Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase

• Published in: PLoS pathogens 2017-07, Vol.13 (7), p.e1006542-e1006542
• Main Authors: Liu, Xi-Juan, Yang, Bo, Huang, Sheng-Nan, Wu, Cong-Cong, Li, Xiao-Jun, Cheng, Shuang, Jiang, Xuan, Hu, Fei, Ming, Ying-Zi, Nevels, Michael, Britt, William J, Rayner, Simon, Tang, Qiyi, Zeng, Wen-Bo, Zhao, Fei, Luo, Min-Hua
• Format: Article
• Language: English
• Subjects: Amino acids; Biochemistry; Biology; Biology and Life Sciences; Brain; Brain research; Cells (biology); Cellular signal transduction; Children; Coding; Congenital diseases; Cytomegalovirus; Cytomegalovirus - genetics; Cytomegalovirus - metabolism; Cytomegalovirus Infections - enzymology; Cytomegalovirus Infections - genetics; Cytomegalovirus Infections - virology; Degradation; Disabilities; Disorders; Down-Regulation; Enhancer-of-split protein; Fetuses; Funding; HES1 protein; Hospitals; Host-Pathogen Interactions; Humans; IE1 protein; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Infections; Laboratories; Ligases; Medicine and Health Sciences; Neural stem cells; Neural Stem Cells - enzymology; Neural Stem Cells - metabolism; Neural Stem Cells - virology; Neurodevelopmental disorders; Notch protein; Pediatrics; Physiological aspects; Proteasomes; Protein Binding; Proteins; Proteolysis; Research and analysis methods; Science; Signal transduction; Supervision; Target recognition; Transcription; Transcription Factor HES-1 - genetics; Transcription Factor HES-1 - metabolism; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Virology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006542

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.