Protein kinase B/Akt is present in activated form throughout the entire replicative cycle of ΔUS3 mutant virus but only at early times after infection with wild-type herpes simplex virus 1
Protein kinase B/Akt is present in activated form throughout the entire replicative cycle of ΔUS3 mutant virus but only at early times after infection with wild-type herpes simplex virus 1
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DOI：
10.1128/jvi.80.7.3341-3348.2006
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发表时间：
2006-04-01
影响因子：
5.4
通讯作者：
Roizman, B
中科院分区：
文献类型：
--
作者：
Benetti, L;Roizman, B
单纯疱疹病毒1型（HSV-1）US 3基因的产物是一种多功能丝氨酸-苏氨酸蛋白激酶，可阻断由促凋亡细胞蛋白、外源因子或复制缺陷型病毒诱导的凋亡。早期的研究表明，U13激酶激活细胞蛋白激酶A（PKA）并在功能上重叠。在这项研究中，我们检查了磷脂酰肌醇3-激酶[PI（3）K]及其效应物蛋白激酶B/Akt（PKB/Akt）的状态，PKB/Akt是哺乳动物抗凋亡信号系统的主要途径的一个组成部分。我们报告如下。(i)用HSV-1感染靶细胞可诱导感染早期PKB/Akt丝氨酸473的瞬时磷酸化，其机制依赖于PI（3）K。抑制PI（3）K可诱导模拟感染或Delta U（S）3突变体病毒感染的细胞凋亡，但在野生型病毒感染的细胞中不诱导凋亡，并减少特定病毒基因产物的积累，包括U（S）3蛋白激酶，但对病毒产量的影响很小。(ii)感染后，PKB/Akt的总量下降，磷酸化PKB/Akt形式消失，这是U（S）3依赖的，而非蛋白磷酸酶2A依赖的。(iii)毛喉素激活PKA并不介导PKB/Akt的显著去磷酸化。我们的研究结果与以下模型一致：PKB/Akt在感染早期被激活，并在U（S）3蛋白激酶积累之前阻断感染细胞的凋亡，并且在缺乏U（S）3蛋白激酶的情况下，它持续存在并继续作为抗凋亡蛋白发挥作用，但一旦U（S）3蛋白激酶积累到有效量，它就变得多余甚至有害。
The product of the herpes simplex virus 1 (HSV-1) US3 gene is a multifunctional serine-threonine protein kinase that can block apoptosis induced by proapoptotic cellular proteins, exogenous agents, or replication-defective viruses. Earlier studies showed that the U,3 kinase activates and functionally overlaps cellular protein kinase A (PKA). In this study we examined the status of phosphatidylinositol 3-kinase [PI(3)K] and of its effector, protein kinase B/Akt (PKB/Akt), a component of a major pathway of mammalian antiapoptotic signaling systems. We report the following. (i) Infection of target cells with HSV-1 induces transient phosphorylation of serine 473 of PKB/Akt early in infection, with a mechanism that is dependent on PI(3)K. Inhibition of PI(3)K induced apoptosis in mock-infected or Delta U(S)3 mutant-virus-infected but not in wild-typevirus-infected cells and reduced the accumulation of specific viral gene products, including the U(S)3 protein kinase, but had a marginal effect on virus yields. (ii) At later times after infection, the total amounts of PKB/Akt decreased and phosphorylated PKB/Akt forms disappeared in a U(S)3-dependent and protein phosphatase 2A-independent manner. (iii) Activation of PKA by forskolin did not mediate significant dephosphorylation of PKB/Akt. Our results are consistent with the model that PKB/Akt is activated early in infection and acts to block apoptosis in infected cells prior to the accumulation of U(S)3 protein kinase and that it persists and continues to function as an antiapoptotic protein in the absence of U,3 but becomes redundant or even inimical once U(S)3 protein kinase accumulates in effective amounts.