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Transfer of cGAMP into bystander cells via LRRC8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity

Authors

  • C. Zhou
  • X. Chen
  • R. Planells-Cases
  • J. Chu
  • L. Wang
  • L. Cao
  • Z. Li
  • K.I. López-Cayuqueo
  • Y. Xie
  • S. Ye
  • X. Wang
  • F. Ullrich
  • S. Ma
  • Y. Fang
  • X. Zhang
  • Z. Qian
  • X. Liang
  • S.Q. Cai
  • Z. Jiang
  • D. Zhou
  • Q. Leng
  • T.S. Xiao
  • K. Lan
  • Ji. Yang
  • H. Li
  • C. Peng
  • Z. Qiu
  • T.J. Jentsch
  • H. Xiao

Journal

  • Immunity

Citation

  • Immunity 52 (5): 767-781

Abstract

  • 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.


DOI

doi:10.1016/j.immuni.2020.03.016