Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity

Immunity. 2020 May 19;52(5):767-781.e6. doi: 10.1016/j.immuni.2020.03.016. Epub 2020 Apr 10.


The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA in infected and malignant cells and catalyzes the formation of 2'3'cGMP-AMP (cGAMP), which in turn triggers interferon (IFN) production via the STING pathway. Here, we examined the contribution of anion channels to cGAMP transfer and anti-viral defense. A candidate screen revealed that inhibition of volume-regulated anion channels (VRACs) increased propagation of the DNA virus HSV-1 but not the RNA virus VSV. Chemical blockade or genetic ablation of LRRC8A/SWELL1, a VRAC subunit, resulted in defective IFN responses to HSV-1. Biochemical and electrophysiological analyses revealed that LRRC8A/LRRC8E-containing VRACs transport cGAMP and cyclic dinucleotides across the plasma membrane. Enhancing VRAC activity by hypotonic cell swelling, cisplatin, GTPγS, or the cytokines TNF or interleukin-1 increased STING-dependent IFN response to extracellular but not intracellular cGAMP. Lrrc8e-/- mice exhibited impaired IFN responses and compromised immunity to HSV-1. Our findings suggest that cell-to-cell transmission of cGAMP via LRRC8/VRAC channels is central to effective anti-viral immunity.

Keywords: 3'3'cGAMP; 3'3'cGMP-AMP; MCMV; VSOAC; VSOR; adenovirus; c-di-AMP; c-di-GMP; cdA; cdG; herpesvirus; innate immunity; retrovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / immunology
  • Antiviral Agents / metabolism
  • Bystander Effect
  • Cell Line
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • HeLa Cells
  • Herpes Simplex / immunology
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / immunology
  • Herpesvirus 1, Human / physiology
  • Humans
  • Interferons / immunology*
  • Interferons / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotides, Cyclic / immunology*
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / immunology
  • Nucleotidyltransferases / metabolism
  • Voltage-Dependent Anion Channels / immunology*
  • Voltage-Dependent Anion Channels / metabolism


  • Antiviral Agents
  • LRRC8A protein, mouse
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Sting1 protein, mouse
  • Voltage-Dependent Anion Channels
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Interferons
  • Nucleotidyltransferases
  • cGAS protein, mouse