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PLSCR1 es un factor de defensa celular autónomo contra la infección por SARS-CoV-2
Dijin Xu1,2,3,4, Weiqian Jiang1,2,3, Lizhen Wu3
1Howard Hughes Medical Institute, New Haven, CT, USA.
Nature
|July 12, 2023
Resumen
La fosfolípida scramblase 1 (PLSCR1) actúa como una defensa celular autónoma contra el SARS-CoV-2, incluidas las variantes como Delta y Omicron. Esta proteína bloquea la entrada del virus al dirigirse a las vesículas y prevenir la fusión, ofreciendo un nuevo objetivo para las estrategias antivirales.
Área de la Ciencia:
- Inmunología
- Virología
- Biología celular
Sus antecedentes:
- Comprender la inmunidad protectora contra el SARS-CoV-2 es vital para la preparación para la pandemia y para combatir las variantes.
- Si bien se estudian los anticuerpos neutralizantes, los mecanismos de defensa autónomos de las células locales también son cruciales.
- Investigaciones anteriores ponen de relieve la importancia de los factores de las células huésped en el control de las infecciones virales.
Objetivo del estudio:
- Para identificar los factores celulares del huésped involucrados en la defensa celular autónoma contra el SARS-CoV-2.
- Para investigar el papel de la fosfolípida scramblase 1 (PLSCR1) en la restricción de la infección por SARS-CoV-2.
- Para aclarar el mecanismo por el cual PLSCR1 inhibe la entrada del virus.
Principales métodos:
- Las pantallas CRISPR-Cas9 de todo el genoma en epitelio pulmonar humano y hepatocitos.
- Estimulación de interferón gamma (IFNγ) para inducir la expresión de PLSCR1.
- Pruebas de infección con SARS-CoV-2 vivo (USA-WA1/2020, Delta, Omicron BA.1) y otros coronavirus.
- La nanoscopia de conmutación de una sola molécula 4Pi y los ensayos de nano-reportador bipartito.
- Estudios de conservación funcional en murciélagos y ratones.
Principales resultados:
- PLSCR1 fue identificado como un potente factor de restricción celular autónomo contra el SARS-CoV-2.
- El PLSCR1 inducido por IFNγ restringió múltiples linajes de SARS-CoV-2 y otros coronavirus patógenos.
- PLSCR1 interfirió tanto con las vías de entrada virales endocíticas como con las dependientes de TMPRSS2.
- PLSCR1 se dirigió directamente a las vesículas virales, evitando la fusión mediada por picos y la fuga viral.
- Un dominio β-barril terminal C de PLSCR1, no su actividad de la lipid scramblase, fue esencial para el bloqueo de la fusión.
Conclusiones:
- PLSCR1 es una proteína crítica de defensa del huésped que inhibe el SARS-CoV-2 en una etapa tardía de la entrada del virus.
- El mecanismo de PLSCR1 consiste en prevenir la fusión de las vesículas virales con las membranas celulares del huésped.
- PLSCR1 representa un objetivo terapéutico potencial para el desarrollo de nuevas estrategias contra el coronavirus.
- Comprender la función de PLSCR1 es importante, especialmente teniendo en cuenta las mutaciones asociadas a COVID en individuos susceptibles.
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