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TNF-RII y c-IAP1 median la ubiquitinación y la degradación de TRAF2

Xiaoming Li¹, Yili Yang, Jonathan D Ashwell

¹Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

|March 22, 2002

Resumen

El factor de necrosis tumoral alfa (TNF-alfa) que se une al TNF-RII desencadena la ubiquitinación y degradación de TRAF2 a través de la actividad de la ligasa c-IAP1 E3. Este mecanismo potencia la apoptosis inducida por el TNF, revelando un papel clave para c-IAP1 en las vías de señalización del TNF.

Área de la Ciencia:

La señalización celular de las células.
Inmunología Inmunología.
Biología molecular La biología molecular.

Sus antecedentes:

El factor de necrosis tumoral alfa (TNF-alfa) es un mediador inflamatorio clave que se une a los receptores TNF (TNF-RI, TNF-RII).
La señalización del receptor TNF involucra proteínas adaptadoras como los factores asociados con TNF-R (TRAF), incluido TRAF2, crucial para la activación de JNK, la activación de NF-kappaB y las señales antiapoptóticas.
Los inhibidores de la apoptosis (IAP), como c-IAP1 y c-IAP2, poseen actividad de E3 ubiquitina ligasa, pero su papel en la señalización del receptor TNF sigue sin estar claro.

Objetivo del estudio:

Para investigar la función de los IAP, específicamente c-IAP1, en la señalización del receptor TNF.
Para dilucidar el mecanismo por el cual c-IAP1 influye en la estabilidad de TRAF2 y las respuestas celulares mediadas por TNF-alfa.
Para determinar si la actividad de c-IAP1 es esencial para la apoptosis inducida por el TNF.

Principales métodos:

Investigó la interacción entre TNF-RII, TRAF2 y c-IAP1 sobre la estimulación del TNF-alfa.
Se evaluó la ubiquitinación de TRAF2 y la degradación proteasómica en presencia de c-IAP1.1.
Se utilizaron mutantes c-IAP1 de tipo salvaje y E3 defectuosos para evaluar su impacto en la degradación de TRAF2 y la apoptosis.

Principales resultados:

La unión de TNF-alfa al TNF-RII indujo la ubiquitinación y la degradación proteasómica de TRAF2.
c-IAP1 se unía directamente al TRAF2 y mediaba su ubiquitinación, dependiendo de su actividad de E3 ligasa.
La expresión del tipo silvestre c-IAP1 condujo a la ubiquitinación y degradación de TRAF2, mientras que un mutante E3 defectuoso inhibió la degradación y apoptosis de TRAF2 inducida por el TNF-alfa.

Conclusiones:

Se identificó un papel fisiológico para c-IAP1 en la señalización del receptor TNF.
Se estableció un mecanismo en el que la actividad de la ligasa de ubiquitina c-IAP1 regulada por TNF-RII promueve la degradación de TRAF2.
Se demostró que esta degradación de TRAF2 mediada por c-IAP1 potencia la apoptosis inducida por el TNF.

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