Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS

Cell. 2019 Jun 27;178(1):176-189.e15. doi: 10.1016/j.cell.2019.05.003. Epub 2019 May 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • DEAD Box Protein 58 / antagonists & inhibitors*
  • DEAD Box Protein 58 / metabolism*
  • Female
  • Glycolysis
  • HEK293 Cells
  • Humans
  • Interferon-beta / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Lactic Acid / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • RAW 264.7 Cells
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / drug effects
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • MAVS protein, human
  • Receptors, Cell Surface
  • Robo3 protein, mouse
  • Lactic Acid
  • Interferon-beta
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58