中国科学家合作揭示LRRC8介导cGAMP转运对抗病毒免

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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。

研究人员揭示了阴离子通道对cGAMP转移和抗病毒防御的贡献。筛选研究表明,抑制体积调节的阴离子通道(VRAC)会增加DNA病毒HSV-1的繁殖,但不会增加RNA病毒VSV的繁殖。LRRC8A/SWELL1(一种VRAC亚基)的化学阻断或遗传敲除会导致IFN对HSV-1的应答出现缺陷。

 

生化和电生理分析表明,含有LRRC8A/LRRC8E的VRAC可以跨质膜转运cGAMP和环状二核苷酸。通过低渗细胞肿胀、顺铂、GTPγS、细胞因子TNF或白细胞介素-1等方法来增强VRAC活性可增加STING依赖性IFN对细胞外cGAMP的应答。Lrrc8e-/-小鼠表现出IFN反应的减弱,以及对HSV-1免疫的下降。

 

这些发现表明,cGAMP通过LRRC8/VRAC通道在细胞间的运输对于有效的抗病毒免疫至关重要。

 

附:英文原文

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

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