Fifty Shades of E(rns): Innate Immune Evasion by the Viral Endonucleases of All Pestivirus Species

The genus Pestivirus, family Flaviviridae, includes four historically accepted species, i.e., bovine viral diarrhea virus (BVDV)-1 and -2, classical swine fever virus (CSFV), and border disease virus (BDV). A large number of new pestivirus species were identified in recent years. A common feature of most members is the presence of two unique proteins, N(pro) and E(rns), that pestiviruses evolved to regulate the host’s innate immune response. In addition to its function as a structural envelope glycoprotein, E(rns) is also released in the extracellular space, where it is endocytosed by neighboring cells. As an endoribonuclease, E(rns) is able to cleave viral ss- and dsRNAs, thus preventing the stimulation of the host’s interferon (IFN) response. Here, we characterize the basic features of soluble E(rns) of a large variety of classified and unassigned pestiviruses that have not yet been described. Its ability to form homodimers, its RNase activity, and the ability to inhibit dsRNA-induced IFN synthesis were investigated. Overall, we found large differences between the various E(rns) proteins that cannot be predicted solely based on their primary amino acid sequences, and that might be the consequence of different virus-host co-evolution histories. This provides valuable information to delineate the structure-function relationship of pestiviral endoribonucleases.