Viperin restricts viral replication by serving as a translational regulator

Innate immune responses induce hundreds of interferon-stimulated genes (ISGs), many of which play an important role in antiviral immunity. Viperin, a member of the radical SAM superfamily of enzymes, is the product of one such ISG and it restricts the replication of a broad spectrum of DNA and RNA viruses. However, a general mechanism that explains all the roles proposed for viperin in the innate immune response remains to be defined. Here we report a previously unknown antiviral mechanism, in which viperin represses translation of viral RNA. We show that viperin interacts with the translation machinery and, primarily through its radical SAM enzymatic activity, inhibits global translation during the interferon response by activating the eIF2 pathway. In cell based-infection assays, viperin inhibits viral protein synthesis and viral replication of Zika virus and Kunjin virus. This study illustrates the importance of translational repression in the antiviral response and identifies viperin as a central translational regulator in innate immunity. Overall design: mRNA profiles of mock- and viperin-transfected 293T cells were generated by deep sequencing, in duplicate, using Illumina Hiseq.