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Bases estructurales para el reconocimiento del ARN viral 5'-PPP-RNA por las proteínas IFIT humanas
Yazan M Abbas1, Andreas Pichlmair, Maria W Górna
1Department of Biochemistry, Groupe de Recherche Axé sur la Structure des Protéines, McGill University, Montreal, Quebec H3G 0B1, Canada.
Nature
|January 22, 2013
Resumen
Las proteínas inducidas por interferón con repeticiones de tetratricopéptido (IFIT) reconocen directamente el ARN viral con un grupo 5'-trifosfato (PPP-ARN). Esta visión estructural revela cómo los IFIT distinguen el ARN viral, crucial para la defensa antiviral innata.
Área de la Ciencia:
- La inmunidad innata es la inmunidad innata.
- Virología molecular Virología molecular.
- Biología estructural Biología estructural.
Sus antecedentes:
- Las proteínas inducidas por interferón con repeticiones de tetratricopéptido (IFIT) son moléculas inmunes innatas.
- Se pensaba que los IFIT funcionaban interrumpiendo el mecanismo de traducción del anfitrión.
- Los hallazgos recientes sugieren que los IFIT reconocen directamente las firmas de ARN viral.
Objetivo del estudio:
- Para aclarar la base estructural del reconocimiento del ARN viral por las proteínas IFIT.
- Para entender cómo los IFITs distinguen el ARN viral del ARN huésped.
- Para investigar el mecanismo de la defensa antiviral mediada por IFIT.
Principales métodos:
- Cristalografía de rayos X de fragmentos humanos de IFIT5 y IFIT1.
- Estudios de formación compleja con ARN 5'-trifosfato (ARN-PPP).
- Análisis mutacional, proteólisis y ensayos de desplazamiento de gel.
Principales resultados:
- Las estructuras cristalinas revelaron un nuevo dominio helicoidal con una cavidad cargada positivamente en IFIT5.
- Esta cavidad se une específicamente al ARN-PPP monocatenario, lo que lo diferencia del RIG-I.
- La unión PPP-ARN no es específica de la secuencia, ya que requiere un 5'-overhang de ~3 nucleótidos.
- La interrupción de la unión PPP-ARN deterioró las respuestas antivirales en las células renales embrionarias humanas.
Conclusiones:
- Las proteínas IFIT reconocen selectivamente el ARN viral a través de un motivo estructural dedicado.
- Este mecanismo de reconocimiento es distinto de otros sensores inmunes innatos conocidos.
- Los hallazgos proporcionan información sobre la base molecular de la inmunidad antiviral mediada por IFIT.
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