The segmented flavivirus Alongshan virus reduces mitochondrial mass by degrading STAT2 to suppress the innate immune response

作者：Y. Zhao, Liyan Sui, Mingming Pan, Fangyu Jin, Yuan Huang, Shu Fang, Mengmeng Wang, Lihe Che, Wenbo Xu, Nan Liu, Haicheng Gao, Zhijun Hou, Fang Du, Zhengkai Wei, Lesley Bell-Sakyi, Jixue Zhao, Kaiyu Zhang, Yicheng Zhao, Quan Liu · 发表于：Journal of Virology · 年份：2024 · DOI：10.1128/jvi.01301-24 · 被引用次数：10 · 研究领域：Mosquito-borne diseases and control、Viral Infections and Vectors、Animal Disease Management and Epidemiology

ABSTRACT Alongshan virus (ALSV) is a newly discovered pathogen in the Flaviviridae family, characterized by a unique multi-segmented genome that is distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of this emerging segmented flavivirus is crucial for the development of effective intervention strategies. In this study, we demonstrate that ALSV can infect various mammalian cells and induce the expression of antiviral genes. Furthermore, ALSV is sensitive to IFN-β, but it has developed strategies to counteract the host’s type I IFN response. Mechanistically, ALSV’s nonstructural protein NSP1 interacts with and degrades human STAT2 through an autophagy pathway, with species-dependent effects. This degradation directly inhibits the expression of interferon-stimulated genes (ISGs). Additionally, NSP1-mediated degradation of STAT2 disrupts mitochondrial dynamics, leading to mitophagy and inhibition of mitochondrial biogenesis. This, in turn, suppresses the host’s innate immune response. Interestingly, we found that inhibiting mitophagy using 3-methyladenine and enhancing mitochondrial biogenesis with the PPARγ agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass could serve as an effective antiviral strategy. Specifically, the NSP1 methyltransferase domain binds to the key sites of F175/R176 located in the coiled-coil domain of STAT2. Our findings provide valuable insights into the intri...