Abstract
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, Npro and Erns, that pestiviruses evolved to regulate the host’s innate immune response. In addition to its function as a structural envelope glycoprotein, Erns is also released in the extracellular space, where it is endocytosed by neighboring cells. As an endoribonuclease, Erns 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 Erns 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 Erns 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.
Highlights
The genus Pestivirus belongs to the family Flaviviridae, and includes pathogens of primary economic importance in livestock
The most impactful species are bovine viral diarrhea virus 1 and 2 (BVDV-1 and BVDV-2), and classical swine fever virus (CSFV), both included in the World Organization for Animal Health (OIE) list of notifiable diseases 2021
The most studied Erns proteins are those from CSFV and BVDV, and it was shown that this peculiar RNase is able to cleave viral single- and dsRNAs [10–13], preventing the stimulation of the innate immune response by such immunostimulatory pathogen-associated molecular patterns (PAMPs) in a dose-dependent fashion [4,9,12,14]
Summary
The genus Pestivirus belongs to the family Flaviviridae, and includes pathogens of primary economic importance in livestock. Most pestiviruses evolved two proteins that are unique to the genus, the N-terminal non-structural autoprotease Npro, and the envelope glycoprotein and endoribonuclease Erns. Both proteins have been shown to be required for a complementary, non-redundant, inhibition of the interferon (IFN) cascade upon double-stranded (ds) RNA stimulation [3,4] (for reviews, see [5–7]). The C-terminal end of Erns contains a positively charged domain that enables the protein to interact with cell surface glycosaminoglycans (GAG) [21–23] The presence of this GAG-binding site is required for cell attachment followed by its uptake via clathrin-mediated endocytosis [9], leading most likely to the localization of Erns in an endolysosomal compartment [7,24]
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