Model of NSUN2 regulation of type I IFN signaling. Upon depletion of NSUN2 in A549 cells, the increase in RPPH1 expression and the decrease in m5C modification in RPPH1 may lead to enhance Pol III activity via regulating RNase P enzymatic activity. The elevation of Pol III–transcribed RNAs, especially 7SL RNAs, leads to an increase in unshielded 7SL RNAs in the cytoplasm, which can be recognized by RIG-I, causing type I IFN signaling. Upon virus infection, the increased PRRs quickly recognize the invading non-self RNAs, further amplifying IFN signaling and leading to a dramatically enhanced type I IFN which in turn inhibits virus propagation.