Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

被引：542

作者：

Zhang, Weina ^{[1
,2
,3
]}

Wang, Guihua ^{[3
,4
,5
]}

Xu, Zhi-Gang ^{[6
]}

Tu, Haiqing ^{[1
,2
]}

Hu, Fuqing ^{[4
,5
]}

Dai, Jiang ^{[1
,2
]}

Chang, Yan ^{[1
,2
]}

Chen, Yaqi ^{[4
,5
]}

Lu, Yanjun ^{[4
,5
]}

Zeng, Haolong ^{[4
,5
]}

Cai, Zhen ^{[3
]}

Han, Fei ^{[3
]}

Xu, Chuan ^{[3
]}

Jin, Guoxiang ^{[3
]}

Sun, Li ^{[3
]}

Pan, Bo-Syong ^{[3
]}

Lai, Shiue-Wei ^{[3
]}

Hsu, Che-Chia ^{[3
]}

Xu, Jia ^{[6
]}

Chen, Zhong-Zhu ^{[6
]}

Li, Hong-Yu ^{[7
]}

Seth, Pankaj ^{[8
]}

Hu, Junbo ^{[4
,5
]}

Zhang, Xuemin ^{[1
,2
]}

Li, Huiyan ^{[1
,2
]}

Lin, Hui-Kuan ^{[3
,9
]}

机构：

[1] Natl Ctr Biomed Anal, Inst Basic Med Sci, State Key Lab Prote, Beijing 100850, Peoples R China

[2] Natl Ctr Biomed Anal, Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing 100850, Peoples R China

[3] Wake Forest Univ, Wake Forest Baptist Med Ctr, Dept Canc Biol, Winston Salem, NC 27101 USA

[4] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Gastrointestinal Surg Ctr, Wuhan 430030, Hubei, Peoples R China

[5] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Lab Med, Wuhan 430030, Hubei, Peoples R China

[6] Chongqing Univ Arts & Sci, Int Acad Targeted Therapeut & Innovat, Chongqing 402160, Peoples R China

[7] Univ Arkansas Med Sci, Coll Pharm, Div Pharmaceut Sci, 200 South Cedar, Little Rock, AR 72202 USA

[8] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[9] China Med Univ, Grad Inst Biomed Sci, Taichung 404, Taiwan

来源：

CELL | 2019年 / 178卷 / 01期

基金：

国家自然科学基金重大项目; 中国国家自然科学基金;

关键词：

I INTERFERON; ENERGY-METABOLISM; MOUSE MODELS; CANCER; INDUCTION; PROMOTES; HEXOKINASE; IMMUNITY; RECEPTOR; PROTEIN;

D O I：

10.1016/j.cell.2019.05.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：176 / +

页数：29

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