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

Publication ,  Journal Article
Zhang, W; Wang, G; Xu, Z-G; 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, B-S ...
Published in: Cell
June 27, 2019

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.

Duke Scholars

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 27, 2019

Volume

178

Issue

1

Start / End Page

176 / 189.e15

Location

United States

Related Subject Headings

  • Transfection
  • Signal Transduction
  • Receptors, Immunologic
  • Receptors, Cell Surface
  • RAW 264.7 Cells
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lactic Acid
 

Citation

APA
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Zhang, W., Wang, G., Xu, Z.-G., Tu, H., Hu, F., Dai, J., … Lin, H.-K. (2019). Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS. Cell, 178(1), 176-189.e15. https://doi.org/10.1016/j.cell.2019.05.003
Zhang, Weina, Guihua Wang, Zhi-Gang Xu, Haiqing Tu, Fuqing Hu, Jiang Dai, Yan Chang, et al. “Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.Cell 178, no. 1 (June 27, 2019): 176-189.e15. https://doi.org/10.1016/j.cell.2019.05.003.
Zhang W, Wang G, Xu Z-G, Tu H, Hu F, Dai J, et al. Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS. Cell. 2019 Jun 27;178(1):176-189.e15.
Zhang, Weina, et al. “Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.Cell, vol. 178, no. 1, June 2019, pp. 176-189.e15. Pubmed, doi:10.1016/j.cell.2019.05.003.
Zhang W, Wang G, Xu Z-G, 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 B-S, Lai S-W, Hsu C-C, Xu J, Chen Z-Z, Li H-Y, Seth P, Hu J, Zhang X, Li H, Lin H-K. Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS. Cell. 2019 Jun 27;178(1):176-189.e15.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

June 27, 2019

Volume

178

Issue

1

Start / End Page

176 / 189.e15

Location

United States

Related Subject Headings

  • Transfection
  • Signal Transduction
  • Receptors, Immunologic
  • Receptors, Cell Surface
  • RAW 264.7 Cells
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lactic Acid