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La señalización de IRE1 afecta el destino celular durante la respuesta de la proteína desplegada
Jonathan H Lin1, Han Li, Douglas Yasumura
1Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA. Jonathan.Lin@ucsf.edu
Science (New York, N.Y.)
|November 10, 2007
Resumen
El estrés persistente en el retículo endoplasmático (ER) favorece la señalización PERK, promoviendo la muerte celular. El mantenimiento de la señalización IRE1 mejora la supervivencia celular, revelando un mecanismo clave en la respuesta de la proteína desplegada (UPR).
Área de la Ciencia:
- Biología celular Biología celular.
- Mecanismos moleculares del estrés de las ER.
- Las vías de señalización de la respuesta proteica desplegada (UPR, por sus siglas en inglés)
Sus antecedentes:
- El estrés del retículo endoplasmático (ER) desencadena la respuesta de la proteína desplegada (UPR) para manejar las proteínas mal plegadas.
- La UPR comprende tres ramas principales: IRE1, PERK y ATF6, que pueden promover la supervivencia celular o la apoptosis.
- El mecanismo por el cual la señalización UPR determina el destino celular (supervivencia vs. apoptosis) sigue sin estar claro.
Objetivo del estudio:
- Investigar cómo el UPR integra las señales pro-supervivencia y pro-apoptóticas bajo estrés ER persistente.
- Determinar el papel de la duración de la señalización de la rama UPR en las decisiones del destino celular.
- Para explorar la relevancia de estos hallazgos en modelos celulares y animales de retinitis pigmentosa.
Principales métodos:
- Análisis de la actividad de la rama UPR (IRE1, PERK, ATF6) en células humanas bajo estrés ER persistente.
- Manipulación de la duración de la señalización de IRE1 para evaluar su impacto en la supervivencia celular.
- Validación de los hallazgos en células fotorreceptoras de modelos animales con rodopsina mutante.
Principales resultados:
- El estrés ER persistente condujo a la atenuación de la actividad de IRE1 y ATF6.
- La señalización PERK, incluida la inhibición traslacional y la inducción de Chop, se mantuvo.
- El mantenimiento artificial de la actividad de IRE1 promovió la supervivencia celular.
- Los hallazgos clave fueron replicados en modelos animales de retinitis pigmentosa.
Conclusiones:
- La duración de la señalización de la rama UPR es crítica para determinar el destino de la célula después del estrés ER.
- La señalización PERK sostenida contribuye a la muerte celular, mientras que la señalización IRE1 sostenida promueve la supervivencia.
- Estos hallazgos ofrecen información sobre los mecanismos de muerte celular inducida por el estrés ER relevantes para la retinitis pigmentosa.
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