier: http://orcid.org/0000-0001-7264-3679
authors.initials: CH
authors.lastname: Mody
authors.affiliation: Soochow University, Institutes of Biology and Medical Sciences, Suzhou, China zheng.alan@hotmail.com.|Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zheng
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002522:Chlorocebus aethiops; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000502:physiology*; D014709:Vero Cells; D014764:Viral Proteins / Q000502:physiology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit; C498143:RELA protein, human; D051996:Transcription Factor RelA; C086267:UL24 protein, Human herpesvirus 1; D014764:Viral Proteins; D016899:Interferon-beta
keywords: DNA sensor; HSV-1; NF-κB; UL24; p65