title: DNA sensing-independent inhibition of herpes simplex virus 1 replication by DAI/ZBP1.
abstract: DNA-dependent activator of interferon regulatory factor (DAI) acts as a cytosolic B-form DNA sensor that induces type I interferons. However, DAI is not required for DNA sensing in certain cell types due to redundancy of the DNA sensing system. Here, we investigated the effect of DAI on herpes simplex virus 1 (HSV-1) infection in HepG2 hepatocellular carcinoma cells. DAI transcription was induced after gamma interferon (IFN-γ) treatment or HSV-1 infection. HSV-1 replication was enhanced by DAI knockdown, and ectopic DAI expression repressed viral replication in a manner requiring the Zβ and D3 domains, but not the Zα domain. This activity of DAI was more prominent at low multiplicity of infection (MOI) and correlated with the reduced expression of viral immediate-early genes. Consistently, DAI repressed the activation of ICP0 promoter in reporter gene assays. DAI knockdown did not affect the B-DNA-mediated IFN-β transcription and IRF3 activation, and overexpression of DAI and RIP1 did not enhance NF-κB activation by B-DNA treatment, demonstrating that DAI is not essential for the B-DNA-mediated IFN production in HepG2 cells. DAI colocalized with ICP0 in a subset of nuclear and cytoplasmic foci in infected cells and interacted with ICP0 in coimmunoprecipitation assays. The anti-HSV-1 effect of DAI was not observed in ICP0-deleted mutant virus infection at a high MOI in HepG2 cells and mouse embryonic fibroblasts. Degradation of IFI16 and PML by ICP0 was enhanced in infection of DAI-knockdown cells. Collectively, these results demonstrate that DAI can suppress HSV-1 growth independent of DNA sensing through mechanisms involving suppression of viral genomes and regulation of ICP0.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Thanh H
authors.initials: TH
authors.lastname: Pham
authors.forename: Ki Mun
authors.initials: KM
authors.lastname: Kwon
authors.forename: Young-Eui
authors.initials: YE
authors.lastname: Kim
authors.forename: Kyeong Kyu
authors.initials: KK
authors.lastname: Kim
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D002460:Cell Line; D004279:DNA, Viral / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000821:virology; D022781:Hepatocytes / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D016601:RNA-Binding Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D016601:RNA-Binding Proteins; C485731:ZBP1 protein, human; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1