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Denitrosilación de proteínas regulada por las tioredoxinas citosólicas y mitocondriales
Moran Benhar1, Michael T Forrester, Douglas T Hess
1Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Science (New York, N.Y.)
|May 24, 2008
Resumen
Las enzimas de tioredoxina regulan la denitrosilación de proteínas, un proceso clave de señalización celular. Este estudio identifica la tioredoxina-1 y la tioredoxina-2 como denitrosilasas cruciales para la caspasa-3, que afectan la señalización celular y la apoptosis.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- La señalización celular.
- Biología Molecular Biología Molecular
Sus antecedentes:
- El óxido nítrico (NO) es vital en la transducción de señales celulares a través de la S-nitrosilación de los residuos de cisteína.
- Los mecanismos que rigen la denitrosilación de proteínas, la eliminación de las modificaciones de NO, son en gran medida desconocidos en la señalización celular.
- Comprender la actividad de la denitrosilasa es crucial para elucidar los procesos celulares mediados por NO.
Objetivo del estudio:
- Para identificar las actividades enzimáticas responsables de la denitrosilación de las proteínas.
- Investigar el papel de las denitrosilasas específicas en la regulación de la caspasa-3.
- Explorar los mecanismos de la denitrosilación de proteínas basal y inducida por estímulos.
Principales métodos:
- Cribado bioquímico para identificar la actividad de la denitrosilasa.
- Centrarse en la caspasa-3 como un sustrato modelo para la denitrosilación.
- Utilizando linfocitos humanos y estimulación de Fas para estudiar las respuestas celulares.
- Inhibición de las tioredoxina-tioredoxina reductasas para identificar sustratos.
Principales resultados:
- La tioredoxina y la tioredoxina reductasa fueron identificadas como actividades de la denitrosilasa.
- La tioredoxina-1 denitrocilada citosólica caspasa-3 en los linfocitos en reposo, manteniendo una baja nitrosilación de S.
- La tioredoxina-2 medió la denitrosilación de la caspasa-3 asociada a las mitocondrias tras la estimulación de Fas, promoviendo la activación y la apoptosis.
- Los estudios de inhibición revelaron sustratos adicionales de S-nitrosilación endógena.
Conclusiones:
- Las enzimas específicas de tioredoxina (tioredoxina-1 y tioredoxina-2) actúan como denitrosilasas.
- Estas enzimas desempeñan funciones distintas en la regulación de la S-nitrosilación basal e inducida por estímulos de la caspasa-3.
- El sistema de tioredoxina es crítico para controlar la denitrosilación de proteínas en las células de mamíferos, influyendo en la señalización celular y la apoptosis.
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