Inositol-Requiring Enzyme 1α Promotes Zika Virus Infection through Regulation of Stearoyl Coenzyme A Desaturase 1-Mediated Lipid Metabolism

• DOI: 10.1128/jvi.01229-20
• Publication Date: 2020-09-21T17:25:28Z
• Authors: Yanxia Huang; Quanshi Lin; Zhiting Huo; Cancan Chen; Shili Zhou; Xiaocao Ma; Huixin Gao; Yuxia Lin; Xiaobo Li; Junfang He; Ping Zhang; Chao Liu
• Keywords: Gene Editing; 0301 basic medicine; Brain; Zika Virus; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; Lipid Metabolism; Virus Replication; Cell Line; 3. Good health; Disease Models, Animal; Gene Knockout Techniques; Mice; 03 medical and health sciences; A549 Cells; Endoribonucleases; Unfolded Protein Response; Animals; Humans; CRISPR-Cas Systems; Inositol; Stearoyl-CoA Desaturase; Oleic Acid

Zika virus (ZIKV) has been linked to serious neurologic disorders and causes widespread concern in the field of global public health. Inositol requiring enzyme 1α (IRE1α) is an ER-related transmembrane protein that mediates unfolded protein response (UPR) pathway. Here, we revealed that IRE1α 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, IRE1α 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 IRE1α proviral effect by modulating lipid metabolism, providing the first evidence of a close relationship between IRE1α-mediated UPR, lipid metabolism, and ZIKV replication and indicating IRE1α inhibitors as potentially effective anti-ZIKV agents.