Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.
Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.
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人巨细胞病毒 IE1 作为潜在的 E3 泛素连接酶下调神经祖细胞中的 Hes1。
DOI：
10.1371/journal.ppat.1006542
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发表时间：
2017-07
期刊：
影响因子：
6.7
通讯作者：
Luo MH
中科院分区：
文献类型：
--
作者：
Liu XJ;Yang B;Huang SN;Wu CC;Li XJ;Cheng S;Jiang X;Hu F;Ming YZ;Nevels M;Britt WJ;Rayner S;Tang Q;Zeng WB;Zhao F;Luo MH
先天性人巨细胞病毒（HCMV）感染是世界范围内儿童神经功能障碍的主要原因，但这些疾病的机制还远未明确。HCMV感染已显示出在人神经祖细胞（NPC）中Notch信号传导途径失调。转录调控因子Hairy and Enhancer of Split 1（Hes 1）作为Notch信号的重要下游效应子，对NPC的命运和胎儿脑发育起着至关重要的作用。在本研究中，我们报告说，HCMV感染下调Hes 1蛋白水平在感染的NPC。HCMV 72-kDa立即早期1蛋白（IE 1）参与Hes 1降解，通过组装泛素化复合物并促进Hes 1作为潜在的E3泛素连接酶的泛素化，然后通过蛋白酶体降解Hes 1。Sp100 A是PML核体的重要组成部分，被认为是IE 1介导的泛素化的另一个靶点。IE 1的C-末端酸性区域，跨越氨基酸451至475，是IE 1/Hes 1物理相互作用和IE 1介导的Hes 1泛素化所必需的，但对于IE 1/Sp100 A相互作用和泛素化是不必要的。我们的研究表明，Hes 1蛋白下调与HCMV感染引起的神经发育障碍有关。我们的研究结果还补充了目前的知识疱疹病毒的鉴定IE 1作为第一个潜在的HCMV编码的E3泛素连接酶。先天性人巨细胞病毒（HCMV）感染是导致儿童神经功能障碍的主要原因，但这种感染的潜在发病机制仍不清楚。Hes 1是Notch信号的重要效应子，控制神经祖细胞（NPC）的命运和胎儿脑发育。在这里，我们证明：（1）HCMV感染导致NPC中Hes 1蛋白的丢失;（2）HCMV立即早期1蛋白（IE 1）通过直接相互作用介导Hes 1蛋白的下调，这需要氨基酸451-475;（3）IE 1组装Hes 1泛素化复合物并介导Hes 1泛素化;（4）IE 1也组装Sp100 A泛素化复合物并介导Sp100 A泛素化，但不需要氨基酸451-475。这些结果表明，HCMV IE 1是一个潜在的E3泛素连接酶。Hes 1通过HCMV感染和IE 1下调意味着Hes 1耗竭与病毒诱导的神经发病机制的新机制。
Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase. Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children, but the underlying pathogenesis of this infection remains unclear. Hes1, an important effector of Notch signaling, governs the fate of neural progenitor cells (NPCs) and fetal brain development. Here we demonstrate that: (1) HCMV infection results in loss of Hes1 protein in NPCs; (2) the HCMV immediate-early 1 protein (IE1) mediates Hes1 protein downregulation through direct interaction, which requires amino acids 451–475; (3) IE1 assembles a Hes1 ubiquitination complex and mediates Hes1 ubiquitination; and (4) IE1 also assembles an Sp100A ubiquitination complex and mediates Sp100A ubiquitination, but does not require amino acids 451–475. These results suggest that HCMV IE1 is a potential E3 ubiquitin ligase. Downregulation of Hes1 by HCMV infection and IE1 implies a novel mechanism linking Hes1 depletion to virus-induced neuropathogenesis.
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