The swine acute diarrhea syndrome coronavirus spike protein promotes syncytial formation via upregulation of cellular cholesterol synthesis

作者：Dakai Liu, Miaomiao Zeng, Jiyu Zhang, Liaoyuan Zhang, Hongyan Shi, Xin Zhang, Jialin Zhang, Jianfei Chen, Zhaoyang Ji, Xiuwen Li, Gu G, Tingshuai Feng, Da Shi, Dongbo Sun, Li Feng · 发表于：mBio · 年份：2025 · DOI：10.1128/mbio.00976-25 · 被引用次数：5 · 研究领域：Animal Virus Infections Studies、SARS-CoV-2 and COVID-19 Research、COVID-19 Clinical Research Studies

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel coronavirus that causes acute diarrhea, vomiting, and high mortality in suckling piglets. Research has demonstrated that certain viruses enhance their replication by modulating intracellular cholesterol metabolism. However, the impact of SADS-CoV infection on cellular cholesterol synthesis remains unclear. Here, we found that SADS-CoV Spike (S) protein promoted syncytium formation by positively regulating cholesterol synthesis. Specifically, the virus upregulated the rate-limiting enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase through the inhibition of AMP-activated protein kinase (AMPK) activity. This inhibition was mediated by the activation of AKT-dependent phosphorylation of AMPKα at Ser485. Further investigation revealed that SADS-CoV S protein activated the PI3K/AKT pathway to promote cholesterol synthesis, a process that required the membrane protein integrin β1 (ITGB1). Importantly, we discovered that cholesterol facilitated cell-to-cell fusion mediated by the viral S protein, which enhanced syncytium formation. In summary, our findings demonstrate that the SADS-CoV S protein enhances cellular cholesterol accumulation by activating the PI3K/AKT/AMPK pathway through ITGB1, and that cholesterol facilitates syncytium formation mediated by the viral S protein. These insights contribute to a better understanding of SADS-CoV infection mechanisms and may inform future therapeutic strategies. IMPORTANCE: Choles...