MicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity

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Abstract

Innate immunity plays a prominent role in the host defense against pathogens and must be precisely regulated. As vital orchestrators in cholesterol homeostasis, microRNA-33/33* have been widely investigated in cellular metabolism. However, their role in antiviral innate immunity is largely unknown. Here, we report that VSV stimulation decreased the expression of miR-33/33* through an IFNAR-dependent manner in macrophages. Overexpression of miR-33/33* resulted in impaired RIG-I signaling, enhancing viral load and lethality whereas attenuating type I interferon production both in vitro and in vivo. In addition, miR-33/33* specifically prevented the mitochondrial adaptor mitochondrial antiviral-signaling protein (MAVS) from forming activated aggregates by targeting adenosine monophosphate activated protein kinase (AMPK), subsequently impeding the mitophagy-mediated elimination of damaged mitochondria and disturbing mitochondrial homeostasis which is indispensable for efficient MAVS activation. Our findings establish miR-33/33* as negative modulators of the RNA virus-triggered innate immune response and identify a previously unknown regulatory mechanism linking mitochondrial homeostasis with antiviral signaling pathways.

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Acknowledgements

We thank Professor Xuetao Cao (Second Military Medical University, Shanghai, China) for the Ifnar−/− mice; professor Wei Liu (Zhejiang University, Hangzhou, China) and Wei Chen (Zhejiang University, Hangzhou, China) for the Mito-YFP and LC3-mCherry plasmids; Guifeng Xiao (Core Facilities, Zhejiang University School of Medicine) and Shuangshuang Liu (Core Facilities, Zhejiang University School of Medicine) for their excellent technical assistance with confocal microscopy; Shasha Chen (Zhejiang University) for help with SDD-AGE; Yuchuan Zhang (Zhejiang University) for help with flow cytometry; and Lijia Zhong (Zhejiang University) and Xinfang He (Zhejiang University) for help with in vivo experiments. This study was supported by the National Natural Science Foundation of China (81401283, 81771699), Zhejiang Provincial Natural Science Foundation of China (LZ19H100001, LY18H100004, and LY15C080001), and Fundamental Research Funds for the Central Universities (2018QNA7008).

Author information

DL, QT, and JZ performed the experiments and data analysis. DL and LL designed the experiments and wrote the manuscript. QW and YL helped with manuscript editing. YZ provided reagents and mice. YX and YS helped with infections of mice and related analysis.

Correspondence to Qingqing Wang or Lihua Lai.

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The authors declare no competing interests.

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Liu, D., Tan, Q., Zhu, J. et al. MicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity. Cell Mol Immunol (2019). https://doi.org/10.1038/s41423-019-0326-x

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Keywords

  • microRNA-33/33*
  • type I interferon
  • MAVS
  • AMPKα
  • mitophagy