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Molecular and Cellular Biology, August 2005, p. 6964-6979, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6964-6979.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Down-Regulation of c-Fos/c-Jun AP-1 Dimer Activity by Sumoylation

Guillaume Bossis,1,{dagger} Cécile E. Malnou,1,{dagger} Rosa Farras,1 Elisabetta Andermarcher,1 Robert Hipskind,1 Manuel Rodriguez,4 Darja Schmidt,3 Stefan Muller,3 Isabelle Jariel-Encontre,1* and Marc Piechaczyk1*

Institute of Molecular Genetics of Montpellier, UMR5535/IFR122, CNRS 1919, Route de Mende, 34293 Montpellier Cedex 05, France,1 Jacques Monod Institute 2, Place Jussieu, 75005 Paris, France,2 University of St. Andrews, North Haugh, St. Andrews, Fife KY169ST, Scotland,4 Max Planck Institute of Biochemistry, Department of Molecular Cell Biology, Am Klopferspitz 18, D-82152 Martinsried, Germany3

Received 26 February 2004/ Returned for modification 16 April 2004/ Accepted 13 May 2005

The inducible transcriptional complex AP-1, composed of c-Fos and c-Jun proteins, is crucial for cell adaptation to many environmental changes. While its mechanisms of activation have been extensively studied, how its activity is restrained is poorly understood. We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers. Using nonsumoylatable mutants of c-Fos and c-Jun as well as a chimeric protein mimicking sumoylated c-Fos, we show that sumoylation entails lower AP-1 transactivation activity. Interestingly, single sumoylation at any of the three acceptor sites of the c-Fos/c-Jun dimer is sufficient to substantially reduce transcription activation. The lower activity of sumoylated c-Fos is not due to inhibition of protein entry into the nucleus, accelerated turnover, and intrinsic inability to dimerize or to bind to DNA. Instead, cell fractionation experiments suggest that decreased transcriptional activity of sumoylated c-Fos is associated with specific intranuclear distribution. Interestingly, the phosphorylation of threonine 232 observed upon expression of oncogenically activated Ha-Ras is known to superactivate c-Fos transcriptional activity. We show here that it also inhibits c-Fos sumoylation, revealing a functional antagonism between two posttranslational modifications, each occurring within a different moiety of a bipartite transactivation domain of c-Fos. Finally we report that the sumoylation of c-Fos is a dynamic process that can be reversed via multiple mechanisms. This supports the idea that this modification does not constitute a final inactivation step that necessarily precedes protein degradation.

* Corresponding author. Mailing address: Institute of Molecular Genetics of Montpellier, UMR5535/IFR122, CNRS 1919, Route de Mende, 34293 Montpellier Cedex 05, France. Phone: 33-4 67 61 36 68. Fax: 33-4 67 04 02 31. E-mail: marc.piechaczyk{at}igmm.cnrs.fr; isabelle.jariel{at}igmm.cnrs.fr.

{dagger} Equally contributing authors.

Molecular and Cellular Biology, August 2005, p. 6964-6979, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.6964-6979.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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