Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

• Published in: Cell Vol. 178; no. 1; pp. 176 - 189.e15
• Main Authors: Zhang, Weina, Wang, Guihua, Xu, Zhi-Gang, Tu, Haiqing, Hu, Fuqing, Dai, Jiang, Chang, Yan, Chen, Yaqi, Lu, Yanjun, Zeng, Haolong, Cai, Zhen, Han, Fei, Xu, Chuan, Jin, Guoxiang, Sun, Li, Pan, Bo-Syong, Lai, Shiue-Wei, Hsu, Che-Chia, Xu, Jia, Chen, Zhong-Zhu, Li, Hong-Yu, Seth, Pankaj, Hu, Junbo, Zhang, Xuemin, Li, Huiyan, Lin, Hui-Kuan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.06.2019
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; DEAD Box Protein 58 - antagonists & inhibitors; DEAD Box Protein 58 - metabolism; energy metabolism; Female; glucose metabolism; Glycolysis; HEK293 Cells; hexokinase; Humans; innate immunity; interferon; Interferon-beta - metabolism; L-Lactate Dehydrogenase - genetics; L-Lactate Dehydrogenase - metabolism; lactate; lactate dehydrogenase; lactic acid; Lactic Acid - pharmacology; Male; MAVS; metabolites; Mice; Mice, Inbred C57BL; Mice, Transgenic; mitochondria; monitoring; neoplasms; RAW 264.7 Cells; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Receptors, Immunologic; RLR signaling; Signal Transduction - drug effects; Transfection; MAVS; lactate; RLR signaling; interferon; glucose metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2019.05.003

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. [Display omitted] •Lactate inhibits RLR-mediated interferon production•This regulation occurs through direct sensing of lactate by MAVS•MAVS associates with hexokinase, but this association is disrupted by RIG-I•Targeting LDHA enhances type I IFN production and viral clearance Lactate acts as a regulator of the adaptor MAVS, allowing a cross-regulation between antiviral signaling and energy metabolism