IRE1 alpha Promotes Zika Virus Infection via XBP1

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 alpha, a component of the cellular response to ER stress. IRE1 alpha is an ER-resident transmembrane protein that possesses a cytosolic RNase domain. Upon activation, IRE1 alpha 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 alpha, including those specific for the nuclease function, prevent ZIKV-induced cytotoxicity, as does genetic disruption of IRE1 alpha. Optimal ZIKV RNA replication requires both IRE1 alpha and XBP1. Spliced XBP1 has been described to cause ER expansion and remodeling and we find that ER redistribution during ZIKV infection requires IRE1 alpha nuclease activity. Finally, we demonstrate that inducible genetic disruption of IRE1 alpha and XBP1 impairs ZIKV replication in a mouse model of infection. Together, our data indicate that the ER stress response component IRE1 alpha promotes ZIKV infection via XBP1 and may represent a potential therapeutic target.