Wu, Cong-Cong and Jiang, Xuan and Wang, Xian-Zhang and Liu, Xi-Juan and Li, Xiao-Jun and Yang, Bo and Ye, Han-Qing and Harwardt, Thomas and Jiang, Man and Xia, Hui-Min and Wang, Wei and Britt, William J. and Paulus, Christina and Nevels, Michael and Luo, Min-Hua (2018) Human Cytomegalovirus Immediate Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus. JOURNAL OF VIROLOGY, 92 (17): e00340-18. ISSN 0022-538X, 1098-5514
Full text not available from this repository. (Request a copy)Abstract
The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss, and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ADULT HUMAN FIBROBLASTS; LONGITUDINAL-FOLLOW-UP; CENTRAL-NERVOUS-SYSTEM; EMBRYONIC STEM-CELLS; PRECURSOR CELLS; NEURONAL DIFFERENTIATION; INTELLECTUAL-DEVELOPMENT; ANOPHTHALMIA SYNDROME; MOUSE FIBROBLASTS; AUTISTIC DISORDER; HCMV; IE1; neural progenitor cells; SOX2; STAT3 |
| Subjects: | 500 Science > 580 Botanical sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Mikrobiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Jan 2020 07:50 |
| Last Modified: | 09 Jan 2020 07:50 |
| URI: | https://pred.uni-regensburg.de/id/eprint/13914 |
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