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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

Immunity. 2020-04; 
Zhou C, Chen X, Planells-Cases R, Chu J, Wang L, Cao L, Li Z, López-Cayuqueo KI, Xie Y, Ye S, Wang X, Ullrich F, Ma S, Fang Y, Zhang X, Qian Z, Liang X, Cai SQ, Jiang Z, Zhou D, Leng Q, Xiao TS,0, Lan K, Yang J, Li H, Peng C, Qiu Z, Jentsch TJ, Xiao H
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摘要

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... More

关键词

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