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El COP9 señalosoma regula la maduración del autofagosoma
Huabo Su1, Faqian Li, Mark J Ranek
1Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 E Clark Street, Vermillion, SD 57069, USA..
Circulation
|October 12, 2011
Resumen
La subunidad 8 (Csn8) del señalosoma (CSN) COP9 regula la autofagia selectiva y la maduración de los autofagosomas. El agotamiento de Csn8 deteriora la eliminación del autofagosoma, lo que lleva a la necrosis de los cardiomiocitos.
Área de la Ciencia:
- Biología celular Biología celular.
- Biología Molecular Biología Molecular
- Biología Cardiovascular Biología Cardiovascular
Sus antecedentes:
- La autofagia es crucial para la homeostasis celular y la patología de la enfermedad.
- Los mecanismos de regulación selectiva de la autofagia no se comprenden completamente.
- El señalosoma COP9 (CSN) regula el sistema ubiquitina-proteasoma, pero se desconoce su papel en la autofagia.
Objetivo del estudio:
- Para investigar el papel de la subunidad 8 (Csn8) de la CNS en la autofagia.
- Para determinar si la CSN juega un papel en la regulación selectiva de la autofagia.
Principales métodos:
- Ratones de knockout restringidos por cardiomiocitos generados para Csn8 (CR-Csn8KO).
- Se evaluaron los marcadores del autofagosoma (LC3-II, p62) y el flujo autofágico.
- Utilizó GFP-LC3, microscopía electrónica y análisis de expresión Rab7.
- Efectos investigados de la deficiencia de Csn8 y la reducción de Rab7 en la muerte de los cardiomiocitos.
Principales resultados:
- El agotamiento de Csn8 en los cardiomiocitos aumentó los niveles de LC3-II y p62, lo que indica una acumulación de autofagosomas.
- La eliminación defectuosa del autofagosoma, no la formación deteriorada, causó la acumulación.
- Se observó un deterioro en la maduración de los autofagosomas y una regulación a la baja de Rab7.
- Los corazones con deficiencia de Csn8 mostraron un aumento de la necrosis de los cardiomiocitos, vinculada a la alteración de la maduración de los autofagosomas.
Conclusiones:
- Csn8 y el complejo CSN son reguladores clave de la autofagia selectiva, no sólo el sistema proteasómico.
- Csn8 regula críticamente la maduración del autofagosoma, probablemente a través de la expresión de Rab7.
- El fracaso en la maduración del autofagosoma conduce a la necrosis de los cardiomiocitos.
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