MicroRNA-33/33*inhibit the activation of MAVS through AMPK in antiviral innate immunity
MicroRNA-33/33*inhibit the activation of MAVS through AMPK in antiviral innate immunity
复制标题
MicroRNA-33/33在抗病毒先天免疫中通过AMPK抑制MAVS的激活
DOI：
10.1038/s41423-019-0326-x
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发表时间：
2021-06-01
影响因子：
24.1
通讯作者：
Lai, Lihua
中科院分区：
文献类型：
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作者：
Liu, Danhui;Tan, Qinchun;Lai, Lihua
先天免疫在宿主抵抗病原体的防御中起着重要作用，必须进行精确的调控。作为胆固醇稳态的重要协调者，microRNA-33/33*在细胞代谢中得到了广泛的研究。然而，它们在抗病毒先天免疫中的作用在很大程度上是未知的。在这里，我们报告VSV刺激通过依赖IFNAR的方式降低巨噬细胞miR-33/33*的表达。在体外和体内，miR-33/33*过表达导致RIG-I信号受损，增加病毒载量和致死率，而抑制I型干扰素的产生。此外，miR-33/33*通过靶向一磷酸腺苷活化蛋白激酶(AMPK)，特异性地阻止线粒体适配器线粒体抗病毒信号蛋白(MAVS)形成激活的聚集体，从而阻止线粒体吞噬介导的受损线粒体的消除，并扰乱线粒体动态平衡，而线粒体动态平衡是有效激活MAVS所必需的。我们的发现证实miR-33/33*是RNA病毒触发的先天性免疫反应的负调控因子，并确定了一种先前未知的调节机制，将线粒体稳态与抗病毒信号通路联系起来。
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.