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
Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China.
Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
Research (Wash D C). 2024 Oct 24;7:0511. doi: 10.34133/research.0511. eCollection 2024.
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.
多种脂质代谢相关因子对寨卡病毒（ZIKV）复制至关重要。在本研究中，我们使用基于短发夹RNA的基因敲低技术揭示了二酰甘油O-酰基转移酶2（DGAT2）在ZIKV复制中的关键作用。在多种细胞系中，DGAT2的缺失显著抑制了ZIKV的复制，并通过与DGAT2的反式互补得以恢复。从机制上讲，DGAT2通过与非结构（NS）蛋白相互作用被招募到病毒复制复合体中。其中，人和鼠的DGAT2均可被NS2B3在R-R-S位点切割。有趣的是，DGAT2的切割产物变得更加稳定，并且足以促进脂滴（LD）形成，而与其酶活性无关。这项工作将DGAT2鉴定为病毒蛋白酶NS2B3的新靶点，并阐明DGAT2被病毒蛋白招募到复制复合体中，从而通过促进LD形成发挥病毒促进作用，这加深了我们对宿主-黄病毒相互作用的理解。
