β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response
β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response
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DOI：
10.1038/s41423-022-00967-x
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发表时间：
2023-01
影响因子：
24.1
通讯作者：
Yi Guo;Xia-Nan Zhang;S. Su;Zilun Ruan;Ming-Ming Hu-Ming;H. Shu
中科院分区：
文献类型：
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作者：
Yi Guo;Xia-Nan Zhang;S. Su;Zilun Ruan;Ming-Ming Hu-Ming;H. Shu
在病毒感染后，细胞质模式识别受体检测病毒核酸并激活衔接蛋白VISA/MAVS或MITA/STING介导的先天性抗病毒应答。先天性抗病毒反应是否以及如何受到神经内分泌功能的调节尚不清楚。在这里，我们发现病毒感染降低了血清中β-肾上腺素能激素肾上腺素和去甲肾上腺素的水平，以及它们的受体ADRB 1和ADRB 2的细胞水平。我们进一步表明，肾上腺素/去甲肾上腺素水平的增加抑制先天性抗病毒反应的ADRB 1-/2依赖性的方式。机制上，肾上腺素/去甲肾上腺素刺激激活下游激酶PKA，其催化MITA在S241、S243和T263处的磷酸化，抑制MITA激活并抑制对DNA病毒的先天免疫应答。此外，PKA磷酸化VISA在T54拮抗RNA病毒的天然免疫反应。这些发现揭示了肾上腺素/去甲肾上腺素的先天抗病毒反应的调节机制，并为在压力和焦虑促进的情况下宿主对病毒感染的易感性增加提供了可能的解释。
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.