小柯机器人

近日，中国科学院上海巴斯德研究所肖辉、德国夏洛特医科大学Thomas J. Jentsch和美国约翰霍普金斯大学Zhaozhu Qiu等研究人员合作发现，cGAMP利用LRRC8体积调节阴离子通道转移至旁观者细胞中，从而增强STING介导的干扰素反应和抗病毒免疫。该项研究成果发表在2020年4月11日的《免疫》上。

病毒和细胞内细菌的入侵和传播通常与细胞质中双链DNA（dsDNA）的存在有关，这会触发多种宿主防御机制，包括I型干扰素（IFN）响应。

环状GMP-AMP合成酶（cGAS）是受感染和恶性细胞中胞质dsDNA的感知分子。与dsDNA结合后，cGAS能够催化2'3'cGMP-AMP（cGAMP）的形成。这是一个直接与STING结合的第二信使。随后，STING触发激酶TBK1的激活，然后激酶TBK1磷酸化转录因子IRF3以诱导强烈的IFN反应。

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

Author: 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 Zhou, Qibin Leng, Tsan S. Xiao, Ke Lan, Jinbo Yang, Huabin Li, Chao Peng, Zhaozhu Qiu, Thomas J. Jentsch, Hui Xiao

Issue&Volume: 2020-04-10

Abstract: The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA in infected and malignantcells and catalyzes the formation of 2′3′cGMP-AMP (cGAMP), which in turn triggersinterferon (IFN) production via the STING pathway. Here, we examined the contributionof anion channels to cGAMP transfer and anti-viral defense. A candidate screen revealedthat inhibition of volume-regulated anion channels (VRACs) increased propagation ofthe DNA virus HSV-1 but not the RNA virus VSV. Chemical blockade or genetic ablationof LRRC8A/SWELL1, a VRAC subunit, resulted in defective IFN responses to HSV-1. Biochemicaland electrophysiological analyses revealed that LRRC8A/LRRC8E-containing VRACs transportcGAMP and cyclic dinucleotides across the plasma membrane. Enhancing VRAC activityby hypotonic cell swelling, cisplatin, GTPγS, or the cytokines TNF or interleukin-1increased STING-dependent IFN response to extracellular but not intracellular cGAMP.Lrrc8e/ mice exhibited impaired IFN responses and compromised immunity to HSV-1. Our findingssuggest that cell-to-cell transmission of cGAMP via LRRC8/VRAC channels is centralto effective anti-viral immunity.

DOI: 10.1016/j.immuni.2020.03.016

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30129-1

Immunity：《免疫》，创刊于1994年。隶属于细胞出版社，最新IF：43.474
官方网址：https://www.cell.com/immunity/home
投稿链接：https://www.editorialmanager.com/immunity/default.aspx