In December 2019, Professor Zheng Hui's research group published a research paper entitled "Targeting UBE4A Revives Viperin Protein in Epithelium to Enhance Host Antiviral Defense " in the Molecular Cell.
The highly frequent gene mutation and outbreak of viruses make it an urgent need to develop broad-spectrum antiviral treatment strategies. Viperin is a broad-spectrum and powerful antiviral protein. Unexpectedly, we found that during viral infection, even under the direct stimulation of interferon (IFN), the host epithelial cells could not effectively induce the production of Viperin protein. Obviously, this defect wastes the antiviral effects of Viperin protein in host epithelial cells. Given that epithelial cells are the first line of host defense against infection of many types of viruses, rescuing the expression of Viperin protein in epithelial cells may significantly improve the host's antiviral defense ability.
Therefore, we explored the regulatory mechanisms of Viperin expression in epithelial cells. We found that virus or IFN stimulation can induce the expression of HAT1, which then induces the acetylation of Lys 197 of Viperin protein. This acetylation promotes the binding of the ubiquitin ligase UBE4A to Viperin. Furthermore, UBE4A catalyzes the K6-linked polyubiquitination of Viperin protein at Lys206, which leads to the rapid degradation of Viperin protein in epithelial cells. We found that the absence of UBE4A can restore the expression of Viperin protein in epithelial cells.
In order to correct the defect of the inability of epithelial cells to express Viperin protein, we further designed interference peptides (IPs) to specifically inhibit the binding between UBE4A and Viperin. We found that VIP-IP3, one of the interfering peptides, restores the ability of epithelial cells to produce Viperin protein, thus enhancing the antiviral activity of cells. Moreover, VIP-IP3 significantly enhances the ability of mice to resist virus infection. These findings may provide a potential new strategy for both enhancing the broad-spectrum antiviral ability of the host and improving the clinical efficacy of IFN-based antiviral therapy.
Yuan Yukang and Miao Ying are the first authors of this paper. In addition, Qian Liping, Zhang Yang, Liu Chao, Liu Jin, Zuo Yibo, et al. participated in the research. This work is supported by the National Natural Science Foundation of China (31370873, 31770177 and 31970846), the National Key R&D Program of China (2018YFC1705500): 2018YFC1705505, the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the program of 1000 Young Talents (2014), and Jiangsu Provincial Distinguished Young Scholars (BK20130004).