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Una vía dependiente de la SUMOilación media la transrepresión de los genes de respuesta inflamatoria por PPAR-gamma
Gabriel Pascual1, Amy L Fong, Sumito Ogawa
1Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Nature
|August 30, 2005
Resumen
Los agonistas del receptor gamma activado por el proliferador peroxisomático (PPAR-gamma) reprimen los genes inflamatorios mediante el reclutamiento de corepresores para atacar a los promotores de genes. Este mecanismo explica cómo el PPAR-gamma se convierte de un activador a un represor, afectando la inmunidad y la homeostasis.
Área de la Ciencia:
- Biología Molecular Biología Molecular
- Biología celular Biología celular.
- Inmunología Inmunología.
Sus antecedentes:
- El receptor-gamma activado por el proliferador peroxisomático (PPAR-gamma) es crucial para la adipogénesis y la homeostasis de la glucosa, objetivo de los medicamentos sensibilizantes a la insulina.
- Los efectos antiinflamatorios de los agonistas de PPAR-gamma a través de la transrepresión del factor nuclear kappa B (NF-kappaB) están relacionados con las acciones antidiabéticas y antiaterogénicas, pero permanecen mecánicamente poco claros.
Objetivo del estudio:
- Para dilucidar la vía molecular por la cual PPAR-gamma reprime la transcripción de genes inflamatorios en los macrófagos de ratón.
- Identificar los pasos iniciales y los actores moleculares clave involucrados en la represión génica mediada por PPAR-gamma.
Principales métodos:
- Se ha investigado la SUMOilación ligando-dependiente del dominio de unión de ligando PPAR-gamma.
- Examinó la orientación de PPAR-gamma hacia el corepresor del receptor nuclear (NCoR) - complejos de histona deacetilasa-3 (HDAC3) en promotores de genes inflamatorios.
- Se evaluó el impacto en el reclutamiento de la ubiquitación/19S en la maquinaria proteasómica y la eliminación del complejo corepresor.
Principales resultados:
- El PPAR-gamma unido a los ligandos se somete a SUMOilación, dirigiéndolo a los complejos NCoR-HDAC3 en los promotores de genes inflamatorios.
- Este reclutamiento impide que la maquinaria del proteasoma de ubicuidad/19S elimine los complejos corepresor.
- En consecuencia, los complejos NCoR permanecen unidos, manteniendo los genes objetivo en un estado reprimido.
Conclusiones:
- Una nueva vía revela cómo el PPAR-gamma ligado al agonista actúa como un represor específico del promotor de los genes diana de NF-kappaB.
- Este mecanismo explica la conversión de PPAR-gamma de un activador de la transcripción a un represor.
- Los hallazgos ofrecen información sobre la regulación de la inmunidad y la homeostasis por PPAR-gamma.
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