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RETRACTADO: Los proapoptóticos BAX y BAK modulan la respuesta de la proteína desplegada por una interacción directa
Claudio Hetz1, Paula Bernasconi, Jill Fisher
1Howard Hughes Medical Institute, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA. chetz@hsph.harvard.edu
Science (New York, N.Y.)
|April 29, 2006
Resumen
Las proteínas proapoptóticas BAX y BAK son cruciales para activar la vía de señalización de la respuesta proteica desplegada (UPR). Su ausencia perjudica la respuesta al estrés del retículo endoplasmático, lo que lleva a daños en el hígado en ratones.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- Respuestas al estrés Respuestas al estrés
Sus antecedentes:
- La acumulación de proteínas mal plegadas en el retículo endoplasmático (ER) inicia la respuesta de proteínas desplegadas (UPR).
- La UPR está mediada principalmente por la enzima 1alfa que requiere inositol (IRE1alpha), una quinasa transmembrana ER y la endoribonucleasa.
- El papel de las proteínas apoptóticas en la señalización de la UPR sigue siendo incompletamente entendido.
Objetivo del estudio:
- Investigar el papel de BAX y BAK en la señalización UPR.
- Examinar el impacto de la ausencia de BAX y BAK en las respuestas al estrés ER in vivo e in vitro.
- Para dilucidar los mecanismos moleculares que vinculan las vías apoptóticas a la UPR.
Principales métodos:
- Utilizó un modelo de ratón de doble nocaut (DKO) BAX y BAK.
- Estrés ER inducido con tunicamicina en ratones DKO y compañeros de camada de control.
- Se analizaron los componentes de señalización de la UPR, incluido el sustrato de IRE1alpha, la proteína 1 de unión a la caja X (XBP1) y sus genes diana.
- Investigó la formación de complejos proteicos entre BAX/BAK e IRE1alpha en células estresadas por ER.
Principales resultados:
- Los ratones DKO exhibieron respuestas anormales al estrés ER inducido por tunicamicina, caracterizado por un daño hepático extenso.
- Las células DKO estresadas por ER mostraron una señalización IRE1alpha deficiente.
- La expresión del sustrato IRE1alpha XBP1 y sus genes diana aguas abajo se redujo significativamente en ratones DKO.
- Se encontró que BAX y BAK forman un complejo proteico con el dominio citosólico de IRE1alpha, esencial para su activación.
Conclusiones:
- BAX y BAK son esenciales para la activación de la señalización UPR mediada por IRE1alpha.
- Estas proteínas proapoptóticas funcionan en la membrana ER para vincular la vía apoptótica del núcleo con la UPR.
- La ausencia de BAX y BAK compromete la respuesta adaptativa al estrés ER, lo que lleva a daños celulares y tisulares.
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