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J. Biol. Chem., Vol. 280, Issue 45, 38035-38046, November 11, 2005

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FLI-1 Functionally Interacts with PIASx, a Member of the PIAS E3 SUMO Ligase Family^*

Emile van den Akker1, Sabine Ano12, Hsiu-Ming Shih, Ling-Chi Wang, Martine Pironin, Jorma J. Palvimo¶, Noora Kotaja||, Olivier Kirsh**, Anne Dejean**, and Jacques Ghysdael3

From the Institut Curie, CNRS UMR 146, 91405 Orsay, France, the Institute of Biomedical Sciences, Academia Sinica, 11529 Taipei, Taiwan, the ^¶Department of Medical Biochemistry, University of Kuopio, FIN 70211 Kuopio, Finland, the ^||Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, FIN 00014 Helsinki, Finland, and the ^**Institut Pasteur, INSERM U579, 75015 Paris, France

FLI-1 is a transcription factor of the ETS family that is involved in several developmental processes and that becomes oncogenic when overexpressed or mutated. As the functional regulators of FLI-1 are largely unknown, we performed a yeast two-hybrid screen with FLI-1 and identified the SUMO E3 ligase PIASx/ARIP3 as a novel in vitro and in vivo binding partner of FLI-1. This interaction involved the ETS domain of FLI-1 and required the integrity of the SAP domain of PIASx/ARIP3. SUMO-1 and Ubc9, the ubiquitin carrier protein component in the sumoylation pathway, were also identified as interactors of FLI-1. Both PIASx/ARIP3 and the closely related PIASx isoform specifically enhanced sumoylation of FLI-1 at Lys⁶⁷, located in its N-terminal activation domain. PIASx/ARIP3 relocalized the normally nuclear but diffusely distributed FLI-1 protein to PIASx nuclear bodies and repressed FLI-1 transcriptional activation as assessed using different ETS-binding site-dependent promoters and different cell systems. PIASx repressive activity was independent of sumoylation and did not result from inhibition of FLI-1 DNA-binding activity. Analysis of the properties of a series of ARIP3 mutants showed that the repressive properties of PIASx/ARIP3 require its physical interaction with FLI-1, identifying PIASx as a novel corepressor of FLI-1.

Received for publication, March 17, 2005 , and in revised form, August 23, 2005.

^* This work was supported in part by CNRS, the Institut Curie, the Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue 2004), and the Association for International Cancer Research (to J. G.) and by the Academy of Finland (to J. J. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported by a predoctoral fellowship from the Ministère de l' Education Nationale et de la Recherche and the Association pour la Recherche contre le Cancer.

³ To whom correspondence should be addressed: Institut Curie, Centre Universitaire, CNRS UMR 146, Bat. 110, 91405 Orsay, France. Tel.: 33-1-6986-3152; Fax: 33-1-6907-4525; E-mail: Jacques.Ghysdael{at}curie.u-psud.fr.

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