ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells

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, unfol...

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Bibliographic Details
Published in:	Journal of neuroinflammation Vol. 15; no. 1; p. 275
Main Authors:	Tan, Zhongyuan, Zhang, Wanpo, Sun, Jianhong, Fu, Zuquan, Ke, Xianliang, Zheng, Caishang, Zhang, Yuan, Li, Penghui, Liu, Yan, Hu, Qinxue, Wang, Hanzhong, Zheng, Zhenhua
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 21-09-2018 BioMed Central BMC
Subjects:	Activating Transcription Factor 6 - metabolism Animals Apoptosis Astrocytoma Brain - metabolism Brain - pathology Brain - virology Cell Line, Transformed Cerebellum Control Disease Models, Animal Disease transmission Endoplasmic reticulum Endoplasmic Reticulum - metabolism Endoplasmic Reticulum - pathology Endoplasmic Reticulum Stress - drug effects Endoplasmic Reticulum Stress - genetics ER stress GADD34 protein Gene Expression Regulation, Viral - genetics Gene Expression Regulation, Viral - physiology Hepatitis Humans Immunofluorescence Immunohistochemistry Infections Interferon Localization Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Transgenic Microcephaly Microencephaly Neonates Neural cell Neurological complications Neurons - metabolism Neurons - virology Neuropathogenesis Packaging Protein folding Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteins Receptor, Interferon alpha-beta - deficiency Receptor, Interferon alpha-beta - genetics Risk factors Sensors Transcription Transcription factors Unfolded protein response Viral infections West Nile virus X-Box Binding Protein 1 - genetics X-Box Binding Protein 1 - metabolism Zika virus Zika Virus - genetics Zika Virus - physiology Zika Virus Infection - metabolism Zika Virus Infection - pathology Uganda Neuropathogenesis ER stress Zika virus Neural cell Unfolded protein response
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Summary:	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. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-2094 1742-2094
DOI:	10.1186/s12974-018-1311-5