title: Estrogen receptor alpha inhibits RLR-mediated immune response via ubiquitinating TRAF3.
abstract: 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 (ERα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is involved in the regulation of innate immune responses. However, the effects of ERα on RLR signaling and the molecular mechanisms are poorly understood. In this study, we identify ERα as a negative regulator of RLR-triggered antiviral immune responses. The expression level of ERα is upregulated following RLR activation in macrophages. In the absence of ligand, VSV infection phosphorylates ERα at serine 167. ERα inhibits VSV-induced IRF3 activation. We further demonstrate that ERα directly interacts with TRAF3 and promotes K48-linked proteasomal degradation of TRAF3. Consistently, ERα inhibits VSV-triggered IFN-β production in macrophages in a ligand independent mechanism. Thus, ERα functions as a negative feedback regulator of RLR-triggered antiviral immune responses. These findings also provide the insights that separate the immune effects of ERα from its ligand-induced hormonal effects.
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China; Department of Cell Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Changxing
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Sheng
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China.
authors.forename: Hefeng
authors.initials: H
authors.lastname: Huang
authors.affiliation: The Key Laboratory of Reproductive Genetics, Ministry of Education (Zhejiang University), Hangzhou, Zhejiang, China; Department of Cell Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China. Electronic address: zhjjwm300@zju.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D054875:Ubiquitination; D018116:Vesiculovirus / Q000276:immunology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
keywords: ERα; IFN-β; IRF3; RLR; TRAF3; Ubiquitination