Cao, J.-M. | Search bioRxiv

bioRxiv2023

Crystal structure of mRNA cap (guanine-N7) methyltransferase E12 subunit from monkeypox virus and discovery of its inhibitors

In July 2022, the World Health Organization announced monkeypox as a public health emergency of international concern (PHEIC), over 85,000 global cases have been reported currently. However, preventive and therapeutic treatments are very limited. The monkeypox virus (MPXV) E12, an mRNA capping enzyme small subunit, is essential for the methyltransferase activity of RNA capping enzymes of MPXV. Here, we solved a 2.16 [A] crystal structure of E12. We also docked the D1 subunit c-terminal domain (D1CTD) of vaccinia virus (VACV) with E12 to analyze the critical residues of interface between them. These residues are used for drug screening. The top six compounds are Rutin, Quercitrin, Epigallocatechin, Rosuvastatin, 5-hydroxy-L-Tryptophan, and Deferasirox. These findings may provide insights into the development of anti-MPXV drugs.

microbiology↗

bioRxiv2022

AGO2a but not AGO2b mediates antiviral defense against the infection of wildtype Cucumber mosaic virus in tomato

Evolutionarily conserved antiviral RNA interference (RNAi) mediates a primary antiviral innate immunity preventing the infection of broad spectrum viruses in plants. However, the detailed mechanism in plants is still largely unknown, especially in important agricultural crops including tomato. On the other aspect, varieties of pathogenic viruses evolve to possess Viral Suppressor of RNA silencing (VSR) to suppress antiviral RNAi in host. Due to the prevalence of VSR, it is still skeptical that antiviral RNAi truly functions to prevent the invasion of natural wildtype viruses in plants and animals. In the research, it is for the first time we applied CRISPR-Cas9 to generate ago2a, ago2b or ago2ab mutants for two differentiated Solanum lycopersicum AGO2, one key effector in antiviral RNAi. We found that AGO2a but not AGO2b was significantly induced to inhibit the propagation of not only VSR-deficient Cucumber mosaic virus (CMV) but also wildtype CMV-Fny in tomato, however, both AGO2a and AGO2b did not regulate disease induction after the infection of either virus. Our findings firstly reveal a prominent role of AGO2a in antiviral RNAi innate immunity in tomato and demonstrate that antiviral RNAi evolves to defend the infection of natural wildtype CMV-Fny in tomato, however AGO2a-mediated antiviral RNAi does not play major roles in promoting tolerance of tomato plants to CMV infection for maintaining health.

immunology↗