On May 25, 2018, researchers at Dr.Zheng’s group published an article entitled “ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3” in Journal of Immunology.
Ataxin-3 (ATXN3) belongs to the Josephin family of deubiquitinases. So far, ATXN3 is majorly linked to the neurodegenerative disease, Machado–Joseph disease. The role of ATXN3 in the antiviral function has not been explored, and the in vivo deubiquitinating activity of ATXN3 remains largely unknown. In this study, we report that ATXN3 is an important positive regulator of type I IFN (IFN-I)–mediated antiviral activity in murine primary lung cells and human epithelial and fibroblast cell lines. We clarify that ATXN3 does not promote IFN-I production, but enhances the IFN-I–mediated signaling pathway. Furthermore, ATXN3 physically interacts with histone deacetylase 3 (HDAC3) and upregulates the level of HDAC3 protein. Moreover, ATXN3 deubiquitinates HDAC3, thereby enhancing HDAC3 protein stability. Interestingly, the interaction between ATXN3 and HDAC3 increases during viral infection, which promotes IFN-I–induced signaling in murine primary lung cells. Finally, we reveal the ATXN3/HDAC3 axis–mediated regulation of IFN-I antiviral response. These findings reveal a novel biological function of ATXN3 and an important antiviral mechanism by which the deubiquitinase ATXN3 positively regulates IFN-I antiviral response, and they may provide a novel strategy for enhancing IFN-based antiviral therapy.
Qian Feng is the first author. Ying Miao, Jun Ge and Yukang Yuan are the co-first authors. Prof. Zheng Hui (Soochow University) and Prof. Yu Zhengyuan (The First Affiliated Hospital of Soochow University) are the co-corresponding authors. This work was supported by National Natural Science Foundation of China Grants 31570865, 31770177, and 81702048, the Program of 1000 Young Talents, Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China Grant PCSIRT-IRT1075, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.