Estrogen Receptor α Inhibits RLR-mediated Immune Response Via Ubiquitinating TRAF3

RIG-I-like receptors (RLRs) function as key sentinel receptor for invading viruses. Moderate activation of RLRs signaling is critical for efficient viral clearance without harmful immunopathology. Estrogen receptor alpha (ERa) is a member of nuclear receptor and is involved in the regulation of innate immune response. However, the effects of ERa on RLR signaling and the molecular mechanisms are poorly understood. In this study, we identified ERa as a negative regulator of RLR-triggered antiviral immune responses. The expression level of ERa was upregulated following VSV infection in macrophages. In the absence of ligand, VSV infection phosphorylated ERα at serine 167.ERa inhibits VSV-induced IRF3 activation via promoting K48-linked proteasomal degradation of TRAF3. Consistently, ERa inhibits VSV-triggered IFN-β production in macrophages in a ligand independent mechanism. Thus, ERa functions as a negative feedback regulator of RLR-triggered antiviral immune responses. These findings also provide the insights that separate the immune effects ERa from its ligand-induced hormoral effects.