METTL3 promotes miR-146a maturation to suppress type I interferon responses in enterovirus 71 infection.

Enterovirus 71 (EV71) is the main causative agent of severe hand, foot, and mouth disease (HFMD) in children. Dysregulation of microRNAs (miRNAs) has been associated with HFMD progression, but the underlying regulatory mechanisms remain incompletely characterized. Rhabdomyosarcoma cells (RD) and human glioblastoma astrocytoma cells (U87-MG) were infected with EV71 at varying multiplicities of infection. In vivo, 5-day-old C57BL/6 mice, with C57 mice treated with STM2457 were intraperitoneally injected with a lethal dose of EV71. Molecular analyses included Western blotting, co-immunoprecipitation, and RNA immunoprecipitation. Clinical blood samples from HFMD patients were used for validation. In this study, we found that EV71 infection increased METTL3 expression and m6A methylation levels in the flanking regions of pri-miR-146a, promoting miR-146a maturation, which in turn suppresses TRAF6 and IRAK1 expression and inhibits IFN-I production, affecting the progression of EV71-induced HFMD. Co-immunoprecipitation and immunofluorescence assays demonstrated interaction between METTL3 and DGCR8, as well as nuclear co-localization of METTL3 with DGCR8. Furthermore, this regulatory mechanism was also confirmed through the intraperitoneal injection of STM2457 (a METTL3 inhibitor) to intervene in EV71 infection. Finally, detection conducted on clinical blood samples of HFMD demonstrated the specificity of IRAK1 in detecting severe HFMD. These findings will not only aid in understanding the mechanisms by which EV71 infection impacts the host immune system but also provide a scientific basis for identifying early diagnostic biomarkers and developing new therapeutic strategies.