Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense

• Published in: Molecular cell 2020-02, Vol.77 (4), p.734-747.e7
• Main Authors: Yuan, Yukang, Miao, Ying, Qian, Liping, Zhang, Yang, Liu, Chao, Liu, Jin, Zuo, Yibo, Feng, Qian, Guo, Tingting, Zhang, Liting, Chen, Xiangjie, Jin, Lincong, Huang, Fan, Zhang, Hongguang, Zhang, Wei, Li, Wei, Xu, Guoqiang, Zheng, Hui
• Format: Article
• Language: English
• Subjects: acetylation; antiviral response; epithelial cells; HAT1; interferon; UBE4A; ubiquitination; Viperin; viral infection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.11.003

Mutation and prevalence of pathogenic viruses prompt the development of broad-spectrum antiviral strategies. Viperin is a potent antiviral protein that inhibits a broad range of viruses. Unexpectedly, we found that Viperin protein production in epithelium is defective in response to both viruses and interferons (IFNs). We further revealed that viruses and IFNs stimulate expression of the acetyltransferase HAT1, which induces Lys197-acetylation on Viperin. Viperin acetylation in turn recruits UBE4A that stimulates K6-linked polyubiquitination at Lys206 of Viperin, leading to Viperin protein degradation. Importantly, UBE4A deficiency restores Viperin protein production in epithelium. We then designed interfering peptides (IPs) to inhibit UBE4A binding with Viperin. We found that VIP-IP3 rescues Viperin protein production in epithelium and therefore enhances cellular antiviral activity. VIP-IP3 renders mice more resistant to viral infection. These findings could provide strategies for both enhancing host broad-spectrum antiviral response and improving the efficacy of IFN-based antiviral therapy. [Display omitted] •Viperin protein induction in epithelium is defective in response to viruses or IFNs•Viruses and IFNs utilize HAT1 to induce Viperin acetylation that recruits UBE4A•UBE4A induces Viperin K6 ubiquitination and degrades Viperin protein in epithelium•VIP-IP3 rescues Viperin protein in epithelium and enhances host antiviral defense Viperin potently inhibits a broad spectrum of viruses. Yuan et al. show that Viperin protein induction in epithelium during viral infection is disrupted by the HAT1-UBE4A axis that results in Viperin acetylation and subsequent ubiquitination, and interfering peptides VIP-IP3 can restore Viperin protein and enhance epithelial antiviral defense.