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[摘要]：The gamma(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 gamma(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 gamma(1)34.5 mutant lacking the amino terminus induces stronger antiviral immunity. This parallels a defect of gamma(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 gamma(1)34.5 amino-terminal deletion mutant replicates at an intermediate level between replication of wild-type virus and that of the gamma(1)34.5 null mutant in TBKI+/+ cells. However, such impaired viral growth is not observed in TBK1(-/-) cells, indicating that the interaction of gamma(1)34.5 with TBK 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 gamma(1)34.5 null mutant. Therefore, in addition to PKR, gamma(1)34.5 negatively regulates TBK1, which contributes viral replication and spread in vivo. |
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