SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Zhang Xu; Jung-Hyun Choi; David L Dai; Jun Luo; Reese Jalal Ladak; Qian Li; Yimeng Wang; Christine Zhang; Shane Wiebe; Alex C H Liu; Xiaozhuo Ran; Jiaqi Yang; Parisa Naeli; Aitor Garzia; Lele Zhou; Niaz Mahmood; Qiyun Deng; Mohamed Elaish; Rongtuan Lin; Lara K Mahal; Tom C Hobman; Jerry Pelletier; Tommy Alain; Silvia M Vidal; Thomas Duchaine; Mohammad T Mazhab-Jafari; Xiaojuan Mao; Seyed Mehdi Jafarnejad; Nahum Sonenberg

doi:10.1073/pnas.2204539119

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Zhang Xu, Jung-Hyun Choi, David L Dai, Jun Luo, Reese Jalal Ladak, Qian Li, Yimeng Wang, Christine Zhang, Shane Wiebe, Alex C H Liu, Xiaozhuo Ran, Jiaqi Yang, Parisa Naeli, Aitor Garzia, Lele Zhou, Niaz Mahmood, Qiyun Deng, Mohamed Elaish, Rongtuan Lin, Lara K MahalTom C Hobman, Jerry Pelletier, Tommy Alain, Silvia M Vidal, Thomas Duchaine, Mohammad T Mazhab-Jafari, Xiaojuan Mao, Seyed Mehdi Jafarnejad, Nahum Sonenberg

Patrick G Johnston Centre for Cancer Research

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Abstract

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Original language	English
Article number	e2204539119
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	119
Issue number	32
Early online date	25 Jul 2022
DOIs	https://doi.org/10.1073/pnas.2204539119
Publication status	Published - 09 Aug 2022

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10.1073/pnas.2204539119Licence: CC BY

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited
Final published version, 2.47 MBLicence: CC BY

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Xu, Z., Choi, J.-H., Dai, D. L., Luo, J., Ladak, R. J., Li, Q., Wang, Y., Zhang, C., Wiebe, S., Liu, A. C. H., Ran, X., Yang, J., Naeli, P., Garzia, A., Zhou, L., Mahmood, N., Deng, Q., Elaish, M., Lin, R., ... Sonenberg, N. (2022). SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation. Proceedings of the National Academy of Sciences of the United States of America, 119(32), Article e2204539119. https://doi.org/10.1073/pnas.2204539119

@article{b90e5d4910a44dc4bbdef5812e1bc5af,

title = "SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation",

abstract = "Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.",

author = "Zhang Xu and Jung-Hyun Choi and Dai, {David L} and Jun Luo and Ladak, {Reese Jalal} and Qian Li and Yimeng Wang and Christine Zhang and Shane Wiebe and Liu, {Alex C H} and Xiaozhuo Ran and Jiaqi Yang and Parisa Naeli and Aitor Garzia and Lele Zhou and Niaz Mahmood and Qiyun Deng and Mohamed Elaish and Rongtuan Lin and Mahal, {Lara K} and Hobman, {Tom C} and Jerry Pelletier and Tommy Alain and Vidal, {Silvia M} and Thomas Duchaine and Mazhab-Jafari, {Mohammad T} and Xiaojuan Mao and Jafarnejad, {Seyed Mehdi} and Nahum Sonenberg",

year = "2022",

month = aug,

day = "9",

doi = "10.1073/pnas.2204539119",

language = "English",

volume = "119",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Xu, Z, Choi, J-H, Dai, DL, Luo, J, Ladak, RJ, Li, Q, Wang, Y, Zhang, C, Wiebe, S, Liu, ACH, Ran, X, Yang, J, Naeli, P, Garzia, A, Zhou, L, Mahmood, N, Deng, Q, Elaish, M, Lin, R, Mahal, LK, Hobman, TC, Pelletier, J, Alain, T, Vidal, SM, Duchaine, T, Mazhab-Jafari, MT, Mao, X, Jafarnejad, SM & Sonenberg, N 2022, 'SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation', Proceedings of the National Academy of Sciences of the United States of America, vol. 119, no. 32, e2204539119. https://doi.org/10.1073/pnas.2204539119

TY - JOUR

T1 - SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

AU - Xu, Zhang

AU - Choi, Jung-Hyun

AU - Dai, David L

AU - Luo, Jun

AU - Ladak, Reese Jalal

AU - Li, Qian

AU - Wang, Yimeng

AU - Zhang, Christine

AU - Wiebe, Shane

AU - Liu, Alex C H

AU - Ran, Xiaozhuo

AU - Yang, Jiaqi

AU - Naeli, Parisa

AU - Garzia, Aitor

AU - Zhou, Lele

AU - Mahmood, Niaz

AU - Deng, Qiyun

AU - Elaish, Mohamed

AU - Lin, Rongtuan

AU - Mahal, Lara K

AU - Hobman, Tom C

AU - Pelletier, Jerry

AU - Alain, Tommy

AU - Vidal, Silvia M

AU - Duchaine, Thomas

AU - Mazhab-Jafari, Mohammad T

AU - Mao, Xiaojuan

AU - Jafarnejad, Seyed Mehdi

AU - Sonenberg, Nahum

PY - 2022/8/9

Y1 - 2022/8/9

N2 - Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

AB - Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

U2 - 10.1073/pnas.2204539119

DO - 10.1073/pnas.2204539119

M3 - Article

C2 - 35878012

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 32

M1 - e2204539119

ER -

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

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