How can an organism accurately detect virus invasion and trigger an anti-virus immune response to eliminate the virus? What is the material basis and molecular mechanism in it? This is one of the most important scientific problems in the field of biomedicine.
On July 19, Science published a long paper online by the team of Cao Xuetao, academician of the Chinese Academy of Engineering and President of Nankai University. According to the paper, the team discovered a new type of innate immune recognition receptor (hnRNP-A2B1) for detecting and screening invasive viral DNA. The receptor molecules can specifically recognize viral DNA in the nucleus like “sentinels”, activate the TBK1-IRF3 pathway, leading to IFN-α/β production, and trigger an anti-virus immune response to eliminate the DNA virus. The discovery of anti-viral “sentinels” in the nucleus offers a new perspective in the field of innate immunity and inflammation, and also provides a new target of drug research and development for anti-viral treatment and inflammation prevention and treatment.
Research on the molecular mechanism of exogenous pathogenic DNA recognized by the organism has been going on for years with great progress. However, natural immune receptors (such as cGAS) exist in the cytoplasm, whereas most DNA viruses, after infecting host cells, will enter the nucleus, release viral genomic DNA and replicate themselves. However, it is unclear whether there are viral DNA-specific natural immune sensors in the nucleus.
In order to screen innate immune receptors in the nucleus that can recognize viral DNA, Prof. Cao Xuetao, together with Wang Lei, associate professor of College of Life Sciences, Nankai University, and Wen Mingyue, lecturer of the State Key Laboratory of Medical Immunology, the Second Military Medical University, under the support of the National Natural Science Foundation of China and the Ministry of Science and Technology, separated DNA-binding proteins from nucleus extracts, using biotin-labeled viral genomic DNA in the first place. Then, mass spectrometry was carried out to identify whether there were protein molecules that could bind viral genomic DNA. On the other hand, they detected proteins that transferred from nucleus to cytoplasm after infected with DNA virus and could activate innate immune signaling pathways, by conducting the two-dimensional electrophoresis - mass spectrometry test. After integrating the results of the above two systems, 23 candidate molecules were obtained. Through subsequent screening of innate immune effects and antiviral functions both in vivo and in vitro, including in vivo tests on mice whose hnRNPA2B1 myeloid-specific genes were eliminated, the team finally identified heterogeneous nuclear ribonucleoprotein A2B1 (heterogeneous nuclear ribonucleoprotein A2B1, hnRNP-A2B1) as a kind of DNA innate immune recognition receptor inside the nucleus, which was capable of recognizing viral DNA and inducing antiviral interferon production.
Subsequently, the team studied the specific molecular mechanism of the activation of innate immunity after hnRNPA2B1 recognizing viral DNA in the nucleus. HnRNPA2B1 dimerized after DNA virus infection and demethylated at the 226 arginine (Arg226) site, and then translocated into the cytoplasm to interact with STING to form a compound, activate TBK 1-IRF3 signal transduction pathway and start gene expression such as interferon.
In addition, the team also found that hnRNPA2B1 could promote m6A modification and nucleation of the currently-known DNA recognition receptors, such as cGAS, IFI16, STING, and signal molecules mRNA, thereby amplifying and enhancing these currently-known cytoplasmic innate immune molecular signaling pathways to induce more interferon production and effectively stimulate the innate immune response against viruses.
The study shows that hnRNPA2B1, as a RNA-binding protein molecule, maintains its RNA-related normal functions while in a non-infectious state; however, when cells are infected with DNA viruses, it could recognize exogenous DNA in the nucleus and polarize its function, and then act as a DNA recognition receptor to activate innate immunity against viruses. In conclusion, this study provides a new idea for the mechanism of innate immune recognition and signal transduction, and deepens our understanding of innate antiviral immunity.
Source: Nankai News
Written by Wu Junhui
Edited by Nankai Translation Center