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Molecular and Cellular Biology, August 2007, p. 5554-5564, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01811-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

SUMO Modification Regulates MafB-Driven Macrophage Differentiation by Enabling Myb-Dependent Transcriptional Repression

Silke Tillmanns ,^1,2,3,, Claas Otto,^1,2,3, Ellis Jaffray,⁴ Camille Du Roure,^1,2,3,¶ Youssef Bakri,^1,2,3,5 Laurent Vanhille,^1,2,3 Sandrine Sarrazin,^1,2,3 Ronald T. Hay,⁴ and Michael H. Sieweke^1,2,3*

Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France,¹ Institut National de la Santé et de la Recherche Médicale, Marseille, France,² Centre National de la Recherche Scientifique, Marseille, France,³ James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, United Kingdom,⁴ Laboratoire de Biochimie-Immunologie, JER3012, Agence Universitaire Francophone, Faculté des Sciences, Rabat, Morocco⁵

Received 24 September 2006/ Returned for modification 6 November 2006/ Accepted 16 May 2007

During the execution of differentiation programs, lineage-specific transcription factors are in competition with antagonistic factors that drive progenitor proliferation. Thus, the myeloid transcription factor MafB promotes macrophage differentiation of myeloid progenitors, but a constitutively active Myb transcription factor (v-Myb) can maintain proliferation and block differentiation. Little is known, however, about the regulatory mechanisms that control such competing activities. Here we report that the small ubiquitin-like protein SUMO-1 can modify MafB in vitro and in vivo on lysines 32 and 297. The absence of MafB SUMO modification increased MafB-driven transactivation and macrophage differentiation potential but inhibited cell cycle progression and myeloid progenitor growth. Furthermore, we observed that direct repression of MafB transactivation by v-Myb was strictly dependent on MafB SUMO modification. Consequently, a SUMOylation-deficient MafB K32R K297R (K32,297R) mutant could specify macrophage fate even after activation of inducible Myb alleles and resist their differentiation-inhibiting activity. Our findings suggest that SUMO modification of MafB affects the balance between myeloid progenitor expansion and terminal macrophage differentiation by controlling MafB transactivation capacity and susceptibility to Myb repression. SUMO modification of lineage-specific transcription factors may thus modulate transcription factor antagonism to control tissue homeostasis in the hematopoietic system.

Published ahead of print on 4 June 2007.

Present address: Institut für Humangenetik, Charité Campus Virchow Klinikum, Forum 4 Augustenburger Platz 1, 13353 Berlin, Germany.

These authors contributed equally to this work.

^¶ Present address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.