Tillmanns Silke, Otto Claas, Jaffray Ellis, Du Roure Camille, Bakri Youssef, Vanhille Laurent, Sarrazin Sandrine, Hay Ronald T, Sieweke Michael H
Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France.
Mol Cell Biol. 2007 Aug;27(15):5554-64. doi: 10.1128/MCB.01811-06. Epub 2007 Jun 4.
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.
在分化程序执行过程中，谱系特异性转录因子与驱动祖细胞增殖的拮抗因子相互竞争。因此，髓系转录因子MafB促进髓系祖细胞向巨噬细胞分化，但组成型活性Myb转录因子（v-Myb）可维持增殖并阻断分化。然而，对于控制这种竞争活性的调控机制知之甚少。在此，我们报告小泛素样蛋白SUMO-1可在体外和体内对MafB的赖氨酸32和297进行修饰。MafB SUMO修饰的缺失增加了MafB驱动的反式激活和巨噬细胞分化潜能，但抑制了细胞周期进程和髓系祖细胞生长。此外，我们观察到v-Myb对MafB反式激活的直接抑制严格依赖于MafB SUMO修饰。因此，即使在诱导型Myb等位基因激活后，SUMO化缺陷的MafB K32R K297R（K32,297R）突变体仍可决定巨噬细胞命运，并抵抗其分化抑制活性。我们的研究结果表明，MafB的SUMO修饰通过控制MafB反式激活能力和对Myb抑制的敏感性，影响髓系祖细胞扩增与终末巨噬细胞分化之间的平衡。因此，谱系特异性转录因子的SUMO修饰可能调节转录因子拮抗作用，以控制造血系统中的组织稳态。
