2. Academic Validation
  3. Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense

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

  • Mol Cell. 2020 Feb 20;77(4):734-747.e7. doi: 10.1016/j.molcel.2019.11.003.
Yukang Yuan 1,  Ying Miao 1,  Liping Qian 1,  Yang Zhang 2,  Chao Liu 3,  Jin Liu 1,  Yibo Zuo 1,  Qian Feng 1,  Tingting Guo 1,  Liting Zhang 1,  Xiangjie Chen 1,  Lincong Jin 1,  Fan Huang 1,  Hongguang Zhang 1,  Wei Zhang 4,  Wei Li 3,  Guoqiang Xu 2,  Hui Zheng 5
Affiliations

Affiliations

  • 1 International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu 215123, China.
  • 2 College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
  • 3 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
  • 4 Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G2W1, Canada.
  • 5 International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: huizheng@suda.edu.cn.
PMID: 31812350 DOI: 10.1016/j.molcel.2019.11.003
Abstract

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.

Keywords

HAT1; UBE4A; Viperin; acetylation; antiviral response; epithelial cells; interferon; ubiquitination; viral infection.

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