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AIM2 reconoce el dsDNA citosólico y forma un inflamasoma activador de caspasa-1 con ASC
Veit Hornung1, Andrea Ablasser, Marie Charrel-Dennis
1Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. veit.hornung@uni-bonn.de
Nature
|January 23, 2009
Resumen
La proteína ausente en el melanoma 2 (AIM2) actúa como un sensor para el ADN citoplasmático, iniciando respuestas inflamatorias. AIM2 forma un complejo inflamatorio con ASC para activar la caspasa-1, crucial para la inmunidad antiviral.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
Sus antecedentes:
- El sistema inmune innato utiliza receptores de reconocimiento de patrones codificados por la línea germinal para detectar ácidos nucleicos.
- Si bien los sensores de ARN están bien caracterizados, los sensores de ADN citoplasmático que desencadenan respuestas antivirales e inflamatorias siguen siendo menos comprendidos.
- Las vías conocidas incluyen la señalización de TBK1-IRF3 para la inducción de interferón tipo I y la activación del inflamatorio a través de caspase-1 para el procesamiento de IL1beta e IL18.
Objetivo del estudio:
- Identificar nuevos receptores para el ADN citosólico que inician la señalización inflamatoria.
- Para dilucidar el mecanismo por el cual el ADN citosólico desencadena la activación del inflamatorio y las respuestas mediadas por caspase-1.
Principales métodos:
- Utilizó ratones y líneas celulares humanas.
- Empleado knockdown de Aim2 para evaluar su papel en la detección de ADN.
- Interacciones proteína-proteína investigadas entre AIM2, ASC y otros componentes de señalización.
- Evaluó la activación de la caspasa-1 en respuesta al ADN de doble cadena y la infección viral.
Principales resultados:
- Identificado como ausente en el melanoma 2 (AIM2), una proteína de la familia PYHIN, como receptor del ADN citosólico.
- Se demostró que el dominio HIN200 de AIM2 se une al ADN, mientras que su dominio pirina interactúa con ASC.
- Se demostró que la activación de AIM2 conduce a la activación de NF-kappaB y caspase-1.
- Se ha confirmado que el knockdown de Aim2 anula la activación de la caspasa-1 en respuesta al dsDNA citoplasmático y al virus de la vacuna.
Conclusiones:
- AIM2 funciona como un sensor crítico para el ADN citoplasmático.
- AIM2 forma un complejo inflamatorio con su ligando de ADN y ASC para activar la caspasa-1.
- Esta vía es esencial para iniciar respuestas inflamatorias y antivirales mediadas por caspase-1.
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