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Prof. Xuetao Cao’s group identified a viral DNA sensor in cell nucleus

 

On July 19th, Prof. Xuetao Cao’s group published a research article in Science entitled "Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses".

Pathogenic nucleic acid can be recognized by innate sensors. For example, cGAS-STING signaling pathway recognizes the presence of cytosolic DNA and alerts the immune system upon viral infection or cellular damage. The majority of DNA viruses direct their genomic DNA into nuclei, suggesting that nuclear-specific sensing also occurs. However, it is unclear how nuclear pathogen-derived DNA triggers innate immune responses. In this study, Wang et al. find that during HSV-1 infection, heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) recognizes pathogenic DNA and amplifies IFN-α/β production.

Upon DNA virus infection, nuclear-localized hnRNPA2B1 binds viral DNA, homodimerizes, and is then demethylated at Arg226 by the arginine demethylase JMJD6. This results in its translocation to the cytosol where it triggers type I interferons (IFN-I) production via the TBK1–IRF3 pathway. Additionally, hnRNPA2B1 facilitates the N6-methyladenosine (m6A) modification and nucleocytoplasmic trafficking of cGAS, IFI16, and STING mRNAs. This, in turn, amplifies the activation of cytoplasmic TBK1–IRF3 mediated by these factors. Thus, hnRNPA2B1 plays important roles initiating IFN-α/β production and enhancing STING-dependent cytoplasmic antiviral signaling.

This study discovers an important host defense mechanism by which innate antiviral responses are initiated and amplified. It has also enlightened how this network of cellular DNA sensors efficiently launch and license innate immune responses to DNA viruses.

Links: https://science.sciencemag.org/content/early/2019/07/17/science.aav0758