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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

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Item Type:Article
Title:Transfer of cGAMP into bystander cells via LRRC8 volume-regulated anion channels augments STING-mediated interferon responses and anti-viral immunity
Creators Name:Zhou, C. and Chen, X. and Planells-Cases, R. and Chu, J. and Wang, L. and Cao, L. and Li, Z. and López-Cayuqueo, K.I. and Xie, Y. and Ye, S. and Wang, X. and Ullrich, F. and Ma, S. and Fang, Y. and Zhang, X. and Qian, Z. and Liang, X. and Cai, S.Q. and Jiang, Z. and Zhou, D. and Leng, Q. and Xiao, T.S. and Lan, K. and Yang, Ji. and Li, H. and Peng, C. and Qiu, Z. and Jentsch, T.J. and Xiao, H.
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.
Keywords:VSOAC, VSOR, 3'3'cGMP-AMP, 3'3'cGAMP, c-di-AMP, cdA, c-di-GMP, cdG, Innate Immunity, Adenovirus, MCMV, Herpesvirus, Retrovirus, Animals, Mice
Source:Immunity
ISSN:1074-7613
Publisher:Cell Press
Volume:52
Number:5
Page Range:767-781
Date:19 May 2020
Official Publication:https://doi.org/10.1016/j.immuni.2020.03.016
PubMed:View item in PubMed

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