Inositol-Requiring Enzyme 1 Alpha Promotes Zika Virus Infection Through Regulation Of Stearoyl Coenzyme A Desaturase 1-Mediated Lipid Metabolism

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus which has become a global epidemic threat due to its rapid spread and association with serious consequences of infection, including neonatal microcephaly. Inositol-requiring enzyme 1 alpha (IRE1 alpha) is an endoplasmic reticulum (ER)-related transmembrane protein that mediates unfolded protein response (UPR) pathway and has been indicated to play an important role in flavivirus replication. However, the mechanism of how IRE1 alpha affects ZIKV replication remains unknown. In this study, we explored the role of IRE1 alpha in ZIKV infection in vitro and in vivo by using CRISPR/Cas9-based gene knockout and RNA interference-based gene knockdown techniques. Both knockout and knockdown of IRE1 alpha dramatically reduced ZIKV replication levels, including viral RNA levels, protein expression, and titers in different human cell lines. Trans complementation with IRE1 alpha restored viral replication levels decreased by IRE1 alpha depletion. Furthermore, the proviral effect of IRE1 alpha was dependent on its kinase and RNase activities. Importantly, we found that IRE1 alpha promoted the replication of ZIKV through upregulating the accumulation of monounsaturated fatty acid (MUFA) rate limiting enzyme stearoyl coenzyme A (stearoyl-CoA) desaturase 1 (SCD1), which further affected the production of oleic acid (OA) and lipid droplet. Finally, our data demonstrated that in the brain tissues of ZIKV-infected mice, the replication levels of ZIKV and virus-related lesions were significantly suppressed by both the kinase and RNase inhibitors of IRE1 alpha. Taken together, our results identified IRE1 alpha as a ZIKV dependency factor which promotes viral replication through affecting SCD1-mediated lipid metabolism, potentially providing a novel molecular target for the development of anti-ZIKV agents.IMPORTANCE Zika virus (ZIKV) has been linked to serious neurologic disorders and causes widespread concern in the field of global public health. Inositol requiring enzyme 1 alpha (IRE1 alpha) is an ER-related transmembrane protein that mediates unfolded protein response (UPR) pathway. Here, we revealed that IRE1 alpha is a proviral factor for ZIKV replication both in culture cells and mice model, which relies on its kinase and RNase activities. Importantly, we further provided evidence that upon ZIKV infection, IRE1 alpha is activated and splices XBP1 mRNA which enhances the expression of monounsaturated fatty acids rate-limiting enzyme stearoyl coenzyme A (stearoyl-CoA) desaturase 1 (SCD1) and subsequent lipid droplet production. Our data uncover a novel mechanism of IRE1 alpha proviral effect by modulating lipid metabolism, providing the first evidence of a close relationship between IRE1 alpha-mediated UPR, lipid metabolism, and ZIKV replication and indicating IRE1 alpha inhibitors as potentially effective anti-ZIKV agents.