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SUMOylation regulates nucleo-cytoplasmic shuttling of Elk-1

¹ Institut de Génétique Moléculaire de Montpellier, UMR5535
² Centre de Recherches en Biochimie Macromoléculaire, FRE2593, Centre National de la Recherche Scientifique, IFR122, 34293 Montpellier, Cedex 05, France

Address correspondence to Robert A. Hipskind, Institut de Génétique Moléculaire de Montpellier, 1919 Route de Mende, 34293 Montpellier, Cedex 05, France. Tel.: 33-46-761-3667. Fax: 33-46-704-0231. email: hipskind{at}igm.cnrs-mop.fr

Abstract

The transcription factor Elk-1 is a nuclear target of mitogen-activated protein kinases and regulates immediate early gene activation by extracellular signals. We show that Elk-1 is also conjugated to SUMO on either lysines 230, 249, or 254. Mutation of all three sites is necessary to fully block SUMOylation in vitro and in vivo. This Elk-1 mutant, Elk-1(3R), shuttles more rapidly to nuclei of Balb/C cells fused to transfected HeLa cells. Coexpression of SUMO-1 or -2 strongly reduces shuttling by Elk-1 without affecting that of Elk-1(3R), indicating that SUMOylation regulates nuclear retention of Elk-1. Accordingly, overexpression of Elk-1(3R) in PC12 cells, where cytoplasmic relocalization of Elk-1 has been linked to differentiation, enhances neurite extension relative to Elk-1. The effect of Elk-1, but not of the 3R mutant, was blocked upon cotransfection with SUMO-1 or -2 and enhanced by coexpression with mutant Ubc-9. Thus, SUMO conjugation is a novel regulator of Elk-1 function through the control of its nuclear-cytoplasmic shuttling.

Key Words: Elk-1; SUMO; neuronal differentiation; nuclear localization

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