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Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex

To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunction...

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Autores principales: Katahira, Jun, Ohmae, Tatsuya, Yasugi, Mayo, Sasaki, Ryosuke, Itoh, Yumi, Kohda, Tomoko, Hieda, Miki, Yokota Hirai, Masami, Okamoto, Toru, Miyamoto, Yoichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415132/
https://www.ncbi.nlm.nih.gov/pubmed/37260089
http://dx.doi.org/10.1093/nar/gkad483
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author Katahira, Jun
Ohmae, Tatsuya
Yasugi, Mayo
Sasaki, Ryosuke
Itoh, Yumi
Kohda, Tomoko
Hieda, Miki
Yokota Hirai, Masami
Okamoto, Toru
Miyamoto, Yoichi
author_facet Katahira, Jun
Ohmae, Tatsuya
Yasugi, Mayo
Sasaki, Ryosuke
Itoh, Yumi
Kohda, Tomoko
Hieda, Miki
Yokota Hirai, Masami
Okamoto, Toru
Miyamoto, Yoichi
author_sort Katahira, Jun
collection PubMed
description To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)(+) RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3′-end processing defects of replication-dependent histone mRNAs by Nsp14. These abnormalities were also observed in SARS-CoV-2-infected cells. A mutation introduced at the guanine-N7-methyltransferase active site of Nsp14 diminished these inhibitory activities. Targeted capillary electrophoresis-mass spectrometry analysis (CE-MS) unveiled the production of N7-methyl-GTP in Nsp14-expressing cells. Association of the nuclear cap-binding complex (NCBC) with the mRNA cap and subsequent recruitment of U1 snRNP and the stem-loop binding protein (SLBP) were impaired by Nsp14. These data suggest that the defects in mRNA processing and export arise from the compromise of NCBC function by N7-methyl-GTP, thus exemplifying a novel viral strategy to block host gene expression.
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spelling pubmed-104151322023-08-12 Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex Katahira, Jun Ohmae, Tatsuya Yasugi, Mayo Sasaki, Ryosuke Itoh, Yumi Kohda, Tomoko Hieda, Miki Yokota Hirai, Masami Okamoto, Toru Miyamoto, Yoichi Nucleic Acids Res RNA and RNA-protein complexes To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)(+) RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3′-end processing defects of replication-dependent histone mRNAs by Nsp14. These abnormalities were also observed in SARS-CoV-2-infected cells. A mutation introduced at the guanine-N7-methyltransferase active site of Nsp14 diminished these inhibitory activities. Targeted capillary electrophoresis-mass spectrometry analysis (CE-MS) unveiled the production of N7-methyl-GTP in Nsp14-expressing cells. Association of the nuclear cap-binding complex (NCBC) with the mRNA cap and subsequent recruitment of U1 snRNP and the stem-loop binding protein (SLBP) were impaired by Nsp14. These data suggest that the defects in mRNA processing and export arise from the compromise of NCBC function by N7-methyl-GTP, thus exemplifying a novel viral strategy to block host gene expression. Oxford University Press 2023-06-01 /pmc/articles/PMC10415132/ /pubmed/37260089 http://dx.doi.org/10.1093/nar/gkad483 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA and RNA-protein complexes
Katahira, Jun
Ohmae, Tatsuya
Yasugi, Mayo
Sasaki, Ryosuke
Itoh, Yumi
Kohda, Tomoko
Hieda, Miki
Yokota Hirai, Masami
Okamoto, Toru
Miyamoto, Yoichi
Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title_full Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title_fullStr Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title_full_unstemmed Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title_short Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex
title_sort nsp14 of sars-cov-2 inhibits mrna processing and nuclear export by targeting the nuclear cap-binding complex
topic RNA and RNA-protein complexes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415132/
https://www.ncbi.nlm.nih.gov/pubmed/37260089
http://dx.doi.org/10.1093/nar/gkad483
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