State Key Laboratory of Virology, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Wuhan Institute of Virology, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
J Virol. 2018 Aug 16;92(17). doi: 10.1128/JVI.00340-18. Print 2018 Sep 1.
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 infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in 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 downregulation 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. 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.
病毒感染导致神经发育损伤的机制仍未完全阐明。先天性人巨细胞病毒（HCMV）感染是胎儿脑发育障碍的主要原因。先前的工作已经将 HCMV 感染与神经细胞命运的改变联系起来，包括神经祖细胞（NPC）的过早分化。在这里，我们表明 HCMV 感染 NPC 会导致 SOX2 蛋白的丢失，SOX2 是一种关键的多能相关转录因子。SOX2 的缺失映射到 HCMV 主要早期（IE）转录单元，并且由 IE1 和 IE2 蛋白单独介导。IE1 通过促进 STAT3 的核积累和抑制其磷酸化来导致 SOX2 下调，STAT3 是 SOX2 表达的转录激活剂。导致关键干细胞蛋白耗竭的信号失调是病毒主要 IE 蛋白可能导致先天性 HCMV 感染引起的脑发育障碍的一种意外机制。人巨细胞病毒（HCMV）感染是儿童脑损伤、听力损失和其他神经发育障碍的主要原因。我们报告说，HCMV 蛋白 IE1 和 IE2 靶向人类 SOX2 的表达，SOX2 是一种中央多能相关转录因子，它控制神经祖细胞（NPC）的命运，是正常脑发育所必需的。在 HCMV 感染期间和单独表达时，IE1 都会导致 NPC 中 SOX2 的丢失。IE1 通过靶向 STAT3 介导 SOX2 的缺失，STAT3 是 SOX2 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，即一种常见病毒如何对发育中的神经系统造成损伤，并为医学干预提供了新的靶点。
