Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS
Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS
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乳酸是一种针对 MAVS 的 RLR 信号传导天然抑制剂
DOI：
10.1016/j.cell.2019.05.003
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发表时间：
2019-06-27
期刊：
影响因子：
64.5
通讯作者：
Lin, Hui-Kuan
中科院分区：
文献类型：
--
作者：
Zhang, Weina;Wang, Guihua;Lin, Hui-Kuan
TLR介导的I型IFN产生在提高宿主免疫力以清除病毒和进行癌症免疫监视中起关键作用。在这里，我们报告，糖酵解，这是在RLR激活失活，作为一个障碍，阻碍I型干扰素生产后，RLR激活。TLR触发的MAVS-RIG-I识别劫持己糖激酶与MAVS的结合，导致己糖激酶线粒体定位和活化受损。乳酸盐作为一种关键代谢产物，通过直接结合MAVS跨膜（TM）结构域并阻止MAVS聚集，负责糖酵解介导的RLR信号传导抑制。值得注意的是，乳酸恢复逆转了乳酸缺乏引起的IFN产生增加。使用药理学和遗传学的方法，我们表明，乳酸减少乳酸脱氢酶A（LDHA）灭活提高I型干扰素的生产，以保护小鼠免受病毒感染。我们的研究建立了glyrolysiq衍生的乳酸在限制RLR信号传导中的关键作用，并将MAVS鉴定为乳酸的直接传感器，其功能是连接能量代谢和先天免疫。
RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localisation and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glyrolysiq-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which function to connect energy metabolism and innate immunity.