Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not req...

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Autores principales:	Joshua M. Thornbrough, Babal K. Jha, Boyd Yount, Stephen A. Goldstein, Yize Li, Ruth Elliott, Amy C. Sims, Ralph S. Baric, Robert H. Silverman, Susan R. Weiss
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bc4737fc08994557a29b4ee680bbd0de
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spelling	oai:doaj.org-article:bc4737fc08994557a29b4ee680bbd0de2021-11-15T15:41:40ZMiddle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation10.1128/mBio.00258-162150-7511https://doaj.org/article/bc4737fc08994557a29b4ee680bbd0de2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00258-16https://doaj.org/toc/2150-7511ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not required for replication of the genome but are likely involved in pathogenesis. Evasion of host innate immunity through interferon (IFN) antagonism is a critical component of viral pathogenesis. The IFN-inducible oligoadenylate synthetase (OAS)-RNase L pathway activates upon sensing of viral double-stranded RNA (dsRNA). Activated RNase L cleaves viral and host single-stranded RNA (ssRNA), which leads to translational arrest and subsequent cell death, preventing viral replication and spread. Here we report that MERS-CoV, a lineage C Betacoronavirus, and related bat CoV NS4b accessory proteins have phosphodiesterase (PDE) activity and antagonize OAS-RNase L by enzymatically degrading 2′,5′-oligoadenylate (2-5A), activators of RNase L. This is a novel function for NS4b, which has previously been reported to antagonize IFN signaling. NS4b proteins are distinct from lineage A Betacoronavirus PDEs and rotavirus gene-encoded PDEs, in having an amino-terminal nuclear localization signal (NLS) and are localized mostly to the nucleus. However, the expression level of cytoplasmic MERS-CoV NS4b protein is sufficient to prevent activation of RNase L. Finally, this is the first report of an RNase L antagonist expressed by a human or bat coronavirus and provides a specific mechanism by which this occurs. Our findings provide a potential mechanism for evasion of innate immunity by MERS-CoV while also identifying a potential target for therapeutic intervention. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV). MERS-CoV, like other coronaviruses, carries genes that encode accessory proteins that antagonize the host antiviral response, often the type I interferon response, and contribute to virulence. We found that MERS-CoV NS4b and homologs from related lineage C bat betacoronaviruses BtCoV-SC2013 (SC2013) and BtCoV-HKU5 (HKU5) are members of the 2H-phosphoesterase (2H-PE) enzyme family with phosphodiesterase (PDE) activity. Like murine coronavirus NS2, a previously characterized PDE, MERS NS4b, can antagonize activation of the OAS-RNase L pathway, an interferon-induced potent antiviral activity. Furthermore, MERS-CoV mutants with deletion of genes encoding accessory proteins NS3 to NS5 or NS4b alone or inactivation of the PDE can activate RNase L during infection of Calu-3 cells. Our report may offer a potential target for therapeutic intervention if NS4b proves to be critical to pathogenesis in in vivo models of MERS-CoV infection.Joshua M. ThornbroughBabal K. JhaBoyd YountStephen A. GoldsteinYize LiRuth ElliottAmy C. SimsRalph S. BaricRobert H. SilvermanSusan R. WeissAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Joshua M. Thornbrough Babal K. Jha Boyd Yount Stephen A. Goldstein Yize Li Ruth Elliott Amy C. Sims Ralph S. Baric Robert H. Silverman Susan R. Weiss Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
description	ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not required for replication of the genome but are likely involved in pathogenesis. Evasion of host innate immunity through interferon (IFN) antagonism is a critical component of viral pathogenesis. The IFN-inducible oligoadenylate synthetase (OAS)-RNase L pathway activates upon sensing of viral double-stranded RNA (dsRNA). Activated RNase L cleaves viral and host single-stranded RNA (ssRNA), which leads to translational arrest and subsequent cell death, preventing viral replication and spread. Here we report that MERS-CoV, a lineage C Betacoronavirus, and related bat CoV NS4b accessory proteins have phosphodiesterase (PDE) activity and antagonize OAS-RNase L by enzymatically degrading 2′,5′-oligoadenylate (2-5A), activators of RNase L. This is a novel function for NS4b, which has previously been reported to antagonize IFN signaling. NS4b proteins are distinct from lineage A Betacoronavirus PDEs and rotavirus gene-encoded PDEs, in having an amino-terminal nuclear localization signal (NLS) and are localized mostly to the nucleus. However, the expression level of cytoplasmic MERS-CoV NS4b protein is sufficient to prevent activation of RNase L. Finally, this is the first report of an RNase L antagonist expressed by a human or bat coronavirus and provides a specific mechanism by which this occurs. Our findings provide a potential mechanism for evasion of innate immunity by MERS-CoV while also identifying a potential target for therapeutic intervention. IMPORTANCE Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV). MERS-CoV, like other coronaviruses, carries genes that encode accessory proteins that antagonize the host antiviral response, often the type I interferon response, and contribute to virulence. We found that MERS-CoV NS4b and homologs from related lineage C bat betacoronaviruses BtCoV-SC2013 (SC2013) and BtCoV-HKU5 (HKU5) are members of the 2H-phosphoesterase (2H-PE) enzyme family with phosphodiesterase (PDE) activity. Like murine coronavirus NS2, a previously characterized PDE, MERS NS4b, can antagonize activation of the OAS-RNase L pathway, an interferon-induced potent antiviral activity. Furthermore, MERS-CoV mutants with deletion of genes encoding accessory proteins NS3 to NS5 or NS4b alone or inactivation of the PDE can activate RNase L during infection of Calu-3 cells. Our report may offer a potential target for therapeutic intervention if NS4b proves to be critical to pathogenesis in in vivo models of MERS-CoV infection.
format	article
author	Joshua M. Thornbrough Babal K. Jha Boyd Yount Stephen A. Goldstein Yize Li Ruth Elliott Amy C. Sims Ralph S. Baric Robert H. Silverman Susan R. Weiss
author_facet	Joshua M. Thornbrough Babal K. Jha Boyd Yount Stephen A. Goldstein Yize Li Ruth Elliott Amy C. Sims Ralph S. Baric Robert H. Silverman Susan R. Weiss
author_sort	Joshua M. Thornbrough
title	Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
title_short	Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
title_full	Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
title_fullStr	Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
title_full_unstemmed	Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation
title_sort	middle east respiratory syndrome coronavirus ns4b protein inhibits host rnase l activation
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/bc4737fc08994557a29b4ee680bbd0de
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Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation

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