Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Weina Zhang; Guihua Wang; Zhi Gang Xu; Haiqing Tu; Fuqing Hu; Jiang Dai; Yan Chang; Yaqi Chen; Yanjun Lu; Haolong Zeng; Zhen Cai; Fei Han; Chuan Xu; Guoxiang Jin; Li Sun; Bo Syong Pan; Shiue Wei Lai; Che Chia Hsu; Jia Xu; Zhong Zhu Chen; Hong Yu Li; Pankaj Seth; Junbo Hu; Xuemin Zhang; Huiyan Li; Hui Kuan Lin

doi:10.1016/j.cell.2019.05.003

Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Weina Zhang, Guihua Wang, Zhi Gang Xu, Haiqing Tu, Fuqing Hu, Jiang Dai, Yan Chang, Yaqi Chen, Yanjun Lu, Haolong Zeng, Zhen Cai, Fei Han, Chuan Xu, Guoxiang Jin, Li Sun, Bo Syong Pan, Shiue Wei Lai, Che Chia Hsu, Jia Xu, Zhong Zhu ChenHong Yu Li, Pankaj Seth, Junbo Hu, Xuemin Zhang, Huiyan Li, Hui Kuan Lin

Research output: Contribution to journal › Article › peer-review

405 Scopus citations

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.

Original language	English (US)
Pages (from-to)	176-189.e15
Journal	Cell
Volume	178
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.05.003
State	Published - Jun 27 2019
Externally published	Yes

Keywords

MAVS
RLR signaling
glucose metabolism
interferon
lactate

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2019.05.003

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Zhang, W, Wang, G, Xu, ZG, Tu, H, Hu, F, Dai, J, Chang, Y, Chen, Y, Lu, Y, Zeng, H, Cai, Z, Han, F, Xu, C, Jin, G, Sun, L, Pan, BS, Lai, SW, Hsu, CC, Xu, J, Chen, ZZ, Li, HY, Seth, P, Hu, J, Zhang, X, Li, H & Lin, HK 2019, 'Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS', Cell, vol. 178, no. 1, pp. 176-189.e15. https://doi.org/10.1016/j.cell.2019.05.003

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title = "Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS",

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",

author = "Weina Zhang and Guihua Wang and Xu, {Zhi Gang} and Haiqing Tu and Fuqing Hu and Jiang Dai and Yan Chang and Yaqi Chen and Yanjun Lu and Haolong Zeng and Zhen Cai and Fei Han and Chuan Xu and Guoxiang Jin and Li Sun and Pan, {Bo Syong} and Lai, {Shiue Wei} and Hsu, {Che Chia} and Jia Xu and Chen, {Zhong Zhu} and Li, {Hong Yu} and Pankaj Seth and Junbo Hu and Xuemin Zhang and Huiyan Li and Lin, {Hui Kuan}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

day = "27",

doi = "10.1016/j.cell.2019.05.003",

language = "English (US)",

volume = "178",

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T1 - Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

AU - Zhang, Weina

AU - Wang, Guihua

AU - Xu, Zhi Gang

AU - Tu, Haiqing

AU - Hu, Fuqing

AU - Dai, Jiang

AU - Chang, Yan

AU - Chen, Yaqi

AU - Lu, Yanjun

AU - Zeng, Haolong

AU - Cai, Zhen

AU - Han, Fei

AU - Xu, Chuan

AU - Jin, Guoxiang

AU - Sun, Li

AU - Pan, Bo Syong

AU - Lai, Shiue Wei

AU - Hsu, Che Chia

AU - Xu, Jia

AU - Chen, Zhong Zhu

AU - Li, Hong Yu

AU - Seth, Pankaj

AU - Hu, Junbo

AU - Zhang, Xuemin

AU - Li, Huiyan

AU - Lin, Hui Kuan

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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.

AB - 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.

KW - MAVS

KW - RLR signaling

KW - glucose metabolism

KW - interferon

KW - lactate

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SP - 176-189.e15

JO - Cell

JF - Cell

IS - 1

ER -

Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Abstract

Keywords

ASJC Scopus subject areas

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