Viperin: An Ancient Radical‐SAM Enzyme Finds its Place in Modern Cellular Metabolism and Innate Immunity

Viperin plays an important and multifaceted role in the innate immune response to viral infection. Viperin is also notable as one of very few radical SAM‐dependent enzymes present in higher animals; however, the enzyme appears broadly conserved across all kingdoms of life, which suggests that it represents an ancient defense mechanism against viral infections. Although viperin was discovered some 20 years ago, only recently was the enzyme's structure determined and its catalytic activity elucidated. The enzyme converts CTP to 3’,4’‐didehydro‐3’‐deoxy‐CTP, which functions as novel chain‐terminating antiviral nucleotide when misincorporated by viral RNA‐dependent RNA polymerases. Moreover, in higher animals, viperin interacts with numerous other host and viral proteins, and it is apparent that this complex network of interactions constitutes another important aspect of the protein's antiviral activity. An emerging theme is that viperin appears to facilitate ubiquitin‐dependent proteasomal degradation of some of the proteins it interacts with. Viperin‐ targeted protein degradation contributes to the antiviral response either by down‐regulating various metabolic pathways important for viral replication or by directly targeting viral proteins for degradation. We will present recent studies from our laboratory that focus on characterizing the interactions between viperin and its various target proteins. We have investigated how viperin regulates the biological activity of the proteins it interacts with, and how these protein‐protein interactions alter the catalytic activity of viperin. These studies have provided insights into the biochemical processes underpinning this unusual enzyme's wide‐ranging antiviral activity.