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IRE1? Promotes Zika Virus Infection via XBP1.

ABSTRACT: Zika virus (ZIKV) is an emergent member of the Flaviviridae family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1?, a component of the cellular response to ER stress. IRE1? is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1? initiates nonconventional cytoplasmic splicing of XBP1 mRNA. Spliced XBP1 encodes a transcription factor, which upregulates ER-related targets. We find that ZIKV infection induces XBP1 mRNA splicing and induction of XBP1 target genes. Small molecule inhibitors of IRE1?, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1?. Optimal ZIKV RNA replication requires both IRE1? and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1? nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1? and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1? promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.

SUBMITTER: Kolpikova EP

PROVIDER: S-EPMC7150863 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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IRE1α Promotes Zika Virus Infection via XBP1.

Kolpikova Elena P EP Tronco Ana R AR Hartigh Andreas B den ABD Jackson Konner J KJ Iwawaki Takao T Fink Susan L SL

Viruses 20200303 3

Zika virus (ZIKV) is an emergent member of the <i>Flaviviridae</i> family which causes severe congenital defects and other major sequelae, but the cellular processes that support ZIKV replication are incompletely understood. Related flaviviruses use the endoplasmic reticulum (ER) as a membranous platform for viral replication and induce ER stress during infection. Our data suggest that ZIKV activates IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane ...[more]

PMID: 32138181

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Project description: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-elF2?, 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-elf2?, 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.

Dataset Information

IRE1? Promotes Zika Virus Infection via XBP1.

Publications

IRE1α Promotes Zika Virus Infection via XBP1.

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