IRE1α Promotes Zika Virus Infection via XBP1.

Elena P Kolpikova,Susan L Fink,Konner J Jackson,Takao Iwawaki,Ana R Tronco,Andreas B Den Hartigh

doi:10.3390/v12030278

Elena P Kolpikova, Susan L Fink + Show 4 more

Open Access

https://doi.org/10.3390/v12030278

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Journal: Viruses	Publication Date: Mar 3, 2020
Citations: 23	License type: CC BY 4.0

Affiliation: University of Washington, Kanazawa Medical University

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 IRE1α, a component of the cellular response to ER stress. IRE1α is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1α 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 IRE1α, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1α. Optimal ZIKV RNA replication requires both IRE1α and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1α nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1α and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1α promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.

Highlights

Zika virus (ZIKV) is a mosquito-borne flavivirus that has recently been associated with severe consequences of infection including congenital microcephaly [1,2]
Our results suggest that inositol-requiring enzyme 1 α (IRE1α) promotes ZIKV-induced cell death, which could be secondary to an effect on viral replication
These results suggest that IRE1α promotes ZIKV replication and subsequent viral cytopathic effect

Summary

Introduction

Zika virus (ZIKV) is a mosquito-borne flavivirus that has recently been associated with severe consequences of infection including congenital microcephaly [1,2]. There remains no specific antiviral in clinical use for ZIKV, reflecting a need for a better understanding of the basic biology of this virus [3,4]. Flaviviruses encode only 10 proteins and rely on the manipulation of host cell processes to facilitate their replication cycle. After receptor-mediated entry, endosome acidification releases the positive sense RNA genome, which is translated and replicated. Flaviviruses induce membrane structures derived from the endoplasmic reticulum (ER), which serve as a scaffold for viral replication [5,6]. Viral packaging occurs on the ER and immature virions bud into the ER lumen for transport to the trans-Golgi and subsequent exocytosis

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