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

Danhui Liu, Qinchun Tan, Jie Zhu, Yuanyuan Zhang, Yue Xue, Yinjing Song, Yang Liu, Qingqing Wang, Lihua Lai

Cellular & molecular immunology 2021 Jun

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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.

Citation

Danhui Liu, Qinchun Tan, Jie Zhu, Yuanyuan Zhang, Yue Xue, Yinjing Song, Yang Liu, Qingqing Wang, Lihua Lai. MicroRNA-33/33* inhibit the activation of MAVS through AMPK in antiviral innate immunity. Cellular & molecular immunology. 2021 Jun;18(6):1450-1462