Non-canonical contribution of human Dicer helicase domain in antiviral innate immune response

ABSTRACT In mammalian somatic cells, the relative contribution of RNAi and the type I interferon response during viral infection is unclear. The apparent inefficiency of antiviral RNAi might be due to self-limiting properties and mitigating co-factors of the key enzyme Dicer. In particular, the helicase domain of human Dicer appears to be an important restriction factor of its activity. We studied the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. All deletion mutants displayed a PKR-dependent antiviral phenotype against certain viruses and one of them, Dicer N1, acted in a complete RNAi-independent manner. Transcriptomic analyses showed that many genes from the interferon and inflammatory response were upregulated in Dicer N1 expressing cells. We could show that some of these genes appear to be controlled by NF-kB and that blocking this pathway abrogated the antiviral phenotype of Dicer N1. Our findings highlight the crosstalk between Dicer, PKR, and the NF-kB pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.