期刊
CELL
卷 178, 期 1, 页码 176-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2019.05.003
关键词
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资金
- Wake Forest Baptist Comprehensive Cancer Center Cell Engineering Shared Resource
- National Cancer Institute's Cancer Center Support Grant [P30CA012197]
- Wake Forest School of Medicine
- NIH [R01CA194094, R01CA197178, R01CA182424, R01CA193813]
- National Key Research and Development Program [2017YFA0503900]
- National Natural Science Foundation of China [31671413]
- Beijing Nova Program [Z161100004916147]
- Major Program of National Natural Science Foundation of China [81790252]
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.
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