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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., Chen, X., Planells-Cases, R., Chu, J., Wang, L., Cao, L., Li, Z., López-Cayuqueo, K.I., Xie, Y., Ye, S., Wang, X., Ullrich, F., Ma, S., Fang, Y., Zhang, X., Qian, Z., Liang, X., Cai, S.Q., Jiang, Z., Zhou, D., Leng, Q., Xiao, T.S., Lan, K., Yang, Ji., Li, H., Peng, C., Qiu, Z., 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 |
| Additional Information: | Copyright © 2020 Elsevier Inc. |
| Official Publication: | https://doi.org/10.1016/j.immuni.2020.03.016 |
| PubMed: | View item in PubMed |
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