Estrogen receptor alpha inhibits RLR-mediated immune response via ubiquitinating TRAF3

RIG-I-like receptors (RLRs) function as key sentinel receptor for invading viruses. Moderate activation of RLR signaling is critical for efficient viral clearance without harmful immunopathology. Estrogen receptor alpha (ER alpha) is a member of the nuclear receptor superfarnily of ligand-activated transcription factors and is involved in the regulation of innate immune responses. However, the effects of ER alpha on RLR signaling and the molecular mechanisms are poorly understood. In this study, we identify ER alpha as a negative regulator of RLR-triggered antiviral immune responses. The expression level of ER alpha is upregulated following RLR activation in macrophages. In the absence of ligand, VSV infection phosphorylates ER alpha at serine 167. ER alpha inhibits VSV-induced IRF3 activation. We further demonstrate that ER alpha directly interacts with TRAF3 and promotes K48-linked proteasomal degradation of TRAF3. Consistently, ER alpha inhibits VSV-triggered IFN-beta production in macrophages in a ligand independent mechanism. Thus, ER alpha functions as a negative feedback regulator of RLR-triggered antiviral immune responses. These findings also provide the insights that separate the immune effects of ER alpha from its ligand-induced hormonal effects. (C) 2015 Elsevier Inc. All rights reserved.