Differential Properties of Cytomegalovirus pUL97 Kinase Isoforms Affect Viral Replication and Maribavir Susceptibility
Differential Properties of Cytomegalovirus pUL97 Kinase Isoforms Affect Viral Replication and Maribavir Susceptibility
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巨细胞病毒 pUL97 激酶亚型的差异特性影响病毒复制和马里巴韦敏感性
DOI：
10.1128/jvi.00192-14
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发表时间：
2014
影响因子：
5.4
通讯作者：
Marschall
中科院分区：
文献类型：
--
作者：
Prichard;Rawlinson;Marschall
人巨细胞病毒（HCMV）编码的激酶pUL97是有效的病毒复制所必需的。先前的研究描述了pUL97的两种同种型，全长同种型（M1）和可能由密码子74处的翻译起始产生的较小同种型（M74）。在这里，我们报告的检测第三pUL97亚型在病毒感染导致翻译起始密码子157（亚型M157）。当密码子157被诱变时，在用临床和实验室适应的HCMV毒株感染期间，作为pUL97的次要组分的同种型M157的一致表达被抑制。产生表达特定同种型的病毒突变体以比较它们的生长和药物敏感性表型，以及pUL97细胞内定位模式和激酶活性。同种型M157的排他性表达导致病毒生长和对pUL97抑制剂Maribavir的耐药性显著降低，同时保留对更昔洛韦的敏感性。共聚焦成像显示与亚型M1相比，氨基末端缺失亚型的核输入减少。异构体M157显示各种底物蛋白相互作用和自磷酸化的效率降低，而Rb磷酸化被保留。这些结果揭示了影响病毒复制的pUL97亚型的差异特性，并暗示了Maribavir的抗病毒功效。重要信息HCMV UL97激酶在抗病毒药物Maribavir靶向的病毒复制中发挥重要作用。在本文中，我们描述了一种天然存在的激酶短亚型，与主要全长对应物相比，其在重组病毒中单独表达时导致细胞内定位改变、生长受损和对Maribavir的高水平耐药性。这是解释Maribavir在细胞培养和体内抗病毒活性不同的另一个因素。
The human cytomegalovirus (HCMV)-encoded kinase pUL97 is required for efficient viral replication. Previous studies described two isoforms of pUL97, the full-length isoform (M1) and a smaller isoform likely resulting from translation initiation at codon 74 (M74). Here, we report the detection of a third pUL97 isoform during viral infection resulting from translation initiation at codon 157 (isoform M157). The consistent expression of isoform M157 as a minor component of pUL97 during infection with clinical and laboratory-adapted HCMV strains was suppressed when codon 157 was mutagenized. Viral mutants expressing specific isoforms were generated to compare their growth and drug susceptibility phenotypes, as well as pUL97 intracellular localization patterns and kinase activities. The exclusive expression of isoform M157 resulted in substantially reduced viral growth and resistance to the pUL97 inhibitor maribavir while retaining susceptibility to ganciclovir. Confocal imaging demonstrated reduced nuclear import of amino-terminal deletion isoforms compared to isoform M1. Isoform M157 showed reduced efficiency of various substrate protein interactions and autophosphorylation, whereas Rb phosphorylation was preserved. These results reveal differential properties of pUL97 isoforms that affect viral replication, with implications for the antiviral efficacy of maribavir.IMPORTANCEThe HCMV UL97 kinase performs important functions in viral replication that are targeted by the antiviral drug maribavir. Here, we describe a naturally occurring short isoform of the kinase that when expressed by itself in a recombinant virus results in altered intracellular localization, impaired growth, and high-level resistance to maribavir compared to those of the predominant full-length counterpart. This is another factor to consider in explaining why maribavir appears to have variable antiviral activity in cell culture andin vivo.
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DOI：
10.1073/pnas.98.4.1895
发表时间：
2001-02
影响因子：
11.1
作者：
D. Wolf;C. T. Courcelle;M. Prichard;E. Mocarski
通讯作者：
D. Wolf;C. T. Courcelle;M. Prichard;E. Mocarski
影响因子：
5.4
作者：
D. Michel;I. Pavić;A. Zimmermann;E. Haupt;K. Wunderlich;M. Heuschmid;T. Mertens
通讯作者：
D. Michel;I. Pavić;A. Zimmermann;E. Haupt;K. Wunderlich;M. Heuschmid;T. Mertens
影响因子：
6.7
作者：
Hamirally S;Kamil JP;Ndassa-Colday YM;Lin AJ;Jahng WJ;Baek MC;Noton S;Silva LA;Simpson-Holley M;Knipe DM;Golan DE;Marto JA;Coen DM
通讯作者：
Coen DM
人巨细胞病毒蛋白激酶 pUL97 的两种亚型在核易位方面受到差异性调节。
DOI：
10.1099/vir.0.026799-0
发表时间：
2011
期刊：
The Journal of general virology
影响因子：
--
作者：
Rike Webel;Jens Milbradt;S. Auerochs;V. Schregel;C. Held;Katharina Nöbauer;E. Razzazi;Christophe Jardin;T. Wittenberg;H. Sticht;M. Marschall
通讯作者：
M. Marschall
影响因子：
3.8
作者：
Becke, Sabine;Fabre-Mersseman, Veronique;Reyda, Sabine
通讯作者：
Reyda, Sabine