Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection Yijie Ma a , Huali Jin a , Tibor Valyi-Nagy b , Youjia Cao c , Zhipeng Yan a and Bin He a a Department of Microbiology and Immunology b Department of Pathology, College of Medicine, University of Illinois, Chicago, Illinois, USA c Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin, People's Republic of China 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 .
Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection
Abstract
Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection Yijie Ma a , Huali Jin a , Tibor Valyi-Nagy b , Youjia Cao c , Zhipeng Yan a and Bin He a a Department of Microbiology and Immunology b Department of Pathology, College of Medicine, University of Illinois, Chicago, Illinois, USA c Tianjin Key Laboratory of Protein Sciences, College of Life Sciences, Nankai University, Tianjin, People's Republic of China 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 .Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Inhibition of TANK Binding Kinase 1 by Herpes Simplex Virus 1 Facilitates Productive Infection
Ma, Yijie; Jin, Huali; Valyi-Nagy, Tibor; Cao, Youjia; Yan, Zhipeng; He, Bin
Follow Journal of Virology
, Volume 86 (4): 2188
American Society For Microbiology – Feb 15, 2012
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