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Las señales opuestas de respuesta de proteína desplegada convergen en el receptor de muerte 5 para controlar la
Min Lu1, David A Lawrence1, Scot Marsters1
1Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Science (New York, N.Y.)
|July 5, 2014
Resumen
El estrés en el retículo endoplasmático (ER) desencadena la respuesta proteica desplegada (UPR). La RPU persistente activa el receptor de muerte 5 (DR5) para inducir la apoptosis, vinculando el estrés ER con la muerte celular.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- Fisiología Fisiología Fisiología.
Sus antecedentes:
- El plegamiento de las proteínas en el retículo endoplasmático (ER) es vital para la función celular.
- El estrés ER interrumpe el plegamiento de las proteínas, lo que lleva a la enfermedad.
- La respuesta proteica desplegada (UPR, por sus siglas en inglés) intenta restaurar la homeostasis del ER.
Objetivo del estudio:
- Para dilucidar los mecanismos por los cuales el estrés ER persistente induce la muerte celular apoptótica.
- Para investigar el papel del receptor de la muerte 5 (DR5) en la apoptosis inducida por el estrés ER.
Principales métodos:
- Investigó el papel de los mediadores de la UPR CHOP e IRE1α en la regulación del DR5.
- Analizó la transcripción de DR5 y la dinámica de desintegración del ARNm bajo estrés ER.
- Se examinó la activación DR5 independiente de los ligandos y el compromiso de la caspasa-8.
Principales resultados:
- El estrés ER no mitigado activa la apoptosis celular autónoma a través del DR5.5 controlado por UPR.
- CHOP media la transcripción de DR5, mientras que IRE1α degrada transitoriamente el ARNm DR5.
- El estrés ER persistente conduce a la acumulación de proteína DR5 intracelular, lo que conduce a la apoptosis.
Conclusiones:
- DR5 actúa como un mediador crítico de la apoptosis en respuesta al estrés ER sostenido.
- El UPR integra señales opuestas para controlar la expresión de DR5 y el destino celular.
- La activación de DR5 acopla el estrés ER a las vías programadas de muerte celular.
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