Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication.

Innate immune responses induce hundreds of interferon-stimulated genes (ISGs). Viperin, a member of the radical S-adenosyl methionine (SAM) superfamily of enzymes, is the product of one such ISG that restricts the replication of a broad spectrum of viruses. Here, we report a previously unknown antiviral mechanism in which viperin activates a ribosome collision-dependent pathway that inhibits both cellular and viral RNA translation. We found that the radical SAM activity of viperin is required for translation inhibition and that this is mediated by viperin's enzymatic product, 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP). Viperin triggers ribosome collisions and activates the MAPKKK ZAK pathway that in turn activates the GCN2 arm of the integrated stress response pathway to inhibit translation. The study illustrates the importance of translational repression in the antiviral response and identifies viperin as a translation regulator in innate immunity. [Display omitted] • Viperin regulates cellular translation to restrict viral translation and replication • Viperin activates the GCN2-arm of the ISR • Viperin induces ribosome collision-mediated translation inhibition • Viperin's product ddhCTP induces ribosome collision Hsu et al. show that viperin, a broad-spectrum antiviral protein, inhibits the viral replication of two medically relevant flaviviruses by limiting viral protein production. Viperin synthesizes a nucleoside derivative, ddhCTP, which induces ribosome collisions, leading to the activation of the integrated stress response and consequently translation inhibition. [ABSTRACT FROM AUTHOR]