Diacylglycerol O-acyltransferase 2, a Novel Target of Flavivirus NS2B3 Protease, Promotes Zika Virus Replication by Regulating Lipid Droplet Formation

• Published in: Research (Washington) Vol. 7; p. 0511
• Main Authors: Luo, Xiaotong, Yuan, Yunxiang, Ma, Xiaocao, Luo, Xin, Chen, Jiannan, Chen, Cancan, Yang, Xiaoyi, Yang, Jinna, Zhu, Xuanfeng, Li, Meiyu, Liu, Yang, Zhang, Ping, Liu, Chao
• Format: Journal Article
• Language: English
• Published: United States AAAS 2024; American Association for the Advancement of Science (AAAS)
• Subjects: Health Science
• ISSN: 2639-5274; 2639-5274
• DOI: 10.34133/research.0511

Various lipid metabolism-related factors are essential for Zika virus (ZIKV) replication. In this study, we revealed a crucial role of diacylglycerol O-acyltransferase 2 (DGAT2) in ZIKV replication using a short hairpin RNA-based gene knockdown technique. The replication of ZIKV was significantly inhibited by DGAT2 depletion in multiple cell lines and restored by trans-complementation with DGAT2. Mechanistically, DGAT2 is recruited in the viral replication complex by interacting with non-structural (NS) proteins. Among them, both human and murine DGAT2s can be cleaved by NS2B3 at the
R-R-S
site. Interestingly, the cleavage product of DGAT2 becomes more stable and is sufficient to promote the lipid droplet (LD) formation independent of its enzymatic activity. This work identifies DGAT2 as a novel target of the viral protease NS2B3 and elucidates that DGAT2 is recruited by viral proteins into the replication complex, thereby playing a proviral role by promoting LD formation, which advances our understanding of host-flavivirus interaction.