SARS-CoV-2 viroporin encoded by ORF3a triggers the NLRP3 inflammatory pathway.
Virology
; 568: 13-22, 2022 03.
Artículo
en Inglés
| MEDLINE | ID: covidwho-1639193
ABSTRACT
Heightened inflammatory response is a prominent feature of severe COVID-19 disease. We report that the SARS-CoV-2 ORF3a viroporin activates the NLRP3 inflammasome, the most promiscuous of known inflammasomes. Ectopically expressed ORF3a triggers IL-1ß expression via NFκB, thus priming the inflammasome. ORF3a also activates the NLRP3 inflammasome but not NLRP1 or NLRC4, resulting in maturation of IL-1ß and cleavage/activation of Gasdermin. Notably, ORF3a activates the NLRP3 inflammasome via both ASC-dependent and -independent modes. This inflammasome activation requires efflux of potassium ions and oligomerization between the kinase NEK7 and NLRP3. Importantly, infection of epithelial cells with SARS-CoV-2 similarly activates the NLRP3 inflammasome. With the NLRP3 inhibitor MCC950 and select FDA-approved oral drugs able to block ORF3a-mediated inflammasome activation, as well as key ORF3a amino acid residues needed for virus release and inflammasome activation conserved in the new variants of SARS-CoV-2 isolates across continents, ORF3a and NLRP3 present prime targets for intervention.
Palabras clave
Texto completo:
Disponible
Colección:
Bases de datos internacionales
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Inflamasomas
/
Proteína con Dominio Pirina 3 de la Familia NLR
/
Proteínas Viroporinas
/
SARS-CoV-2
/
COVID-19
Tópicos:
Variantes
Límite:
Humanos
Idioma:
Inglés
Revista:
Virology
Año:
2022
Tipo del documento:
Artículo
País de afiliación:
J.VIROL.2022.01.003
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