Unc-13 homologue D mediates an antiviral effect of the chromosome 19 microRNA cluster miR-517a

Abstract

The function of microRNAs (miRNAs) can be cell autonomous or communicated to other cell types, and has been implicated in diverse biological processes. We previously demonstrated that miR-517a-3p (miR-517a), the highly expressed member of the chromosome 19 miRNA cluster (C19MC) that are transcribed almost exclusively in human trophoblasts, attenuates viral replication via induction of autophagy in non-trophoblastic, recipient cells. However, the molecular mechanisms underlying these effects remain unknown. Here we identified Unc-13 homologue D (UNC13D) as a direct, autophagy-related gene target of miR-517a, leading to repression of UNC13D. In line with the antiviral activity of miR-517a, silencing UNC13D suppressed replication of vesicular stomatitis virus (VSV), whereas overexpression of UNC13D increased VSV levels, suggesting a role for UNC13D silencing in the antiviral activity of miR-517a. We also found that miR-517a activated NFκB signaling in HEK-293XL cells expressing TLR8, but the effect was not-specific to C19MC miRNA. Together, we define mechanistic pathways that link C19MC miRNA with inhibition of viral replication.