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Translocación citoplasmática esencial de un complejo de señalización ensamblado por un receptor de citoquinas
Atsushi Matsuzawa1, Ping-Hui Tseng, Sivakumar Vallabhapurapu
1Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
Science (New York, N.Y.)
|July 19, 2008
Resumen
La señalización de citocinas implica un complejo ensamblaje en los receptores. La activación de la quinasa requiere que este complejo se mueva al citosol después de la degradación de TRAF3, separando las vías de señalización.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología celular Biología celular.
- La señalización molecular.
Sus antecedentes:
- La señalización de citocinas se basa en la activación de la proteína quinasa receptor-próxima dentro de complejos multicomponentes.
- El receptor del factor de necrosis tumoral (TNFR), miembro de la familia CD40, inicia la señalización a través de la formación de complejos.
Objetivo del estudio:
- Para dilucidar el mecanismo del ensamblaje del complejo de señalización inducido por CD40 y la activación de la quinasa.
- Para investigar el papel de las moléculas adaptadoras específicas y la degradación de proteínas en la transducción de señales.
Principales métodos:
- Investigó la formación de complejos de señalización CD40 en respuesta a la unión de ligandos.
- Utilizó co-inmunoprecipitación y Western blotting para identificar las proteínas que interactúan y evaluar la actividad de la quinasa.
- Se examinó el impacto de la degradación de TRAF3 en la localización del complejo de señalización y la activación de la quinasa aguas abajo.
Principales resultados:
- CD40 forma un complejo con TRAF2, TRAF3, Ubc13, c-IAP1/2, IKKgamma (NEMO) y MEKK1 después de la ligadura.
- TRAF2, Ubc13 e IKKgamma son esenciales para el ensamblaje complejo y la activación en cascada de MEKK1/MAPK.
- La activación de la quinasa depende de la translocación del complejo de señalización al citosol, mediada por la degradación de TRAF3 inducida por c-IAP1/2.
Conclusiones:
- Un mecanismo de señalización en dos etapas gobierna la señalización de citoquinas mediada por CD40.
- Este mecanismo implica un ensamblaje complejo inicial en el receptor seguido de una translocación citosólica, lo que permite la separación espacial y temporal de la señalización MAPK e IKK.
- Este modelo puede ser aplicable a otras vías de señalización de los receptores inmunes innatos.
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