SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ
SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ
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DOI：
10.1182/blood-2011-04-347930
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发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Vinkemeier, Uwe
中科院分区：
文献类型：
--
作者：
Begitt, Andreas;Droescher, Mathias;Vinkemeier, Uwe
IFN γ 的生物学效应由转录因子 STAT1 介导。 STAT1 的活性受到小泛素样修饰剂 (SUMO) 结合的抑制。这既可以直接通过降低 STAT1 酪氨酸磷酸化来实现，也可以间接通过促进 STAT1 去磷酸化来实现，后者会因副晶体组装受到抑制而导致 STAT1 溶解度增加。然而，SUMO 结合的生理学意义仍不清楚。在这里，我们使用表达无 SUMO STAT1 的敲入小鼠的成纤维细胞和骨髓源性巨噬细胞 (BMM) 来探索 STAT1 sumoylation 对 IFN γ 信号传导的影响。我们的实验证明了副晶体对激活的 STAT1 具有缓冲特性，因此 SUMO 介导的副晶体分散显着降低了 STAT1 的磷酸化，从而影响了激活酪氨酸 701 和转录增强丝氨酸 727。因此，SUMO 缀合导致细胞核中 STAT1 活性的减少导致 IFN γ 反应基因的转录减少；并将在骨髓来源的巨噬细胞中触发脂多糖诱导的细胞毒性所需的 IFN γ 浓度提高了 100 倍以上。这些实验确定了 STAT1 的 SUMO 结合是一种永久减弱细胞 IFN γ 敏感性的机制，从而防止对这种细胞因子的过度反应及其潜在的自我毁灭性后果。这将 SUMO 介导的抑制模式与迄今为止已知的其他负 STAT 调节因子区分开来。 （血。2011；118（4）：1002-1007）
The biologic effects of IFN gamma are mediated by the transcription factor STAT1. The activity of STAT1 is inhibited by small ubiquitin-like modifier (SUMO) conjugation. This occurs both directly through decreasing STAT1 tyrosine phosphorylation and indirectly by facilitating STAT1 dephosphorylation consequential to increased STAT1 solubility because of suppressed paracrystal assembly. However, the physiologic implications of SUMO conjugation have remained unclear. Here, we used fibroblasts and bone marrow-derived macrophages (BMMs) from knockin mice expressing SUMO-free STAT1 to explore the consequences of STAT1 sumoylation for IFN gamma signaling. Our experiments demonstrated buffer property of paracrystals for activated STAT1, such that SUMO-mediated paracrystal dispersal profoundly reduced phosphorylation of STAT1, which affected both the activating tyrosine 701 and the transcription-enhancing serine 727. Accordingly, the curtailed STAT1 activity in the nucleus caused by SUMO conjugation resulted in diminished transcription of IFN gamma responsive genes; and increased the IFN gamma concentration more than 100-fold required to trigger lipopolysaccharide-induced cytotoxicity in bone marrow-derived macrophages. These experiments identify SUMO conjugation of STAT1 as a mechanism to permanently attenuate the IFN gamma sensitivity of cells, which prevents hyperresponsiveness to this cytokine and its potentially self-destructive consequences. This sets the mode of SUMO-mediated inhibition apart from the other negative STAT regulators known to date. (Blood. 2011; 118(4): 1002-1007)