Transcriptome screening identifies TIPARP as an antiviral host factor against the Getah virus

作者：Houqi Jiao, Ziqing Yan, Xiaofeng Zhai, Yichen Yang, Ningning Wang, Xiaoling Li, Zhiwen Jiang, Shuo Su · 发表于：Journal of Virology · 年份：2023 · DOI：10.1128/jvi.00591-23 · 被引用次数：15 · 研究领域：Viral Infections and Outbreaks Research、Mosquito-borne diseases and control、Cytomegalovirus and herpesvirus research

ABSTRACT Alphaviruses are emerging and re-emerging viruses that cause severe disease and threaten public health worldwide. To advance the understanding of the underlying mechanisms of alphavirus replication and identify new host restriction factors, we performed RNA-seq and identified antiviral host factors on the Getah virus (GETV), a re-emerging alphavirus. We identified tetrachlorodibenzo-p-dioxin-inducible poly(ADP ribose) polymerase (TIPARP) as a host antiviral factor. TIPARP is downregulated in GETV-infected Vero cells, and its overexpression significantly inhibits GETV replication, while TIPARP deficiency results in significantly increased viral titers. We demonstrated that TIPARP interacts with the viral E2 glycoprotein, inducing k48-linked ubiquitination and subsequent proteasomal degradation. Additionally, we found that TIPARP recruits the E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8) to modify the ubiquitination, leading to the degradation of E2. Lys253 in E2 was identified as the TIPARP-facilitated ubiquitination site. A mutation in Lys253 resulted in the loss of TIPARP’s anti-GETV effect. Our study demonstrated for the first time that host TIPARP is a restricting factor against GETV replication. Investigating the underlying mechanisms and understanding TIPARP for GETV will be essential to fully understanding viral pathogenesis and developing novel broad-spectrum therapeutic strategies against alphavirus infection. IMPORTANCE Alphaviruses threaten pub...