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Nsp1 facilitates SARS-CoV-2 replication through calcineurin-NFAT signaling.
Lui, Wai-Yin; Ong, Chon Phin; Cheung, Pak-Hin Hinson; Ye, Zi-Wei; Chan, Chi-Ping; To, Kelvin Kai-Wang; Yuen, Kit-San; Jin, Dong-Yan.
Afiliación
  • Lui W-Y; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • Ong CP; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • Cheung P-HH; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • Ye Z-W; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • Chan C-P; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • To KK-W; Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong.
  • Yuen K-S; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
  • Jin D-Y; School of Nursing, Tung Wah College, Kowloon, Hong Kong.
mBio ; 15(4): e0039224, 2024 Apr 10.
Article en En | MEDLINE | ID: mdl-38411085
ABSTRACT
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. 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas no Estructurales Virales / SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: MBio Año: 2024 Tipo del documento: Article País de afiliación: Hong Kong Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas no Estructurales Virales / SARS-CoV-2 / COVID-19 Límite: Humans Idioma: En Revista: MBio Año: 2024 Tipo del documento: Article País de afiliación: Hong Kong Pais de publicación: Estados Unidos