Dicer is cleaved by the Leader protease encoded by foot-and-mouth disease virus to promote infection in mammalian cells.

The endoribonuclease Dicer is a central component of the posttranscriptional gene silencing mechanism based on RNA interference (RNAi) in eukaryotes. The antiviral role of RNAi in mammalian cells remains controversial while a number of viral suppressors of RNAi (VSR) able to inhibit Dicer activity and promote infection have been identified. Here, we explored the integrity and functional role of Dicer during FMDV infection. These studies showed that the FMDV-encoded Leader protease (Lpro) specifically cleaves Dicer at a conserved DExD/H helicase motif releasing the complete N-terminal helicase domain. Dicer cleavage by Lpro suppressed small hairpin RNA (shRNA)-induced RNAi in swine cells. Silencing of Dicer conferred increased susceptibility to an Lpro-deficient FMDV, revealing a Dicer-dependent antiviral effect which can be effectively counteracted by Lpro. This mutant generated a remarkably different profile of viral small RNAs (vsRNAs) in infected cells compared with the wild-type virus. Overall, we identified a viral mechanism of dampening or modulating antiviral defenses based on Dicer proteolytic degradation.