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SUMOylation Regulates the Transcriptional Activity of JunB in T Lymphocytes¹

Institut de Génétique Moléculaire de Montpellier, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5535, Montpellier, France

The AP-1 family member JunB is a critical regulator of T cell function. JunB is a transcriptional activator of various cytokine genes, such as IL-2, IL-4, and IL-10; however, the post-translational modifications that regulate JunB activity in T cells are poorly characterized. We show here that JunB is conjugated with small ubiquitin-like modifier (SUMO) on lysine 237 in resting and activated primary T cells and T cell lines. Sumoylated JunB associated with the chromatin-containing insoluble fraction of cells, whereas nonsumoylated JunB was also in the soluble fraction. Blocking JunB sumoylation by mutation or use of a dominant-negative form of the SUMO-E2 Ubc-9 diminished its ability to transactivate IL-2 and IL-4 reporter genes. In contrast, nonsumoylable JunB mutants showed unimpaired activity with reporter genes controlled by either synthetic 12-O-tetradecanoylphorbol-13-acetate response elements or NF-AT/AP-1 and CD28RE sites derived from the IL-2 promoter. Ectopic expression of JunB in activated human primary CD4⁺ T cells induced activation of the endogenous IL-2 promoter, whereas the nonsumoylable JunB mutant did not. Thus, our work demonstrates that sumoylation of JunB regulates its ability to induce cytokine gene transcription and likely plays a critical role in T cell activation.

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 This work was supported by the l’Institut National du Cancer/Cancéropôle Grand Sud-Ouest (to M.V.), "La Ligue Nationale Contre le Cancer. Comité de la Lozère" (to M.V.), "Association pour la Recherche sur le Cancer" (to R.A.H.), and fellowships from "La Ligue Nationale Contre le Cancer. Comite Nationale" (to J.G.) and "La Ligue Nationale Contre le Cancer. Region Languedoc-Rousillon" (to S.C.). M.P. is an "Equipe labellisée" by the "La Ligue Nationale Contre le Cancer". R.F. was a Human Frontier Science Program postdoctoral fellow.

² Address correspondence and reprint requests to Dr. Johan Garaude or Dr. Martin Villalba, Institut de Génétique Moléculaire de Montpellier, 1919 route de Mende, 34293 Montpellier cedex 5, France. E-mail addresses: martin.villalba{at}igmm.cnrs.fr and jgaraude{at}gmail.com

³ Current address: Mount Sinai Medical School, New York, NY 10029.

⁴ Current address: Centro de Investigación Príncipe Felipe, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.

⁵ Abbreviations used in this paper: TPA, 12-O-tetradecanoylphorbol-13-acetate; SUMO, small ubiquitin-like modifier; TRE, TPA response element; HA, hemagglutinin; wt, wild type; DN, dominant negative; NEM, N-ethylmaleimide; Q-PCR, quantitative-PCR; IMAC, immobilized metal affinity chromatography.