HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation
HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation
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DOI：
10.1073/pnas.1323414111
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发表时间：
2014-02-04
影响因子：
11.1
通讯作者：
Roizman, Bernard
中科院分区：
文献类型：
--
作者：
Kalamvoki, Maria;Roizman, Bernard
SING(干扰素基因刺激物)激活干扰素途径，以响应胞浆DNA。单纯疱疹病毒1型(HSV-1)在小鼠体内的基因敲除可加重其致病性。在这里，我们报告如下：(I)在感染野生型HSV-1的癌症来源的Hep-2或HeLa细胞中，STING是稳定的，但在缺乏编码功能性感染细胞蛋白0(ICP0)、ICP4或US3蛋白激酶(US3-PK)基因的突变体感染的细胞中，STING被降解。在Hep-2细胞中，shRNA耗尽STING导致野生型或ICP0病毒产量下降。(Ii)在人类胚胎肺细胞(HEL)或来自正常组织的HEK293T细胞中，无论是野生型病毒还是ICP0突变病毒，斯汀在感染过程中都是稳定的。在这些细胞中，STING的耗尽导致野生型和ICP0病毒的产量都较高。(3)US3PK也是稳定核DNA传感器IFI16所必需的。然而，IFI16的稳定性与STING的稳定性不存在正相关或负相关。IFI16在野生型病毒感染的无刺激性HEL细胞中稳定存在。与HEL细胞相比，在去刺痛的Hep-2细胞中检测不到IFI16，因此不能确定HSV-1在维持IFI16中的作用。结果表明，在HSV-1感染的细胞中，IFI16的稳定性以及STING的功能和稳定性依赖于细胞来源、ICP0的功能完整性和US3-PK，这表明在野生型病毒感染的细胞中，这两种蛋白都是活跃稳定的。在Hep-2细胞中，IFI16的稳定性需要刺激性。
STING (stimulator of IFN genes) activates the IFN pathway in response to cytosolic DNA. Knockout of STING in mice was reported to exacerbate the pathogenicity of herpes simplex virus 1 (HSV-1). Here we report the following: (i) STING is stable in cancer-derived HEp-2 or HeLa cells infected with wild-type HSV-1 but is degraded in cells infected with mutants lacking the genes encoding functional infected cell protein 0 (ICP0), ICP4, or the US3 protein kinase (US3-PK). In HEp-2 cells, depletion of STING by shRNA results in a decrease in the yields of wild-type or.ICP0 viruses. (ii) STING is stable throughout infection with either wild-type or ICP0 mutant viruses in human embryonic lung cells (HEL) or HEK293T cells derived from normal tissues. In these cells, depletion of STING results in higher yields of both wild-type and.ICP0 viruses. (iii) The US3PK is also required for stabilization of IFI16, a nuclear DNA sensor. However, the stability of IFI16 does not correlate positively or negatively with that of STING. IFI16 is stable in STING-depleted HEL cells infected with wild-type virus. In contrast to HEL cells, IFI16 was undetectable in STING-depleted HEp-2 cells, and hence the role of HSV-1 in maintaining IFI16 could not be ascertained. The results indicate that in HSV-1-infected cells the stability of IFI16 and the function and stability of STING are dependent on cell derivation, the functional integrity of ICP0, and US3-PK, an indication that in wild-type virus-infected cells both proteins are actively stabilized. In HEp-2 cells, the stability of IFI16 requires STING.