Tan, Z;
Zhang, W;
Sun, J;
Fu, Z;
Ke, X;
Zheng, C;
Zhang, Y;
Li, P;
Liu, Y;
Hu, Q;
et al.
Tan, Z; Zhang, W; Sun, J; Fu, Z; Ke, X; Zheng, C; Zhang, Y; Li, P; Liu, Y; Hu, Q; Wang, H; Zheng, Z
(2018)
ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells.
J Neuroinflammation, 15 (1).
p. 275.
ISSN 1742-2094
https://doi.org/10.1186/s12974-018-1311-5
SGUL Authors: Hu, Qinxue
Abstract
BACKGROUND: Many viruses depend on the extensive membranous network of the endoplasmic reticulum (ER) for their translation, replication, and packaging. Certain membrane modifications of the ER can be a trigger for ER stress, as well as the accumulation of viral protein in the ER by viral infection. Then, unfolded protein response (UPR) is activated to alleviate the stress. Zika virus (ZIKV) is a mosquito-borne flavivirus and its infection causes microcephaly in newborns and serious neurological complications in adults. Here, we investigated ER stress and the regulating model of UPR in ZIKV-infected neural cells in vitro and in vivo. METHODS: Mice deficient in type I and II IFN receptors were infected with ZIKV via intraperitoneal injection and the nervous tissues of the mice were assayed at 5 days post-infection. The expression of phospho-IRE1, XBP1, and ATF6 which were the key markers of ER stress were analyzed by immunohistochemistry assay in vivo. Additionally, the nuclear localization of XBP1s and ATF6n were analyzed by immunohistofluorescence. Furthermore, two representative neural cells, neuroblastoma cell line (SK-N-SH) and astrocytoma cell line (CCF-STTG1), were selected to verify the ER stress in vitro. The expression of BIP, phospho-elF2α, phospho-IRE1, and ATF6 were analyzed through western blot and the nuclear localization of XBP1s was performed by confocal immunofluorescence microscopy. RT-qPCR was also used to quantify the mRNA level of the UPR downstream genes in vitro and in vivo. RESULTS: ZIKV infection significantly upregulated the expression of ER stress markers in vitro and in vivo. Phospho-IRE1 and XBP1 expression significantly increased in the cerebellum and mesocephalon, while ATF6 expression significantly increased in the mesocephalon. ATF6n and XBP1s were translocated into the cell nucleus. The levels of BIP, ATF6, phospho-elf2α, and spliced xbp1 also significantly increased in vitro. Furthermore, the downstream genes of UPR were detected to investigate the regulating model of the UPR during ZIKV infection in vitro and in vivo. The transcriptional levels of atf4, gadd34, chop, and edem-1 in vivo and that of gadd34 and chop in vitro significantly increased. CONCLUSION: Findings in this study demonstrated that ZIKV infection activates ER stress in neural cells. The results offer clues to further study the mechanism of neuropathogenesis caused by ZIKV infection.
Item Type: |
Article
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Additional Information: |
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
Keywords: |
ER stress, Neural cell, Neuropathogenesis, Unfolded protein response, Zika virus, Activating Transcription Factor 6, Animals, Brain, Cell Line, Transformed, Disease Models, Animal, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Gene Expression Regulation, Viral, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Protein-Serine-Threonine Kinases, Receptor, Interferon alpha-beta, X-Box Binding Protein 1, Zika Virus, Zika Virus Infection, Brain, Neurons, Cell Line, Transformed, Endoplasmic Reticulum, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, Disease Models, Animal, Protein-Serine-Threonine Kinases, Membrane Proteins, Gene Expression Regulation, Viral, Activating Transcription Factor 6, Receptor, Interferon alpha-beta, Endoplasmic Reticulum Stress, Zika Virus, Zika Virus Infection, X-Box Binding Protein 1, Zika virus, Neural cell, Neuropathogenesis, ER stress, Unfolded protein response, 1103 Clinical Sciences, 1109 Neurosciences, 1107 Immunology, Neurology & Neurosurgery |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
J Neuroinflammation |
ISSN: |
1742-2094 |
Language: |
eng |
Dates: |
Date | Event |
---|
21 September 2018 | Published | 10 September 2018 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
|
PubMed ID: |
30241539 |
Web of Science ID: |
WOS:000445228100002 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111757 |
Publisher's version: |
https://doi.org/10.1186/s12974-018-1311-5 |
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