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Los estímulos proinflamatorios inducen la fosforilación mediada por IKKalpha de PIAS1 para restringir la inflamación
Bin Liu1, Yonghui Yang, Vasili Chernishof
1Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Cell
|June 2, 2007
Resumen
Las señales inflamatorias activan IKKalpha para fosforilar PIAS1, un regulador clave que reprime la inflamación al bloquear la activación del gen. Esta fosforilación es esencial para el PIAS1.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- El Reglamento de transcripción es el Reglamento de transcripción.
Sus antecedentes:
- Los mecanismos por los cuales los estímulos inflamatorios señalan al núcleo para restringir la inflamación no se comprenden completamente.
- El inhibidor de la proteína de STAT1 activado (PIAS1) es un regulador transcripcional con una pequeña actividad de la ligasa E3 del modificador relacionado con la ubiquitina (SUMO), que inhibe las respuestas inmunes al bloquear la unión de NF-kappaB y STAT1 a los promotores de genes.
Objetivo del estudio:
- Para aclarar la vía de señalización por la cual los estímulos inflamatorios conducen a la represión nuclear de la inflamación.
- Para investigar el papel de la fosforilación de PIAS1 en la regulación de la activación del gen inflamatorio.
Principales métodos:
- Se utilizaron estudios de mutación para evaluar la función de la fosforilación de PIAS1 en Ser90.
- Empleó tratamiento con TNF y analizó la asociación de PIAS1 de tipo salvaje y mutante con promotores de genes.
- Interacciones in vivo investigadas entre IKKalpha, IKKbeta y PIAS1.
Principales resultados:
- PIAS1 se fosforila rápidamente en Ser90 en respuesta a estímulos inflamatorios.
- La fosforilación de Ser90 es crítica para la actividad de represión transcripcional de PIAS1.
- El PIAS1 de tipo salvaje, pero no el mutante Ser90A, se asocia con los promotores del gen diana NF-kappaB tras el tratamiento con TNF.
- IKKalpha, no IKKbeta, interactúa con PIAS1 y media la fosforilación de Ser90, dependiendo de la actividad de la ligasa SUMO de PIAS1.
Conclusiones:
- Identificó una vía de señalización donde los estímulos inflamatorios activan IKKalpha.
- IKKalpha media la fosforilación dependiente de la sumoilación de PIAS1 en el Ser90.
- Este proceso conduce a la represión inmediata de la activación del gen inflamatorio por PIAS1.
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