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Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
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Los modos de activación de la IRE1alfa quinasa controlan las salidas alternas de la endoribonucleasa para determinar
Dan Han1, Alana G Lerner, Lieselotte Vande Walle
1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-2520, USA.
Cell
|August 12, 2009
Resumen
La respuesta proteica desplegada (UPR) puede desencadenar la muerte celular durante el estrés del retículo endoplasmático (ER). Los inhibidores de la quinasa pueden bloquear esta apoptosis al alterar la actividad de la IRE1alfa RNasa, promoviendo la supervivencia celular.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- La bioquímica es la bioquímica.
Sus antecedentes:
- El estrés del retículo endoplasmático (ER) activa la respuesta proteica desplegada (UPR) para restaurar la homeostasis.
- Si no se logra la homeostasis, la UPR puede desencadenar la apoptosis o muerte celular programada.
- IRE1alfa, una ER transmembrana quinasa / endoribonucleasa (RNase), juega un papel crítico en este interruptor apoptótico.
Objetivo del estudio:
- Investigar el papel de IRE1alpha en la mediación de la apoptosis durante el estrés de ER.
- Explorar mecanismos para modular la actividad de IRE1alpha para promover la supervivencia celular.
Principales métodos:
- Utilizó la genética química para estudiar la función IRE1alpha.
- Se han realizado ensayos de reconstitución in vitro.
- Analizó las vías de empalme y decaimiento del ARNm.
Principales resultados:
- El estrés de ER induce la autofosforilación de IRE1alpha, activando su RNasa para empalmar el ARNm XBP1 y degradar otros ARNm localizados en ER.
- Los inhibidores de la quinasa pasan por alto la autofosforilación de IRE1alfa, activando la RNasa a través de un modo alternativo.
- Esta activación alterna promueve el empalme de XBP1 al tiempo que previene la desintegración del ARNm, evitando así la apoptosis.
Conclusiones:
- Las actividades duales de kinasa y RNasa de IRE1alpha son cruciales para determinar el destino celular durante el estrés ER.
- La modulación de la actividad de la IRE1alfa RNasa con inhibidores de la quinasa puede cambiar el equilibrio hacia la supervivencia celular.
- La orientación de IRE1alpha ofrece una estrategia terapéutica potencial para las condiciones que implican estrés ER.
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