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

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

  • Research (Wash D C). 2024 Oct 24:7:0511. doi: 10.34133/research.0511.
Xiaotong Luo 1 2,  Yunxiang Yuan 1 2,  Xiaocao Ma 1 2,  Xin Luo 1 2,  Jiannan Chen 1 2,  Cancan Chen 3,  Xiaoyi Yang 1 2,  Jinna Yang 1 2,  Xuanfeng Zhu 1 2,  Meiyu Li 1 4,  Yang Liu 5,  Ping Zhang 1 2,  Chao Liu 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China.
  • 2 Department of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 3 Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 4 Experimental Teaching Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 5 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
PMID: 39449854 DOI: 10.34133/research.0511
Abstract

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 122R-R-S124 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.

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