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Bcl-x(L) retrotransloca a Bax desde las mitocondrias hacia el citosol

Frank Edlich¹, Soojay Banerjee, Motoshi Suzuki

¹Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.

|April 5, 2011

Resumen

Las proteínas Bcl-2 de Prosurvival, como Bcl-x(L), inhiben la apoptosis al devolver constantemente Bax de las mitocondrias al citosol. Este mecanismo de retrotranslocación mantiene a Bax en su estado citosólico inactivo.

Área de la Ciencia:

Biología Molecular Biología Molecular
Biología celular Biología celular.
La bioquímica es la bioquímica.

Sus antecedentes:

La proteína Bax inicia la apoptosis trasladándose a las mitocondrias y permeabilizando la membrana externa.
Las proteínas Bcl-2 de Prosurvival contrarrestan a Bax, pero su mecanismo inhibidor no está claro debido a la falta de complejos estables o colocalización.
Comprender la regulación de Bax es crucial para controlar la muerte celular programada.

Objetivo del estudio:

Investigar el mecanismo por el cual las proteínas Bcl-2 de la prosurvivencia inhiben la apoptosis mediada por Bax.
Para determinar si la retrotranslocación de Bax desde las mitocondrias es un paso regulador clave.
Para aclarar el papel de Bcl-x(L) en el mantenimiento de Bax en el citosol.

Principales métodos:

Utilizó ataduras intramoleculares de disulfuro para restringir Bax en su conformación citosólica nativa dentro de las células.
Se empleó la pérdida de fluorescencia en el foto blanqueamiento (FLIP) para rastrear la dinámica de la translocación de Bax.
Se evaluó la actividad de permeabilización de la membrana externa mitocondrial (MOMP) in vitro y en células.

Principales resultados:

Las ataduras de Bax interrumpieron la interacción Bcl-x(L) y la actividad de MOMP libre de células, pero causaron la acumulación de Bax en las mitocondrias.
FLIP demostró una retrotranslocación constante de Bax de tipo salvaje desde las mitocondrias hasta el citoplasma en células sanas.
Tethered Bax mostró una reducción significativa de la retrotranslocación, que se correlaciona con la acumulación mitocondrial.
La retrotranslocación de Bax fue dependiente de las proteínas de la familia Bcl-2 de prosurvivencia.

Conclusiones:

Las proteínas Bcl-2 de Prosurvival, específicamente Bcl-x(L), inhiben a Bax facilitando su constante retrotranslocación desde las mitocondrias de regreso al citosol.
Esta retrotranslocación continua es un mecanismo primario para mantener a Bax en su estado citosólico inactivo y prevenir la apoptosis.
Dirigirse a la retrotranslocación de Bax podría ofrecer nuevas estrategias terapéuticas para enfermedades que involucran apoptosis aberrante.

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