Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

Ke Zhang; Lisa Miorin; Tadashi Makio; Ishmael Dehghan; Shengyan Gao; Yihu Xie; Hualin Zhong; Matthew Esparza; Thomas Kehrer; Anil Kumar; Tom C. Hobman; Christopher Ptak; Boning Gao; John D. Minna; Zhijian Chen; Adolfo García-Sastre; Yi Ren; Richard W. Wozniak; Beatriz M.A. Fontoura

doi:10.1126/sciadv.abe7386

Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

Ke Zhang, Lisa Miorin, Tadashi Makio, Ishmael Dehghan, Shengyan Gao, Yihu Xie, Hualin Zhong, Matthew Esparza, Thomas Kehrer, Anil Kumar, Tom C. Hobman, Christopher Ptak, Boning Gao, John D. Minna, Zhijian Chen, Adolfo García-Sastre, Yi Ren, Richard W. Wozniak, Beatriz M.A. Fontoura

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140 Scopus citations

Abstract

The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.

Original language	English
Article number	eabe7386
Journal	Science advances
Volume	7
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.abe7386
State	Published - 5 Feb 2021

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Zhang, K., Miorin, L., Makio, T., Dehghan, I., Gao, S., Xie, Y., Zhong, H., Esparza, M., Kehrer, T., Kumar, A., Hobman, T. C., Ptak, C., Gao, B., Minna, J. D., Chen, Z., García-Sastre, A., Ren, Y., Wozniak, R. W., & Fontoura, B. M. A. (2021). Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression. Science advances, 7(6), Article eabe7386. https://doi.org/10.1126/sciadv.abe7386

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title = "Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression",

abstract = "The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.",

author = "Ke Zhang and Lisa Miorin and Tadashi Makio and Ishmael Dehghan and Shengyan Gao and Yihu Xie and Hualin Zhong and Matthew Esparza and Thomas Kehrer and Anil Kumar and Hobman, {Tom C.} and Christopher Ptak and Boning Gao and Minna, {John D.} and Zhijian Chen and Adolfo Garc{\'i}a-Sastre and Yi Ren and Wozniak, {Richard W.} and Fontoura, {Beatriz M.A.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2021",

month = feb,

day = "5",

doi = "10.1126/sciadv.abe7386",

language = "English",

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Zhang, K, Miorin, L, Makio, T, Dehghan, I, Gao, S, Xie, Y, Zhong, H, Esparza, M, Kehrer, T, Kumar, A, Hobman, TC, Ptak, C, Gao, B, Minna, JD, Chen, Z, García-Sastre, A, Ren, Y, Wozniak, RW & Fontoura, BMA 2021, 'Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression', Science advances, vol. 7, no. 6, eabe7386. https://doi.org/10.1126/sciadv.abe7386

TY - JOUR

T1 - Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

AU - Zhang, Ke

AU - Miorin, Lisa

AU - Makio, Tadashi

AU - Dehghan, Ishmael

AU - Gao, Shengyan

AU - Xie, Yihu

AU - Zhong, Hualin

AU - Esparza, Matthew

AU - Kehrer, Thomas

AU - Kumar, Anil

AU - Hobman, Tom C.

AU - Ptak, Christopher

AU - Gao, Boning

AU - Minna, John D.

AU - Chen, Zhijian

AU - García-Sastre, Adolfo

AU - Ren, Yi

AU - Wozniak, Richard W.

AU - Fontoura, Beatriz M.A.

N1 - Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2021/2/5

Y1 - 2021/2/5

N2 - The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.

AB - The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.

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DO - 10.1126/sciadv.abe7386

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AN - SCOPUS:85100984113

SN - 2375-2548

VL - 7

JO - Science advances

JF - Science advances

IS - 6

M1 - eabe7386

ER -

Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

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