Canonical and non-canonical contributions of human Dicer helicase domain in antiviral defense

ABSTRACT In mammals, the co-existence of RNAi and the type I interferon response in somatic cells begs the question of their compatibility and relative contribution during viral infection. Previous studies provided hints that both mitigating co-factors and self-limiting properties of key proteins such as Dicer could explain the apparent inefficiency of antiviral RNAi. Indeed, the helicase domain of human Dicer limits its processing activity and acts as an interaction platform for co-factors that could hinder its function. We studied the involvement of several helicase-truncated mutants of human Dicer in the antiviral response. We show that all deletion mutants display an antiviral phenotype against alphaviruses and an enterovirus. While only one of them, Dicer N1, is antiviral in an RNAi-independent manner, they all require the expression of PKR to be active. To elucidate the mechanism underlying the antiviral phenotype of Dicer N1 expressing cells, we analyzed their transcriptome and found that many genes from the interferon and inflammatory response were upregulated. We could show that these genes appear to be controlled by transcription factors such as STAT-1, STAT-2, and NF-kB. Finally, we demonstrated that blocking the NF-kB pathway in Dicer N1 cells abrogated their antiviral phenotype. Our findings highlight the crosstalk between Dicer, PKR, and the IFN-I pathway, and suggest that human Dicer may have repurposed its helicase domain to prevent basal activation of antiviral and inflammatory pathways.