Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense
| Autor: | Yang Zhang, Yibo Zuo, Liting Zhang, Tingting Guo, Guoqiang Xu, Fan Huang, Hong-Guang Zhang, Wei Zhang, Wei Li, Hui Zheng, Qian Feng, Yukang Yuan, Ying Miao, Liping Qian, Xiangjie Chen, Chao Liu, Lincong Jin, Jin Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Oxidoreductases Acting on CH-CH Group Donors
Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Antiviral protein Biology Protein degradation Cell Line Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin Interferon medicine Protein biosynthesis Animals Humans Molecular Biology Cells Cultured 030304 developmental biology 0303 health sciences Ubiquitination Proteins Acetylation Epithelial Cells Cell Biology Cell biology Mice Inbred C57BL Acetyltransferase Viperin biology.protein Interferons Peptides HAT1 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Molecular Cell. 77:734-747.e7 |
| ISSN: | 1097-2765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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