Here, we provide several lines of evidence to demonstrate that the host promotes DDX21 cleavage to temper immune responses: (i) cleavage of DDX21 was observed at the late stage of infection; (ii) cleavage was a universal phenomenon not only for virus but also for RNA and DNA mimics; (iii) the blockage of DDX21 (D126A) cleavage increases IFN production, and cleaved DDX21 (aa 127 to 784) inhibits IFN production; (iv) the cleavage of DDX21 did not affect virus replication at the late stage of infection; and (v) the cleavage of DDX21 inhibited the formation of the DDX1-DDX21-DHX36 complex. The gene discussed is DDX21; the disease is infection.