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

Chun Zhou, Xia Chen, Rosa Planells-Cases, Jiachen Chu, Li Wang, Limin Cao, Zhihong Li, Karen I. López-Cayuqueo, Yadong Xie, Shiwei Ye, Xiang Wang, Florian Ullrich, Shixin Ma, Yiyuan Fang, Xiaoming Zhang, Zhikang Qian, Xiaozheng Liang, Shi Qing Cai, Zhengfan Jiang, Dongming ZhouQibin Leng, Tsan S. Xiao, Ke Lan, Jinbo Yang, Huabin Li, Chao Peng, Zhaozhu Qiu, Thomas J. Jentsch, Hui Xiao

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)767-781.e6
JournalImmunity
Volume52
Issue number5
DOIs
StatePublished - May 19 2020

Keywords

  • 3'3'cGAMP
  • 3'3'cGMP-AMP
  • MCMV
  • VSOAC
  • VSOR
  • adenovirus
  • c-di-AMP
  • c-di-GMP
  • cdA
  • cdG
  • herpesvirus
  • innate immunity
  • retrovirus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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