Err Alpha Negatively Regulates Type I Interferon Induction By Inhibiting Tbk1-Irf3 Interaction

Estrogen-related receptor a (ERR alpha) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERR alpha deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERR alpha inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERR alpha stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERR alpha on IFN-I production was independent of its transcriptional activity and PCG-1 alpha. Notably, ERR alpha chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERR alpha as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy.