ICP0 induces the accumulation of colocalizing conjugated ubiquitin
ICP0 induces the accumulation of colocalizing conjugated ubiquitin
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DOI：
10.1128/jvi.74.21.9994-10005.2000
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发表时间：
2000-11-01
影响因子：
5.4
通讯作者：
Everett, RD
中科院分区：
文献类型：
--
作者：
Everett, RD
单纯疱疹病毒1型(HSV-1)即刻早期蛋白ICP0是病毒基因表达的通用激活剂，可刺激病毒裂解感染的启动和静止期和潜伏期的重新激活。ICP0对HSV-1感染生物学的重要性激发了人们对其作用模式的兴趣。以前的研究已经报道了ICP0与其他病毒调节分子、翻译装置、细胞周期蛋白D3以及泛素特异性蛋白酶的相互作用，已经证明ICP0能够诱导许多细胞蛋白质的蛋白酶体依赖的降解，包括着丝粒的成分和称为ND10或PML核体的小核亚结构。ICP0有一个环指锌结合结构域，这是其功能所必需的。鉴于最近几个其他环指蛋白通过作为E3泛素连接酶复合体的组成部分来调节特定靶蛋白的稳定性，本研究探索了ICP0是否可能通过类似的机制发挥作用。有证据表明，在转基因和感染细胞中积累的ICP0病灶包含高水平的结合泛素。这一效应依赖于ICP0的环指区域，对一些ICP0突变体的性质的比较表明，ICP0先前建立的功能与其诱导共定位结合泛素浓度的能力之间具有很好的相关性。这些结果有力地支持了这样的假设，即ICP0影响病毒感染的机制中的一个主要因素是它通过与泛素-蛋白酶体途径相互作用而诱导特定细胞靶点的降解。
Herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 is a general activator of viral gene expression which stimulates the initiation of lytic infection and reactivation from quiescence and latency. The importance of ICP0 to the biology of HSV-1 infection has stimulated interest in its mode of action. Previous studies have reported its interactions with other viral regulatory molecules, with the translation apparatus, with cyclin D3, and with a ubiquitin-specific protease, It has been demonstrated that ICP0 is able to induce the proteasome-dependent degradation of a number of cellular proteins, including components of centromeres and small nuclear substructures known as ND10 or PML nuclear bodies. ICP0 has a RING finger zinc-binding domain which is essential for its functions. In view of several recent examples of other RING finger proteins which modulate the stability of specific target proteins by acting as components of E3 ubiquitin ligase complexes, this study has explored whether ICP0 might operate via a similar mechanism. Evidence that the foci of accumulated ICP0 in transfected and infected cells contain enhanced levels of conjugated ubiquitin is presented. This effect was dependent on the RING finger region of ICP0, and comparison of the properties of a number of ICP0 mutants revealed an excellent correlation between previously established functions of ICP0 and its ability to induce concentrations of colocalizing conjugated ubiquitin. These results strongly support the hypothesis that a major factor in the mechanism by which ICP0 influences virus infection is its ability to induce the degradation of specific cellular targets by interaction with the ubiquitin-proteasome pathway.