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First published online August 24, 2006
doi: 10.1242/10.1242/jcs.03086

Journal of Cell Science 119, 3695-3704 (2006)
Published by The Company of Biologists 2006
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Research Article

Efficient nuclear export of p65-I{kappa}B{alpha} complexes requires 14-3-3 proteins

Cristina Aguilera, Vanessa Fernández-Majada, Julia Inglés-Esteve, Verónica Rodilla, Anna Bigas* and Lluís Espinosa*

Centre Oncologia Molecular, IDIBELL-Institut de Recerca Oncologica, Gran Via km 2.7, Hospitalet, Barcelona 08907, Spain

* Authors for correspondence (e-mail: abigas{at}iro.es; llespinosa{at}iro.es)

Accepted 6 June 2006

I{kappa}B are responsible for maintaining p65 in the cytoplasm under non-stimulating conditions and promoting the active export of p65 from the nucleus following NF{kappa}B activation to terminate the signal. We now show that 14-3-3 proteins regulate the NF{kappa}B signaling pathway by physically interacting with p65 and I{kappa}B{alpha} proteins. We identify two functional 14-3-3 binding domains in the p65 protein involving residues 38-44 and 278-283, and map the interaction region of I{kappa}B{alpha} in residues 60-65. Mutation of these 14-3-3 binding domains in p65 or I{kappa}B{alpha} results in a predominantly nuclear distribution of both proteins. TNF{alpha} treatment promotes recruitment of 14-3-3 and I{kappa}B{alpha} to NF{kappa}B-dependent promoters and enhances the binding of 14-3-3 to p65. Disrupting 14-3-3 activity by transfection with a dominant-negative 14-3-3 leads to the accumulation of nuclear p65-I{kappa}B{alpha} complexes and the constitutive association of p65 with the chromatin. In this situation, NF{kappa}B-dependent genes become unresponsive to TNF{alpha} stimulation. Together our results indicate that 14-3-3 proteins facilitate the nuclear export of I{kappa}B{alpha}-p65 complexes and are required for the appropriate regulation of NF{kappa}B signaling.

Key words: NF{kappa}B, I{kappa}B{alpha}, 14-3-3, Nuclear export, TNF{alpha}


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JCS 2006 119: 1703. [Full Text]  



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