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 localization 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 glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

中文翻译：

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乳酸是一种针对 MAVS 的 RLR 信号传导天然抑制剂。


RLR 介导的 I 型 IFN 产生在提高宿主免疫力以进行病毒清除和癌症免疫监视方面发挥着关键作用。在这里，我们报道了在 RLR 激活过程中失活的糖酵解，作为阻碍 RLR 激活时 I 型 IFN 产生的屏障。 RLR 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激活受损。乳酸作为一种关键代谢物，通过直接结合 MAVS 跨膜 (TM) 结构域并防止 MAVS 聚集，负责糖酵解介导的 RLR 信号传导抑制。值得注意的是，乳酸恢复可以逆转乳酸缺乏引起的干扰素产生增加。通过药理学和遗传学方法，我们发现通过乳酸脱氢酶 A (LDHA) 失活来减少乳酸可以提高 I 型干扰素的产生，从而保护小鼠免受病毒感染。我们的研究确定了糖酵解衍生的乳酸在限制 RLR 信号传导中的关键作用，并将 MAVS 确定为乳酸的直接传感器，其功能是将能量代谢和先天免疫联系起来。