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La preasociación de Fas requerida para la señalización de la apoptosis y la inhibición dominante por mutaciones
R M Siegel1, J K Frederiksen, D A Zacharias
1Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Science (New York, N.Y.)
|July 6, 2000
Resumen
Las mutaciones en el receptor Fas interrumpen la apoptosis de los linfocitos en el síndrome linfoproliferativo autoinmune al causar interacciones independientes de los ligandos. Los complejos Fas preformados son esenciales para la señalización Fas y la enfermedad, revelando un nuevo mecanismo en los trastornos autoinmunes humanos.
Área de la Ciencia:
- Inmunología Inmunología.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- El síndrome linfoproliferativo autoinmune (ALPS) se caracteriza por una apoptosis linfocítica deteriorada.
- Las mutaciones heterocigotas en el receptor Fas están implicadas en la interferencia dominante con la apoptosis inducida por Fas.
- El mecanismo preciso de esta interferencia dominante aún no se entiende por completo.
Objetivo del estudio:
- Investigar el mecanismo por el cual las mutaciones heterocigotas de Fas interfieren con la apoptosis linfocítica inducida por Fas en el ALPS.
- Para determinar si la oligomerización del receptor inducida por ligando o las interacciones independientes del ligando son responsables de la interferencia dominante.
- Para aclarar el papel de los complejos de receptores de Fas preformados en la señalización de Fas y la patogénesis de ALPS.
Principales métodos:
- Utilizó la transferencia de energía de resonancia de fluorescencia (FRET) entre variantes de proteína fluorescente verde (GFP) para detectar interacciones de receptores en células vivas.
- Se analizaron las interacciones independientes de los ligandos entre los receptores de tipo salvaje y los receptores de Fas mutantes.
- Investigó el papel de dominios extracelulares específicos en la asociación de receptores.
Principales resultados:
- Se demostró que la interferencia dominante por los receptores Fas mutantes no depende de la oligomerización inducida por ligandos.
- Se identificó una interacción ligando-independiente entre los receptores Fas de tipo salvaje y mutantes a través de una región específica del dominio extracelular.
- Se observaron complejos de Fas preasociados en células vivas utilizando FRET, lo que indica su formación antes de la unión de ligando.
Conclusiones:
- La formación de complejos de receptores Fas preasociados es un paso necesario para la señalización Fas.
- Las interacciones independientes de ligandos entre los receptores Fas de tipo salvaje y los receptores Fas mutantes impulsan la interferencia dominante en el ALPS humano.
- Estos hallazgos revelan un nuevo mecanismo de patogénesis de la enfermedad en la ALPS y resaltan la importancia de los complejos de receptores preformados en la señalización mediada por receptores.
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