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Mechanism and regulation of protein kinase functions in HSV nuclear egress

HSV核出口中蛋白激酶功能的机制和调控

基本信息

批准号：
10088400
负责人：
RICHARD J ROLLER
金额：
$ 19.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-24 至 2022-12-31
项目状态：
已结题

项目摘要

Alphaherpesviruses encode two proteins kinases that are critical regulators of pathogenesis, pUS3 and pUL13. pUS3 has multiple functions in infection including facilitation of nuclear egress, protection from apoptosis, promotion of viral protein synthesis, and inhibition of antigen presentation to the immune system. The regulation of the activity of pUS3 is, therefore, of great interest, both as a tool for understanding the molecular biology of herpesvirus infections, and as an avenue for exploring antiviral therapies based on inhibition of its various activities. pUS3 kinase activity has been reported to be regulated both by autophosphorylation and by phosphorylation by another herpesvirus-encoded kinase, pUL13. Intriguingly, regulation of pUS3 activity by pUL13 appears to affect some pUS3 functions, but not others. Specifically, it appears to be necessary for at least some of the activities of pUS3 in egress of virus capsids from the nucleus, but not for protection of infected cells from some pro-apoptotic stimuli (). These observations highlight two very significant gaps in our understanding of the interaction between pUL13 and pUS3. First, it is unclear which pUS3 functions are regulated by pUL13, and what distinguished UL13-dependent from UL13-independent functions. We propose the simple hypothesis that phosphorylation of pUS3 by pUL13 specifically regulates its nuclear functions by regulating its access to the nucleus. Second, the mechanism and functional significance of pUL13 regulation of pUS3 is unclear. It is known that pUL13 phosphorylates pUS3, but it is not clear whether this phosphorylation is necessary for pUL13 regulation of pUS3. A recently published proteomic analysis of HSV infected cells suggests that pUL13 phosphorylates pUS3 at S139. We will use a genetic approach to test the hypothesis that S139 is the critical residue for regulation of pUS3 by pUL13, and then to test the significance of S139 phosphorylation for viral growth and spread.

甲疱疹病毒编码两种蛋白激酶，pUS3和pUL13是发病机制的关键调节因子。pUS3在感染中具有多种功能，包括促进核出口、防止细胞凋亡、促进病毒蛋白合成和抑制抗原向免疫系统的递呈。因此，对pUS3活性的调控是非常有趣的，它既是理解疱疹病毒感染分子生物学的工具，也是探索基于抑制其各种活性的抗病毒治疗的途径。据报道，pUS3激酶活性受自磷酸化和另一种疱疹病毒编码的激酶pUL13的磷酸化调节。有趣的是，pUL13对pUS3活性的调节似乎会影响pUS3的一些功能，但不会影响其他功能。具体来说，在病毒衣壳从细胞核流出的过程中，pUS3的至少部分活性似乎是必需的，但在保护受感染细胞免受某些促凋亡刺激方面则不是必需的（）。这些观察结果突出了我们对pUL13和pUS3之间相互作用的理解中的两个非常重要的空白。首先，目前尚不清楚pUL13调节哪些pUS3功能，以及区分ul13依赖性和ul13非依赖性功能的原因。我们提出了一个简单的假设，即pUL13对pUS3的磷酸化通过调节其进入细胞核来特异性地调节其核功能。其次，pUL13调控pUS3的机制和功能意义尚不清楚。已知pUL13磷酸化pUS3，但不清楚这种磷酸化对于pUL13调控pUS3是否必要。最近发表的一项HSV感染细胞的蛋白质组学分析表明，pUL13在S139位点磷酸化pUS3。我们将使用遗传学方法验证S139是pUL13调控pUS3的关键残基的假设，然后验证S139磷酸化对病毒生长和传播的意义。