Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells

作者：Xiaojun Li, Xiaojian Liu, Bo Yang, Yaru Fu, Fei Zhao, Zhang‐Zhou Shen, Ling-Feng Miao, Simon Rayner, Stéphane Chavanas, Hua Zhu, William J. Britt, Qiyi Tang, Michael A. McVoy, Min‐Hua Luo · 发表于：Journal of Virology · 年份：2015 · DOI：10.1128/jvi.00351-15 · 被引用次数：49 · 研究领域：Cytomegalovirus and herpesvirus research、Anesthesia and Neurotoxicity Research、Fetal and Pediatric Neurological Disorders

UNLABELLED: 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 infe...