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 signalling pathway to limit viral infection. Viperin co-localised with the key signalling 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-sulphur 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 signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling 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. This data further defines viperin’s role as a positive regulator of innate immune signalling, offering a mechanism of viperin’s broad antiviral capacity.
Footnotes
Additional data figures have been added, which (1) describes the radical SAM enzymatic activity of viperin in the context of its ability to interact with the signalling adapter molecules of the dsDNA signalling pathway (Figure 7), and (2) describes viperin’s interaction with the cytosolic iron-sulphur assembly protein CIA2A in the context of its ability to enhance dsDNA signalling (Figure 8). Consequently, multiple hypotheses from our original discussion have now been substantiated, and as such, the discussion in this revised submission has been extensively altered to include the new data sets. Additionally, Figures 1 and 9 have been added as schematic representations to aid the readers understanding of the research content covered in this revised submission.
