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Mecanismo estructural para la orientación de GSDMD mediante caspases automáticas en la piroptosis
Kun Wang1, Qi Sun2, Xiu Zhong1
1Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, 102206 Beijing, China; National Institute of Biological Sciences, Beijing, 102206 Beijing, China.
Cell
|February 29, 2020
Resumen
Las caspasas activadas por el inflammasoma (caspasa-1, -4, -11) dividen la gasdermina D (GSDMD) para desencadenar la piroptosis. Este estudio revela cómo la caspasa-4/11 activada utiliza una interfaz hidrofóbica única para unirse a GSDMD, impulsando la piroptosis y ofreciendo nuevos objetivos terapéuticos.
Área de la Ciencia:
- Biología molecular
- Inmunología
- Biología estructural
Sus antecedentes:
- La gasdermina D (GSDMD) es una proteína ejecutora clave en la piroptosis, una forma proinflamatoria de muerte celular programada.
- La activación del inflammasoma conduce a la escisión de la caspasa-1 o caspasa-11/4/5 de la GSDMD, iniciando la lisis celular.
- Los mecanismos precisos por los cuales las caspasas reconocen GSDMD y cómo esto se relaciona con la activación de la caspasa siguen siendo en gran medida desconocidos.
Objetivo del estudio:
- Elucidar el mecanismo molecular del reconocimiento de GSDMD por caspasas activadas por inflamasomas.
- Investigar la base estructural para la escisión de GSDMD mediada por caspasa y la inducción de piroptosis.
- Identificar objetivos potenciales para el desarrollo de inhibidores específicos de las caspasas piroptóticas.
Principales métodos:
- Análisis de autoprocesamiento específico del sitio de la caspasa-4/11.
- Co-cristalización y determinación estructural de los complejos caspase-4/11-GSDMD-C y caspase-1-GSDMD-C.
- Ensayos bioquímicos para evaluar las afinidades de unión y las consecuencias funcionales.
Principales resultados:
- El autoprocesamiento específico del sitio de la caspasa-4/11 en su producto p10 es esencial y suficiente para la escisión de GSDMD y la piroptosis.
- La caspasa-4/11 autoprocesada exhibe una unión de alta afinidad con el dominio terminal C de GSDMD a través de una interfaz hidrofóbica inducida.
- Esta interacción promueve la dimerización y activación de la caspasa, lo que lleva a la escisión de GSDMD independiente del motivo tetrapeptido canónico.
- El análisis estructural reveló un modo de reconocimiento GSDMD similar para la caspasa-1.
Conclusiones:
- Se ha descubierto un nuevo mecanismo de reconocimiento de sustrato para caspasas que involucra una interfaz hidrofóbica inducida.
- Los hallazgos proporcionan información crítica sobre la regulación de la piroptosis.
- La interfaz hidrofóbica identificada presenta una vía prometedora para el desarrollo de inhibidores dirigidos para las caspasas piroptóticas.
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