Journal article

Publication year: 2020

Journal: PLoS Neglected Tropical Diseases

Volume number: 14

Issue number: 9

ISSN: 1935-2735

Open access status: Gold

DOI Link: https://doi.org/10.1371/journal.pntd.0008610

Publisher: Public Library of Science

Abstract: 

Crimean-Congo Hemorrhagic Fever virus (CCHFV; familyNairoviridae) is an extremely pathogenic member of theBunyaviralesorder. Previous studies have shown that the N-terminal domain of the CCHFV polymerase (L) contains an ovarian tumor-type protease (OTU) domain with the capability to remove both ubiquitin and ISG15 molecules from proteins. The approximately 200 amino acids-long OTU domain, if ectopically expressed, can interfere with both the induction of antiviral type I interferons (IFN) as well as the IFN-stimulated signaling. A OTU protease mutant (C40A), by contrast, was inactive in that respect. However, the effect of the OTU protease activity in the context of the full-length L protein (approximately 4000 amino acids) is only poorly characterized, and recombinant CCHFV with the C40A mutation could not be rescued. Here, we employed transcriptionally active virus-like particles (tc-VLPs) to investigate the interaction between the L-embedded OTU protease and the IFN system. Our data show acisrequirement of the OTU protease for optimal CCHFV polymerase activity in human HuH-7 cells. The L-embedded OTU did not influence IFN signaling, the sensitivity to IFN, or IFN induction. Moreover, the attenuation of OTU C40A-mutated L could not be relieved by inactivating the IFN response, but after overexpression of conjugation-competent ISG15 the polymerase activity recovered to wild-type levels. Consequently, ISG15 was used to produce OTU-deficient tc-VLPs, a potential vaccine candidate. Our data thus indicate that in the context of full-length L the OTU domain is important for the regulation of CCHFV polymerase by ISG15.

Harvard Citation style: Devignot, S., Kromer, T., Mirazimi, A. and Weber, F. (2020) ISG15 overexpression compensates the defect of Crimean-Congo hemorrhagic fever virus polymerase bearing a protease-inactive ovarian tumor domain, PLoS Neglected Tropical Diseases, 14(9), Article e0008610. https://doi.org/10.1371/journal.pntd.0008610

APA Citation style: Devignot, S., Kromer, T., Mirazimi, A., & Weber, F. (2020). ISG15 overexpression compensates the defect of Crimean-Congo hemorrhagic fever virus polymerase bearing a protease-inactive ovarian tumor domain. PLoS Neglected Tropical Diseases. 14(9), Article e0008610. https://doi.org/10.1371/journal.pntd.0008610