HUI XIAO’s group at Institut Pasteur of Shanghai found a new mechanism for cGAMP cell-to-cell transmission and STING activation during viral infection


On May 19, the Cell Press journal IMMUNITY published the research article “Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels (VRACs) Augments STING-Mediated Interferon Responses and Anti-viral Immunity”. This study led by Dr. Hui Xiao’s group at IPS, in collaboration with Dr. Thomas J. Jentsch’s group at FMP/MDC and Dr. Zhaozhu Qiu’s group at Johns Hopkins University, revealed that the cell membrane anion channel LRRC8/VRAC is a cGAMP transporter that can transmit cGAMP from virus infected cells to non-infected cells to activate STING signaling and interferon responses. This finding demonstrates a novel cooperation among infected cells and non-infected cells during viral infections and provide insights into the development of vaccines and therapeutic intervention of infection and cancer.

Dr. Hui Xiao’s group has a long-standing interest in the identification of novel components of the so-called pattern-recognition receptor signaling pathways and the elucidation of immune mechanisms involved in antiviral defense. Through a previously established cell-based screening platform by themselves, they screened for a library of small chemical compounds targeting anion channels and made an unexpected observation that the anion channel LRRC8/VRAC, which is best known for its crucial role in cell swelling response, had an important role in the host defense against the DNA virus herpes virus HSV-1. Whereas HSV-1 infection triggers the activation of the cytosolic DNA sensor cGAS, which then synthesize the second message cGAMP to activate STING for IFN-I response, VRAC does not seem to affect cGAS activation or cGAMP production in HSV-1 infected cells. Instead, the whole-cell patch-clamp electrophysiological analyses and liquid chromatography-tandem mass spectrometry assays collectively demonstrate that LRRC8/VRAC acts as a cGAMP transporter that conducts both cGAMP efflux and influx along the concentration gradient, promoting the activation of STING signaling and the induction of IFN-I responses in bystander uninfected cells. Whereas the hypotonic condition being the most potent stimulus for VRAC activation, the researchers also identified proinflammatory cytokines TNF and IL-1 as potential activators for VRAC during viral infection. Presumably, during viral infections, while cGAMP being synthesized by cGAS in the infected cells, VRAC is also opened by proinflammatory cytokines to transport cGAMP to the distant bystander cells, wherein eliciting reinforcing IFN response. In support of this hypothesis, genetic ablation of VRAC in mice led to diminished IFN responses but heightened viral propagation during HSV-1 infection, culminating on severe disease symptoms. These results demonstrate that in addition to its well-established role in transport chloride and organic compounds such as aspartate, glutamate and cisplatin, VRAC also has a crucial role in conducting cGAMP transmission for host defense, hence implicating an unexpected contribution to the antiviral IFN response from bystander cells. Considering the ability of LRRC8/VRAC to transport cGAMP from both virus-infected cells and cancer cells, and cyclic dinucleotides (CDNs) from bacteria, this study provides new insight into the development of vaccine and immunotherapy for infectious diseases and cancers.

Zhou Chun, Ph.D. student at the University of The Chinese Academy of Sciences, and Chen Xia, a Ph.D. student at Lanzhou University/Institut Pasteur of Shanghai, and Rosa Planells-Cases, a postdoctoral fellow at the Leibniz Institute of Molecular Pharmacology in Germany, are the co-first authors of the paper, and Professor Thomas J. Jentsch of the Leibnitz Institute of Molecular Pharmacology in Germany and Professor Zhu Qiu of Johns Hopkins University School of Medicine in the United States are the co-corresponding authors of the paper.

VRAC-mediated cGAMP transmission leads to the activation of STING signaling in bystander cells and the induction of reinforcing IFN response to curb viral propagation in virus-infected cells

This study was supported by the Key Development and Research project 2016YFA0502100 of China; the National Natural Science Foundation of China (81720108019, 81725004, and 31700784), China; the Key Cooperation Program of International Partnership Program (153831KYSB20180003), the Strategic Priority Research Program (XDB29030302), and the External Cooperation Program (153211KYSB20160001) of the Chinese Academy of Sciences, China; the Shanghai Municipal Science and Technology Major Project (2019SHZDZX02), Shanghai, China; the Joint Research grant with State Key Laboratory of Microbial Metabolism, School of Life Science and Biotechnology, Shanghai Jiao Tong University (MMLKF16-11 to C.P.), Shanghai, China; the European Research Council Advanced Grant 740537 (VolSignal) to T.J.J., European Union; and the Klingenstein-Simons Fellowship in Neuroscience and the Sloan Research Fellowship to Z.Q., USA.