Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells
Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells
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人类巨细胞病毒感染导致神经祖细胞中 NICD1 和 Jag1 的定位和稳定性失调
DOI：
10.1128/jvi.00351-15
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发表时间：
2015-07-01
影响因子：
5.4
通讯作者：
Luo, Min-Hua
中科院分区：
文献类型：
--
作者：
Li, Xiao-Jun;Liu, Xi-Juan;Luo, Min-Hua
人类巨细胞病毒（HCMV）感染发育中的胎儿经常导致严重的神经发育损害。在先前的研究中，HCMV被证明下调神经祖细胞/干细胞（NPC）标记并诱导异常分化。由于Notch信号在维持干细胞状态中起着至关重要的作用，并且是控制NPC分化的开关，因此我们研究了HCMV感染对NPC中Notch信号通路的影响。HCMV下调Notch1及其配体Jag1的mRNA水平，降低蛋白水平，改变Jag1的细胞内定位和Notch1的细胞内效应形式NICD1。这些作用需要HCMV基因表达，似乎是通过增强蛋白酶体降解介导的。病毒被膜蛋白pp71和UL26的瞬时表达内源性和外源性降低了NICD1和Jag1蛋白水平。考虑到Notch信号在鼻咽癌生长和分化中的关键作用，这些发现揭示了HCMV在体外干扰神经细胞发育的重要机制。在胎儿大脑先天性感染期间，体内类似的事件可能与hcmv介导的神经发病机制有关。先天性人类巨细胞病毒（HCMV）感染是导致出生缺陷的主要原因，主要表现为神经功能障碍。神经祖细胞（Neural progenitor cells, npc）是胎儿大脑中HCMV感染最易感的细胞类型，在胎儿大脑发育中起着关键作用。研究表明，NPC完全允许HCMV感染，导致神经细胞丢失和过早分化，从而扰乱NPC的命运。阐明控制鼻咽癌增殖和分化的病毒-宿主相互作用对理解神经发病机制至关重要。Notch信号通路对于维持干细胞状态至关重要，并作为npc分化的开关。我们研究了HCMV感染对这一通路的影响，发现HCMV通过改变Notch配体Jag1、Notch1及其活性效应物在npc中的表达来失调Notch信号。这些结果提示HCMV感染诱导的神经发病机制包括鼻咽癌分化和增殖的改变。
ABSTRACT Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.