Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) infection can result in a severe hemorrhagic syndrome for which there are no antiviral interventions available to date. Certain RNA viruses, such as CCHFV, encode cysteine proteases of the ovarian tumor (OTU) family that antagonize interferon (I...

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Autores principales:	Florine E. M. Scholte, Brian L. Hua, Jessica R. Spengler, John V. Dzimianski, JoAnn D. Coleman-McCray, Stephen R. Welch, Laura K. McMullan, Stuart T. Nichol, Scott D. Pegan, Christina F. Spiropoulou, Éric Bergeron
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Nairoviridae RNA replication antiviral agents bunyavirus innate immunity interferon-stimulated gene-15 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/640e7af79e2e4deb96661b33a8af2153
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spelling	oai:doaj.org-article:640e7af79e2e4deb96661b33a8af21532021-11-15T16:22:08ZStable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection10.1128/mBio.01065-192150-7511https://doaj.org/article/640e7af79e2e4deb96661b33a8af21532019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01065-19https://doaj.org/toc/2150-7511ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) infection can result in a severe hemorrhagic syndrome for which there are no antiviral interventions available to date. Certain RNA viruses, such as CCHFV, encode cysteine proteases of the ovarian tumor (OTU) family that antagonize interferon (IFN) production by deconjugating ubiquitin (Ub). The OTU of CCHFV, a negative-strand RNA virus, is dispensable for replication of the viral genome, despite being part of the large viral RNA polymerase. Here, we show that mutations that prevent binding of the OTU to cellular ubiquitin are required for the generation of recombinant CCHFV containing a mutated catalytic cysteine. Similarly, the high-affinity binding of a synthetic ubiquitin variant (UbV-CC4) to CCHFV OTU strongly inhibits viral growth. UbV-CC4 inhibits CCHFV infection even in the absence of intact IFN signaling, suggesting that its antiviral activity is not due to blocking the OTU’s immunosuppressive function. Instead, the prolonged occupancy of the OTU with UbV-CC4 directly targets viral replication by interfering with CCHFV RNA synthesis. Together, our data provide mechanistic details supporting the development of antivirals targeting viral OTUs. IMPORTANCE Crimean-Congo hemorrhagic fever virus is an important human pathogen with a wide global distribution for which no therapeutic interventions are available. CCHFV encodes a cysteine protease belonging to the ovarian tumor (OTU) family which is involved in host immune suppression. Here we demonstrate that artificially prolonged binding of the OTU to a substrate inhibits virus infection. This provides novel insights into CCHFV OTU function during the viral replicative cycle and highlights the OTU as a potential antiviral target.Florine E. M. ScholteBrian L. HuaJessica R. SpenglerJohn V. DzimianskiJoAnn D. Coleman-McCrayStephen R. WelchLaura K. McMullanStuart T. NicholScott D. PeganChristina F. SpiropoulouÉric BergeronAmerican Society for MicrobiologyarticleNairoviridaeRNA replicationantiviral agentsbunyavirusinnate immunityinterferon-stimulated gene-15MicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nairoviridae RNA replication antiviral agents bunyavirus innate immunity interferon-stimulated gene-15 Microbiology QR1-502
spellingShingle	Nairoviridae RNA replication antiviral agents bunyavirus innate immunity interferon-stimulated gene-15 Microbiology QR1-502 Florine E. M. Scholte Brian L. Hua Jessica R. Spengler John V. Dzimianski JoAnn D. Coleman-McCray Stephen R. Welch Laura K. McMullan Stuart T. Nichol Scott D. Pegan Christina F. Spiropoulou Éric Bergeron Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
description	ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) infection can result in a severe hemorrhagic syndrome for which there are no antiviral interventions available to date. Certain RNA viruses, such as CCHFV, encode cysteine proteases of the ovarian tumor (OTU) family that antagonize interferon (IFN) production by deconjugating ubiquitin (Ub). The OTU of CCHFV, a negative-strand RNA virus, is dispensable for replication of the viral genome, despite being part of the large viral RNA polymerase. Here, we show that mutations that prevent binding of the OTU to cellular ubiquitin are required for the generation of recombinant CCHFV containing a mutated catalytic cysteine. Similarly, the high-affinity binding of a synthetic ubiquitin variant (UbV-CC4) to CCHFV OTU strongly inhibits viral growth. UbV-CC4 inhibits CCHFV infection even in the absence of intact IFN signaling, suggesting that its antiviral activity is not due to blocking the OTU’s immunosuppressive function. Instead, the prolonged occupancy of the OTU with UbV-CC4 directly targets viral replication by interfering with CCHFV RNA synthesis. Together, our data provide mechanistic details supporting the development of antivirals targeting viral OTUs. IMPORTANCE Crimean-Congo hemorrhagic fever virus is an important human pathogen with a wide global distribution for which no therapeutic interventions are available. CCHFV encodes a cysteine protease belonging to the ovarian tumor (OTU) family which is involved in host immune suppression. Here we demonstrate that artificially prolonged binding of the OTU to a substrate inhibits virus infection. This provides novel insights into CCHFV OTU function during the viral replicative cycle and highlights the OTU as a potential antiviral target.
format	article
author	Florine E. M. Scholte Brian L. Hua Jessica R. Spengler John V. Dzimianski JoAnn D. Coleman-McCray Stephen R. Welch Laura K. McMullan Stuart T. Nichol Scott D. Pegan Christina F. Spiropoulou Éric Bergeron
author_facet	Florine E. M. Scholte Brian L. Hua Jessica R. Spengler John V. Dzimianski JoAnn D. Coleman-McCray Stephen R. Welch Laura K. McMullan Stuart T. Nichol Scott D. Pegan Christina F. Spiropoulou Éric Bergeron
author_sort	Florine E. M. Scholte
title	Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
title_short	Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
title_full	Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
title_fullStr	Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
title_full_unstemmed	Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection
title_sort	stable occupancy of the crimean-congo hemorrhagic fever virus-encoded deubiquitinase blocks viral infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/640e7af79e2e4deb96661b33a8af2153
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Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection

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