Abstract
Viperin is an interferon-inducible protein that is critical for eliciting an effective immune response against many diverse viral pathogens. As such, viperin has been implicated in interactions with many functionally unrelated host and viral proteins, making it increasingly difficult to determine a unifying mechanism of viperin’s antiviral activity. We report here that viperin acts synergistically to enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1, via direct binding to STING; inducing enhanced K63-linked ubiquitination of TBK1. Consistently, viperin’s interaction with these molecules resulted in an enhanced type-I interferon response to Hepatitis B virus and significantly lowered Hepatitis B viral levels in an in vitro transfection model. Subsequent analysis identified the necessity of N-terminal sequences and viperin’s radical SAM domain to enhance the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhansosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway; which results in an enhanced antiviral state. This data further defines viperin’s role as a positive regulator of innate immune signalling, complementary to its role in TLR7/9 signalling, offering a mechanism of viperin’s broad antiviral capacity.