Human Cytomegalovirus Immediate-Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus
Human Cytomegalovirus Immediate-Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus
复制标题
DOI：
10.1101/308171
复制
发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Cong-Cong Wu-Cong;Xuan Jiang;Xian-Zhang Wang;Xi-Juan Liu;Xiao-Jun Li;Bo Yang;Hanqing Ye;Thomas Harwardt-Tho
中科院分区：
文献类型：
--
作者：
Cong-Cong Wu-Cong;Xuan Jiang;Xian-Zhang Wang;Xi-Juan Liu;Xiao-Jun Li;Bo Yang;Hanqing Ye;Thomas Harwardt-Tho
病毒感染引起的神经发育损伤的机制仍然不清楚。先天性人巨细胞病毒（HCMV）感染是导致胎儿脑发育障碍的主要原因。以前的工作已经将HCMV与神经细胞命运的扰动联系起来，包括神经祖细胞（NPC）的过早分化。在这里，我们表明，HCMV感染的NPC的结果在损失的SOX 2蛋白，一个关键的多能性相关的转录因子。SOX 2耗竭映射到HCMV主要的立即早期（IE）转录单位，并分别由IE1和IE2蛋白介导。IE1通过促进核积累和抑制STAT3（SOX 2表达的转录激活因子）的磷酸化而引起SOX 2下调。导致关键干细胞蛋白耗尽的紊乱信号传导是病毒主要IE蛋白可能导致先天性HCMV感染引起的脑发育障碍的意外机制。人类巨细胞病毒（HCMV）感染是导致儿童脑损伤、听力损失和其他神经功能障碍的主要原因。我们报告称，被称为IE1和IE2的HCMV蛋白靶向表达人SOX 2，一种中枢多能性相关转录因子，支配神经祖细胞（NPC）的命运，是正常大脑发育所必需的。在HCMV感染期间和单独表达时，IE1都会导致SOX 2从NPC中丢失。IE1通过靶向STAT3介导SOX 2耗竭，STAT3是SOX 2表达的关键上游调节因子。我们的研究结果揭示了一种意想不到的机制，一种常见的病毒可能会对发育中的神经系统造成损害，并为医学干预提供了新的靶点。
The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here we show that HCMV infection of NPCs results in the loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate-early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 down-regulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.