Abstract
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.
Highlights
As a leading cause of birth defects, congenital human cytomegalovirus (HCMV) infection causes irreversible maldevelopment of the central nervous system (CNS) in newborns and children [1,2,3,4]
We demonstrate that: (1) HCMV infection results in loss of Hes1 protein in neural progenitor cells (NPCs); (2) the HCMV immediate-early 1 protein (IE1) mediates Hes1 protein downregulation through direct interaction, which requires amino acids 451–475; (3) IE1 assembles a Hes1 ubiquitination complex and mediates Hes1 ubiquitination; and (4) IE1 assembles an Sp100A ubiquitination complex and mediates Sp100A ubiquitination, but does not require amino acids 451–475. These results suggest that HCMV IE1 is a potential E3 ubiquitin ligase
Human NPCs are fully permissive for HCMV replication [6,7,8,9], and our previous work has demonstrated that HCMV infection dysregulates NICD1 and Jag1 in NPCs, which are two essential components upstream of Hes1 in the Notch signaling pathway [5]
Summary
As a leading cause of birth defects, congenital human cytomegalovirus (HCMV) infection causes irreversible maldevelopment of the central nervous system (CNS) in newborns and children [1,2,3,4]. Notch signaling is one of the best-characterized pathways governing NPC maintenance, proliferation and differentiation [11,12,13] This regulatory role is achieved, at least partially, through essential downstream effectors such as the Hairy and Enhancer of Split (Hes) proteins, which belong to the repressor-type basic helix-loop-helix family [14, 15]. Studies in mice have shown that Hes1-deficient murine NPC neurospheres fail to expand, and Hes knockout accelerates neurogenesis from radial glial cells representing NPCs in mice [21,22,23,24] These evidences imply that the dysregulation of Hes expression leads to abnormal NPC differentiation and proliferation, potentially contributing to fetal brain developmental disorders. As an important downstream effector in Notch signaling, the regulation of Hes expression in NPCs is disrupted by HCMV infection [25]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
