ATXN3 Positively Regulates Type I IFN Antiviral Response by Deubiquitinating and Stabilizing HDAC3

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.