Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response

ABSTRACT A 32-nucleotide (nt) RNA motif located at the 3′ end of the transmissible gastroenteritis coronavirus (TGEV) genome was found to specifically interact with the host proteins glutamyl-prolyl-tRNA synthetase (EPRS) and arginyl-tRNA synthetase (RRS). This RNA motif has high homology in sequenc...

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Autores principales:	Silvia Marquez-Jurado, Aitor Nogales, Sonia Zuñiga, Luis Enjuanes, Fernando Almazán
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/431f56efb9e64692b37a9a71d46c8417
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spelling	oai:doaj.org-article:431f56efb9e64692b37a9a71d46c84172021-11-15T15:41:32ZIdentification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response10.1128/mBio.00105-152150-7511https://doaj.org/article/431f56efb9e64692b37a9a71d46c84172015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00105-15https://doaj.org/toc/2150-7511ABSTRACT A 32-nucleotide (nt) RNA motif located at the 3′ end of the transmissible gastroenteritis coronavirus (TGEV) genome was found to specifically interact with the host proteins glutamyl-prolyl-tRNA synthetase (EPRS) and arginyl-tRNA synthetase (RRS). This RNA motif has high homology in sequence and secondary structure with the gamma interferon-activated inhibitor of translation (GAIT) element, which is located at the 3′ end of several mRNAs encoding proinflammatory proteins. The GAIT element is involved in the translation silencing of these mRNAs through its interaction with the GAIT complex (EPRS, heterogeneous nuclear ribonucleoprotein Q, ribosomal protein L13a, and glyceraldehyde 3-phosphate dehydrogenase) to favor the resolution of inflammation. Interestingly, we showed that the viral RNA motif bound the GAIT complex and inhibited the in vitro translation of a chimeric mRNA containing this RNA motif. To our knowledge, this is the first GAIT-like motif described in a positive RNA virus. To test the functional role of the GAIT-like RNA motif during TGEV infection, a recombinant coronavirus harboring mutations in this motif was engineered and characterized. Mutations of the GAIT-like RNA motif did not affect virus growth in cell cultures. However, an exacerbated innate immune response, mediated by the melanoma differentiation-associated gene 5 (MDA5) pathway, was observed in cells infected with the mutant virus compared with the response observed in cells infected with the parental virus. Furthermore, the mutant virus was more sensitive to beta interferon than the parental virus. All together, these data strongly suggested that the viral GAIT-like RNA motif modulates the host innate immune response. IMPORTANCE The innate immune response is the first line of antiviral defense that culminates with the synthesis of interferon and proinflammatory cytokines to limit virus replication. Coronaviruses encode several proteins that interfere with the innate immune response at different levels, but to date, no viral RNA counteracting antiviral response has been described. In this work, we have characterized a 32-nt RNA motif located at the 3′ end of the TGEV genome that specifically interacted with EPRS and RRS. This RNA motif presented high homology with the GAIT element, involved in the modulation of the inflammatory response. Moreover, the disruption of the viral GAIT-like RNA motif led to an exacerbated innate immune response triggered by MDA5, indicating that the GAIT-like RNA motif counteracts the host innate immune response. These novel findings may be of relevance for other coronaviruses and could serve as the basis for the development of novel antiviral strategies.Silvia Marquez-JuradoAitor NogalesSonia ZuñigaLuis EnjuanesFernando AlmazánAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Silvia Marquez-Jurado Aitor Nogales Sonia Zuñiga Luis Enjuanes Fernando Almazán Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
description	ABSTRACT A 32-nucleotide (nt) RNA motif located at the 3′ end of the transmissible gastroenteritis coronavirus (TGEV) genome was found to specifically interact with the host proteins glutamyl-prolyl-tRNA synthetase (EPRS) and arginyl-tRNA synthetase (RRS). This RNA motif has high homology in sequence and secondary structure with the gamma interferon-activated inhibitor of translation (GAIT) element, which is located at the 3′ end of several mRNAs encoding proinflammatory proteins. The GAIT element is involved in the translation silencing of these mRNAs through its interaction with the GAIT complex (EPRS, heterogeneous nuclear ribonucleoprotein Q, ribosomal protein L13a, and glyceraldehyde 3-phosphate dehydrogenase) to favor the resolution of inflammation. Interestingly, we showed that the viral RNA motif bound the GAIT complex and inhibited the in vitro translation of a chimeric mRNA containing this RNA motif. To our knowledge, this is the first GAIT-like motif described in a positive RNA virus. To test the functional role of the GAIT-like RNA motif during TGEV infection, a recombinant coronavirus harboring mutations in this motif was engineered and characterized. Mutations of the GAIT-like RNA motif did not affect virus growth in cell cultures. However, an exacerbated innate immune response, mediated by the melanoma differentiation-associated gene 5 (MDA5) pathway, was observed in cells infected with the mutant virus compared with the response observed in cells infected with the parental virus. Furthermore, the mutant virus was more sensitive to beta interferon than the parental virus. All together, these data strongly suggested that the viral GAIT-like RNA motif modulates the host innate immune response. IMPORTANCE The innate immune response is the first line of antiviral defense that culminates with the synthesis of interferon and proinflammatory cytokines to limit virus replication. Coronaviruses encode several proteins that interfere with the innate immune response at different levels, but to date, no viral RNA counteracting antiviral response has been described. In this work, we have characterized a 32-nt RNA motif located at the 3′ end of the TGEV genome that specifically interacted with EPRS and RRS. This RNA motif presented high homology with the GAIT element, involved in the modulation of the inflammatory response. Moreover, the disruption of the viral GAIT-like RNA motif led to an exacerbated innate immune response triggered by MDA5, indicating that the GAIT-like RNA motif counteracts the host innate immune response. These novel findings may be of relevance for other coronaviruses and could serve as the basis for the development of novel antiviral strategies.
format	article
author	Silvia Marquez-Jurado Aitor Nogales Sonia Zuñiga Luis Enjuanes Fernando Almazán
author_facet	Silvia Marquez-Jurado Aitor Nogales Sonia Zuñiga Luis Enjuanes Fernando Almazán
author_sort	Silvia Marquez-Jurado
title	Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
title_short	Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
title_full	Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
title_fullStr	Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
title_full_unstemmed	Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
title_sort	identification of a gamma interferon-activated inhibitor of translation-like rna motif at the 3′ end of the transmissible gastroenteritis coronavirus genome modulating innate immune response
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/431f56efb9e64692b37a9a71d46c8417
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Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response

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