Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase
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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.
Liu , X-J , Yang , B , Huang , S-N , Wu , C-C , Li , X-J , Cheng , S , Jiang , X , Hu , F , Ming , Y-Z , Nevels , M M , Britt , W J , Rayner , S , Tang , Q , Zeng , W-B , Zhao , F & Luo , M-H 2017 , ' Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase ' PLoS Pathogens , vol 13 , no. 7 , e1006542 . DOI: 10.1371/journal.ppat.1006542
© 2017 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This work was supported by: National Natural Science Foundation of China http://www.nsfc.gov.cn/; #81620108021: Fetal Brain Maldevelopment Caused by Sox2 Downregulation during Congenital Cytomegalovirus Infection; #31600145: The mechanism of HCMV-IE1 regulating Hes1 expression and rhythm in neural progenitor cells; #81571355: Construction of Murine Cytomegalovirus Derived viral tools for Specific Glia Tracing; #81271850: The regulation mechanism of HCMV infection on Notch signaling pathway in NPCs; and Sino-Africa Joint Research Center, Chinese Academy of Sciences http://www.sinafrica.cas.cn/; #SAJC201605: Geographical distribution and genetic variation of pathogens in Africa. This work is tightly linked to or is an important component of the above list projects, and is financially supported by all the fundings.
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