Estrogen receptorα-mediated signaling inhibits type Ⅰ interferon response to promote breast carcinogenesis

Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.

β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response

Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.