Viperin binds STING and enhances the type- I interferon response following dsDNA detection

Abstract

Viperin is an interferon- inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin- s broad antiviral activity by demonstrating the protein- s ability to synergistically enhance the innate immune dsDNA signaling pathway to limit viral infection. Viperin co- localized with the key signaling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63- linked polyubiquitination of TBK1. Subsequent analysis identified viperin- s necessity to bind the cytosolic iron- sulfur assembly component 2A, to prolong its enhancement of the type- I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signaling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signaling pathway, which results in an enhanced antiviral state. We also provide evidence for viperin- s radical SAM enzymatic activity to self- limit its immunomodulatory functions. These data further define viperin- s role as a positive regulator of innate immune signaling, offering a mechanism of viperin- s broad antiviral capacity.Here we show for the first time that the antiviral protein viperin is able to enhance the type- I interferon response to dsDNA. Viperin directly binds STING to facilitate effective activation of TBK1 through K63 polyubiquitination, resulting in an enhanced antiviral response. This process is driven by an interaction between viperin and CIA2A, demonstrating a novel role for iron- sulfur cluster assembly proteins in the regulation of innate immune signaling.