title: Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection.
abstract: The γ(1)34.5 protein of herpes simplex viruses (HSV) is essential for viral pathogenesis, where it precludes translational arrest mediated by double-stranded-RNA-dependent protein kinase (PKR). Paradoxically, inhibition of PKR alone is not sufficient for HSV to exhibit viral virulence. Here we report that γ(1)34.5 inhibits TANK binding kinase 1 (TBK1) through its amino-terminal sequences, which facilitates viral replication and neuroinvasion. Compared to wild-type virus, the γ(1)34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of γ(1)34.5 for interacting with TBK1 and reducing phosphorylation of interferon (IFN) regulatory factor 3. This activity is independent of PKR. Although resistant to IFN treatment, the γ(1)34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the γ(1)34.5 null mutant in TBK1(+/+) cells. However, such impaired viral growth is not observed in TBK1(-/-) cells, indicating that the interaction of γ(1)34.5 with TBK1 dictates HSV infection. Upon corneal infection, this mutant replicates transiently but barely invades the trigeminal ganglia or brain, which is a difference from wild-type virus and the γ(1)34.5 null mutant. Therefore, in addition to PKR, γ(1)34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Ma
authors.forename: Huali
authors.initials: H
authors.lastname: Jin
authors.forename: Tibor
authors.initials: T
authors.lastname: Valyi-Nagy
authors.forename: Youjia
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yan
authors.forename: Bin
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D006561:Herpes Simplex / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D050838:Interferon Regulatory Factor-3; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases