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 aneffective immune response against an array of diverse viral pathogens. Here wedescribe a mechanism of viperin’s broad antiviral activity by demonstrating theprotein’s ability to synergistically enhance the innate immune dsDNA signalingpathway to limit viral infection. Viperin co-localized with the key signalingmolecules of the innate immune dsDNA sensing pathway, STING and TBK1;binding directly to STING and inducing enhanced K63-linkedpolyubiquitination of TBK1. Subsequent analysis identified viperin's necessityto bind the cytosolic iron-sulfur assembly component 2A, to prolong itsenhancement of the type-I interferon response to aberrant dsDNA. Here weshow that viperin facilitates the formation of a signaling enhanceosome, tocoordinate efficient signal transduction following activation of the dsDNAsignaling pathway, which results in an enhanced antiviral state. We alsoprovide evidence for viperin’s radical SAM enzymatic activity to self-limit itsimmunomodulatory functions. These data further define viperin's role as apositive regulator of innate immune signaling, offering a mechanism ofviperin’s broad antiviral capacity. Show more