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Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling

Lui et al., Virology, doi:10.1128/mbio.00392-24
Feb 2024  
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In Vitro study showing cyclosporine A (CsA) and the calcineurin-NFAT inhibitor VIVIT inhibit SARS-CoV-2 infection in lung epithelial Calu-3 cells. Authors find SARS-CoV-2 protein Nsp1 hijacks host NFAT signaling by binding calcineurin A, displacing regulator RCAN3 to drive NFAT activation. This induces DEAD-box helicase DDX5 to facilitate viral replication. Combining CsA or VIVIT with SARS-CoV-2 protease inhibitor nirmatrelvir shows synergistic antiviral effects. The results suggest targeting NFAT-DDX5 pathways may mitigate SARS-CoV-2 infection, while calcineurin inhibitors could enable protease inhibitor treatment for immunosuppressed patients.
Lui et al., 27 Feb 2024, peer-reviewed, 8 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperMiscellaneousAll
Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling
Wai-Yin Lui, Chon Phin Ong, Pak-Hin Hinson Cheung, Zi-Wei Ye, Chi-Ping Chan, Kelvin Kai-Wang To, Kit-San Yuen, Dong-Yan Jin
mBio, doi:10.1128/mbio.00392-24
SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signal ing to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors. IMPORTANCE Cyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.
DIRECT CONTRIBUTION This article is a direct contribution from Dong-Yan Jin, a Fellow of the American Academy of Microbiology, who arranged for and secured reviews by Haitao Guo, University of Pittsburgh, and Jianming Qiu, The University of Kansas Medical Center. DATA AVAILABILITY All data reported in this paper will be shared by lead upon request.
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DOI record: { "DOI": "10.1128/mbio.00392-24", "ISSN": [ "2150-7511" ], "URL": "http://dx.doi.org/10.1128/mbio.00392-24", "abstract": "<jats:title>ABSTRACT</jats:title>\n <jats:sec>\n <jats:title />\n <jats:p>SARS-CoV-2, the causative agent of COVID-19, has been intensely studied in search of effective antiviral treatments. The immunosuppressant cyclosporine A (CsA) has been suggested to be a pan-coronavirus inhibitor, yet its underlying mechanism remained largely unknown. Here, we found that non-structural protein 1 (Nsp1) of SARS-CoV-2 usurped CsA-suppressed nuclear factor of activated T cells (NFAT) signaling to drive the expression of cellular DEAD-box helicase 5 (DDX5), which facilitates viral replication. Nsp1 interacted with calcineurin A (CnA) to displace the regulatory protein regulator of calcineurin 3 (RCAN3) of CnA for NFAT activation. The influence of NFAT activation on SARS-CoV-2 replication was also validated by using the Nsp1-deficient mutant virus. Calcineurin inhibitors, such as CsA and VIVIT, inhibited SARS-CoV-2 replication and exhibited synergistic antiviral effects when used in combination with nirmatrelvir. Our study delineated the molecular mechanism of CsA-mediated inhibition of SARS-CoV-2 replication and the anti-SARS-CoV-2 action of calcineurin inhibitors.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>IMPORTANCE</jats:title>\n <jats:p>Cyclosporine A (CsA), commonly used to inhibit immune responses, is also known to have anti-SARS-CoV-2 activity, but its mode of action remains elusive. Here, we provide a model to explain how CsA antagonizes SARS-CoV-2 through three critical proteins: DDX5, NFAT1, and Nsp1. DDX5 is a cellular facilitator of SARS-CoV-2 replication, and NFAT1 controls the production of DDX5. Nsp1 is a viral protein absent from the mature viral particle and capable of activating the function of NFAT1 and DDX5. CsA and similar agents suppress Nsp1, NFAT1, and DDX5 to exert their anti-SARS-CoV-2 activity either alone or in combination with Paxlovid.</jats:p>\n </jats:sec>", "alternative-id": [ "10.1128/mbio.00392-24" ], "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2024-02-06" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 1, "value": "2024-02-08" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 2, "value": "2024-02-27" } ], "author": [ { "affiliation": [ { "name": "School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong" } ], "family": "Lui", "given": "Wai-Yin", "sequence": "first" }, { "affiliation": [ { "name": "School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong" } 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