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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.

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, GTPĪ³S, 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.
AuthorsChun 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 Zhou, Qibin Leng, Tsan S Xiao, Ke Lan, Jinbo Yang, Huabin Li, Chao Peng, Zhaozhu Qiu, Thomas J Jentsch, Hui Xiao
JournalImmunity (Immunity) Vol. 52 Issue 5 Pg. 767-781.e6 (05 19 2020) ISSN: 1097-4180 [Electronic] United States
PMID32277911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2020 Elsevier Inc. All rights reserved.
Chemical References
  • 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
Topics
  • Animals
  • Antiviral Agents (immunology, metabolism)
  • Bystander Effect
  • Cell Line
  • Cells, Cultured
  • Embryo, Mammalian (cytology, metabolism)
  • Fibroblasts (cytology, immunology, metabolism)
  • HeLa Cells
  • Herpes Simplex (immunology, virology)
  • Herpesvirus 1, Human (immunology, physiology)
  • Humans
  • Interferons (immunology, metabolism)
  • Membrane Proteins (genetics, immunology, metabolism)
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotides, Cyclic (immunology, metabolism)
  • Nucleotidyltransferases (genetics, immunology, metabolism)
  • Voltage-Dependent Anion Channels (immunology, metabolism)

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