Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice
Hsp90 inhibition destabilizes Ezh2 protein in alloreactive T cells and reduces graft-versus-host disease in mice
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Hsp90 抑制可破坏同种反应性 T 细胞中 Ezh2 蛋白的稳定性，并减少小鼠移植物抗宿主病
DOI：
10.1182/blood-2016-08-735886
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发表时间：
2017-05-18
期刊：
影响因子：
20.3
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
--
作者：
Huang, Qingrong;He, Shan;Zhang, Yanyun
调节T细胞同种异体反应性是减少移植物抗宿主病（GVHD）的主要策略，GVHD是异基因造血干细胞移植（HSCT）后危及生命的并发症。催化组蛋白H3在赖氨酸27（H3 K27 me 3）处的三甲基化的T细胞Ezh 2的遗传缺失抑制GVHD。因此，减少Ezh 2介导的H3 K27 me 3被认为是抑制GVHD所必需的。我们在小鼠GVHD模型中测试了这一假设。出乎意料的是，施用Ezh 2抑制剂GSK 126（其特异性降低H3 K27 me 3而不影响Ezh 2蛋白）未能预防该疾病。相反，通过使用其特异性抑制剂AUY 922抑制Hsp 90来使T细胞Ezh 2蛋白不稳定，减少了接受同种异体HSCT的小鼠中的GVHD。体内施用AUY 922选择性地诱导活化的T细胞的凋亡，并减少产生干扰素γ和肿瘤坏死因子α的效应细胞的产生，类似于Ezh 2的遗传缺失。将Ezh 2引入同种异体反应性T细胞恢复了它们在AUY 922处理后的扩增和效应细胞因子的产生，表明通过抑制Hsp 90而受损的T细胞同种异体反应性主要通过耗尽Ezh 2来实现。机制分析表明，酶促SET域Ezh 2直接与热休克蛋白90，以防止Ezh 2在活化的T细胞中的快速降解。重要的是，Hsp 90的药理学抑制保留了供体T细胞的抗白血病活性，从而改善了同种异体HSCT后受体小鼠的总体存活率。我们的研究结果确定了Ezh 2-Hsp 90相互作用是以前未被认识到的T细胞反应所必需的机制，也是控制GVHD的有效靶点。
Modulating T-cell alloreactivity has been a main strategy to reduce graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem-cell transplantation (HSCT). Genetic deletion of T-cell Ezh2, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3), inhibits GVHD. Therefore, reducing Ezh2-mediated H3K27me3 is thought to be essential for inhibiting GVHD. We tested this hypothesis in mouse GVHD models. Unexpectedly, administration of the Ezh2 inhibitor GSK126, which specifically decreases H3K27me3 without affecting Ezh2 protein, failed to prevent the disease. In contrast, destabilizing T-cell Ezh2 protein by inhibiting Hsp90 using its specific inhibitor AUY922 reduced GVHD in mice undergoing allogeneic HSCT. In vivo administration of AUY922 selectively induced apoptosis of activated T cells and decreased the production of effector cells producing interferon gamma and tumor necrosis factor a, similar to genetic deletion of Ezh2. Introduction of Ezh2 into alloreactive T cells restored their expansion and production of effector cytokines upon AUY922 treatment, suggesting that impaired T-cell alloreactivity by inhibiting Hsp90 is achieved mainly through depleting Ezh2. Mechanistic analysis revealed that the enzymatic SET domain of Ezh2 directly interacted with Hsp90 to prevent Ezh2 from rapid degradation in activated T cells. Importantly, pharmacological inhibition of Hsp90 preserved antileukemia activity of donor T cells, leading to improved overall survival of recipient mice after allogeneic HSCT. Our findings identify the Ezh2-Hsp90 interaction as a previously unrecognized mechanism essential for T-cell responses and an effective target for controlling GVHD.