Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity

ABSTRACT The 2′,5′-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-in...

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Autores principales:	Abhishek Asthana, Christina Gaughan, Beihua Dong, Susan R. Weiss, Robert H. Silverman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	2-5A AKAP7 OAS RNase L coronavirus innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/817fafeb64f249a9b658828a1f2de837
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spelling	oai:doaj.org-article:817fafeb64f249a9b658828a1f2de8372021-11-10T18:37:52ZSpecificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity10.1128/mBio.01781-212150-7511https://doaj.org/article/817fafeb64f249a9b658828a1f2de8372021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01781-21https://doaj.org/toc/2150-7511ABSTRACT The 2′,5′-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2′,5′-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2′,5′-PEs. 2′,5′-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3′,5′-oligoribonucleotides, they all cleaved 2′,5′-oligoadenylates efficiently but with variable activity against other 2′,5′-oligonucleotides. The 2′,5′-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2′,5′-p3A3) producing mono- or diadenylates with 2′,3′-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2′,5′-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2′,5′-PEs, specifically degrade 2′,5′-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2′,5′- and not 3′,5′-phosphodiester bonds, producing cleavage products with cyclic 2′,3′-phosphate termini. Our study defines 2′,5′-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.Abhishek AsthanaChristina GaughanBeihua DongSusan R. WeissRobert H. SilvermanAmerican Society for Microbiologyarticle2-5AAKAP7OASRNase Lcoronavirusinnate immunityMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	2-5A AKAP7 OAS RNase L coronavirus innate immunity Microbiology QR1-502
spellingShingle	2-5A AKAP7 OAS RNase L coronavirus innate immunity Microbiology QR1-502 Abhishek Asthana Christina Gaughan Beihua Dong Susan R. Weiss Robert H. Silverman Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
description	ABSTRACT The 2′,5′-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L, is a principal mediator of the interferon (IFN) antiviral response. Therefore, the regulation of cellular levels of 2-5A is a key point of control in antiviral innate immunity. Cellular 2-5A levels are determined by IFN-inducible 2′,5′-oligoadenylate synthetases (OASs) and by enzymes that degrade 2-5A. Importantly, many coronaviruses (CoVs) and rotaviruses encode 2-5A-degrading enzymes, thereby antagonizing RNase L and its antiviral effects. A-kinase-anchoring protein 7 (AKAP7), a mammalian counterpart, could possibly limit tissue damage from excessive or prolonged RNase L activation during viral infections or from self-double-stranded RNAs that activate OAS. We show that these enzymes, members of the two-histidine phosphoesterase (2H-PE) superfamily, constitute a subfamily referred here as 2′,5′-PEs. 2′,5′-PEs from the mouse CoV mouse hepatitis virus (MHV) (NS2), Middle East respiratory syndrome coronavirus (MERS-CoV) (NS4b), group A rotavirus (VP3), and mouse (AKAP7) were investigated for their evolutionary relationships and activities. While there was no activity against 3′,5′-oligoribonucleotides, they all cleaved 2′,5′-oligoadenylates efficiently but with variable activity against other 2′,5′-oligonucleotides. The 2′,5′-PEs are shown to be metal ion-independent enzymes that cleave trimer 2-5A (2′,5′-p3A3) producing mono- or diadenylates with 2′,3′-cyclic phosphate termini. Our results suggest that the elimination of 2-5A might be the sole function of viral 2′,5′-PEs, thereby promoting viral escape from innate immunity by preventing or limiting the activation of RNase L. IMPORTANCE Viruses often encode accessory proteins that antagonize the host antiviral immune response. Here, we probed the evolutionary relationships and biochemical activities of two-histidine phosphoesterases (2H-PEs) that allow some coronaviruses and rotaviruses to counteract antiviral innate immunity. In addition, we investigated the mammalian enzyme AKAP7, which has homology and shared activities with the viral enzymes and might reduce self-injury. These viral and host enzymes, which we refer to as 2′,5′-PEs, specifically degrade 2′,5′-oligoadenylate activators of the antiviral enzyme RNase L. We show that the host and viral enzymes are metal ion independent and exclusively cleave 2′,5′- and not 3′,5′-phosphodiester bonds, producing cleavage products with cyclic 2′,3′-phosphate termini. Our study defines 2′,5′-PEs as enzymes that share characteristic conserved features with the 2H-PE superfamily but have specific and distinct biochemical cleavage activities. These findings may eventually lead to pharmacological strategies for developing antiviral drugs against coronaviruses, rotaviruses, and other viruses.
format	article
author	Abhishek Asthana Christina Gaughan Beihua Dong Susan R. Weiss Robert H. Silverman
author_facet	Abhishek Asthana Christina Gaughan Beihua Dong Susan R. Weiss Robert H. Silverman
author_sort	Abhishek Asthana
title	Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
title_short	Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
title_full	Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
title_fullStr	Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
title_full_unstemmed	Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity
title_sort	specificity and mechanism of coronavirus, rotavirus, and mammalian two-histidine phosphoesterases that antagonize antiviral innate immunity
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/817fafeb64f249a9b658828a1f2de837
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Specificity and Mechanism of Coronavirus, Rotavirus, and Mammalian Two-Histidine Phosphoesterases That Antagonize Antiviral Innate Immunity

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