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

Cellular & Molecular Immunology volume 20, pages 175–188 (2023)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32188101, 31830024, 31922021 and 32170713) and the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-071).

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Authors and Affiliations

  1. Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University; College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University; Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan, China

    Yi Guo, Xia-Nan Zhang, Shan Su, Zi-Lun Ruan, Ming-Ming Hu & Hong-Bing Shu

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  1. Yi Guo
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MMH, YG, and HBS conceived and designed the study. YG, ZLR, XNZ, and SS performed the experiments. MMH, YG, and HBS analyzed all the data and wrote the manuscript.

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Correspondence to Ming-Ming Hu or Hong-Bing Shu.

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Guo, Y., Zhang, XN., Su, S. et al. β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response. Cell Mol Immunol 20, 175–188 (2023). https://doi.org/10.1038/s41423-022-00967-x

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