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Cell. 2019 May 20. pii: S0092-8674(19)30501-X. doi: 10.1016/j.cell.2019.05.003. [Epub ahead of print]

Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.

Author information

1
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis; State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, Beijing 100850, China; Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC 27101, USA.
2
Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC 27101, USA; Department of Gastrointestinal Surgery Center and Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
3
International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, China.
4
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, National Center of Biomedical Analysis; State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, National Center of Biomedical Analysis, Beijing, Beijing 100850, China.
5
Department of Gastrointestinal Surgery Center and Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
6
Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC 27101, USA.
7
University of Arkansas for Medical Sciences, College of Pharmacy, Division of Pharmaceutical Science, 200 South Cedar, Little Rock, AR 72202, USA.
8
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
9
Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC 27101, USA; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan. Electronic address: hulin@wakehealth.edu.

Abstract

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.

KEYWORDS:

MAVS; RLR signaling; glucose metabolism; interferon; lactate

PMID:
31155231
DOI:
10.1016/j.cell.2019.05.003

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