Efficient nuclear export of p65-IkappaBalpha complexes requires 14-3-3 proteins.

Abstract:

:IkappaB are responsible for maintaining p65 in the cytoplasm under non-stimulating conditions and promoting the active export of p65 from the nucleus following NFkappaB activation to terminate the signal. We now show that 14-3-3 proteins regulate the NFkappaB signaling pathway by physically interacting with p65 and IkappaBalpha 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 IkappaBalpha in residues 60-65. Mutation of these 14-3-3 binding domains in p65 or IkappaBalpha results in a predominantly nuclear distribution of both proteins. TNFalpha treatment promotes recruitment of 14-3-3 and IkappaBalpha to NFkappaB-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-IkappaBalpha complexes and the constitutive association of p65 with the chromatin. In this situation, NFkappaB-dependent genes become unresponsive to TNFalpha stimulation. Together our results indicate that 14-3-3 proteins facilitate the nuclear export of IkappaBalpha-p65 complexes and are required for the appropriate regulation of NFkappaB signaling.

journal_name

J Cell Sci

journal_title

Journal of cell science

authors

Aguilera C,Fernández-Majada V,Inglés-Esteve J,Rodilla V,Bigas A,Espinosa L

doi

10.1242/jcs.03086

subject

Has Abstract

pub_date

2006-09-01 00:00:00

pages

3695-704

issue

Pt 17

eissn

0021-9533

issn

1477-9137

pii

119/17/3695

journal_volume

119

pub_type

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