Immunity- Pasteur's shochu found a new mechanism for cGAMP trans-cell activation stinging anti-viral infection.

DNA pattern recognition receptor CGAs can recognize the double stranded DNA in the cytoplasm of virus infected cells or tumor cells and catalyze the synthesis of secondary messenger cgamp.cgamp can activate tbk1 / IRF3 signaling pathway by binding with sting, a adaptor molecule on Er of endoplasmic reticulum, to induce IFN-I expression and initiate host defense or tumor immunity.although it is traditionally believed that the role of cgamp should be limited to the cells that synthesize it, recent evidence suggests that cgamp can also be transported between cells, especially from virus infected or tumor cells to bystander cells to activate sting and induce IFN expression.however, the molecular mechanism and physiological significance of cgamp transport by cells under viral infection are still unclear.lrrc8 / VRAC is an anion channel which was discovered only five years ago to regulate hypotonic response and cell volume. The heterohexamer is formed by lrrc8a and its homologous subunit lrrc8b-e.VRAC is activated rapidly under low osmotic pressure, which mediates Cl - efflux to reduce intracellular osmotic pressure and prevent cell expansion.in addition to transporting chloride ions, VRAC can also transport some organic molecules, including aspartic acid and glutamic acid, neurotransmitter GABA and cisplatin, which are involved in regulating growth and development or affecting diabetes and stroke.recently, Xiao Hui research group of Shanghai Pasteur Institute of Chinese Academy of Sciences published a research paper entitled "transfer of cgamp into bystander cells via lrrc8 volume regulated ion channels (vracs) fragments sting mediated interchange responses and anti viral immunity in the sub Journal of cell immunity.this study found that the anion channel lrrc8 / VRAC is a transmembrane transporter of cgamp, which can transport cgamp produced by virus infected cells to non infected cells and activate sting signal and interferon response.this discovery shows the unique mechanism of the body to resist virus infection, and also provides new ideas for vaccine development and immunotherapy.through in vitro screening, the researchers of Xiao Hui group unexpectedly found that lrrc8 / VRAC, an anion channel that regulates hypotonic response, plays an important role in anti HSV-1 infection.by using patch clamp electrophysiological techniques and liquid chromatography-mass spectrometry (LC-MS), we have qualitatively and quantitatively proved that VRAC is a cgamp transporter, which can conduct cgamp efflux or influx along the concentration gradient.in addition to hypotonic conditions, the researchers found that inflammatory cytokines TNF and IL-1 can also activate VRAC.therefore, when VRAC is activated by inflammatory factors, it can transport cgamp synthesized by virus infected cells and transfer them to co cultured uninfected cells through Transwell to activate sting and induce IFN expression.in VRAC knockout mice, the IFN response induced by HSV-1 infection was decreased and the viral load was increased, which indicated that IFN induced by cgamp in bystander cells was very important in resisting HSV-1 infection.this study not only revealed the mechanism and physiological function of lrrc8 / VRAC in regulating cgamp transport, but also provided a new idea for developing antiviral vaccine and optimizing tumor immunotherapy.Zhou Chun, doctoral student of Chinese Academy of Sciences; Chen Xia, a doctoral student jointly trained by Lanzhou University / Shanghai Pasteur Institute; Rosa planells cases, postdoctoral student of Leibniz Institute of molecular pharmacology, Germany, are the co first authors of the paper, and researcher Xiao Hui and Thomas J Professor Jentsch and Professor Zhao Zhu Qi of Johns Hopkins University School of medicine were co authors of the paper. the research was supported by the key R & D program of the Ministry of science and technology of the people's Republic of China, the National Natural Science Foundation of China, the international cooperation key project of Chinese Academy of Sciences and the strategic pilot project. paper links: ා% 20