Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

family Bunyaviridae members (~2500 amino acids). Additional sequences are present in the N-terminal region of nairovirus L proteins that are not found in other Bunyaviridae genomes. This finding suggests that amino acids 1-609 may contain domains with non-classical L function, such as the ovarian tumor (OTU) cysteine protease. Sequences located between the OTU domain and the RdRp conserved motifs contain a potential leucine zipper and a C2H2 zinc finger motif important for binding NP the N-terminal region of the L protein [64, 85] (Figure 4 ). The most extensively studied region of the CCHF L protein is the N-terminal OTU domain (residues 1-152). The OTU domain removes ubiquitin (Ub) and Ub-like protein IFN-stimulated gene-15 (ISG15) from their protein substrates [92] [93] [94] . Viral OTUs and papain-like proteases with similar activity have previously been found in both positive-and negative-stranded RNA viruses, including Dugbe virus, Nairobi sheep disease virus, rice stripe virus, porcine reproductive and respiratory syndrome virus, equine arteritis virus, murine hepatitis virus, severe acute respiratory syndrome coronavirus, human coronavirus NL63, and Middle East respiratory syndrome coronavirus [86, 92, [94] [95] [96] [97] [98] [99] [100] [101] . In addition, deubiquitinases of positive-strand RNA viruses proteolytically process the viral polyproteins and are therefore necessary for replication [94] . In CCHFV, the L protein is not proteolytically processed by the OTU domain, and the OTU cysteine protease activity is dispensable for CCHFV transcription and replication of minigenomes [26] .