The methyltransferase WBSCR22/Merm1 enhances glucocorticoid receptor function and is regulated in lung inflammation and cancer.
The methyltransferase WBSCR22/Merm1 enhances glucocorticoid receptor function and is regulated in lung inflammation and cancer.
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DOI：
10.1074/jbc.m113.540906
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发表时间：
2014-03-28
期刊：
影响因子：
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通讯作者：
Ray DW
中科院分区：
文献类型：
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作者：
Jangani M;Poolman TM;Matthews L;Yang N;Farrow SN;Berry A;Hanley N;Williamson AJ;Whetton AD;Donn R;Ray DW
背景：糖皮质激素（GC）在炎症中的作用是重要的，但知之甚少。结果：Merm 1调节糖皮质激素受体（GR）向基因组的募集并介导随后的组蛋白修饰。GC抵抗的促炎细胞因子诱导伴随着Merm 1降解; Merm 1表达的恢复挽救了GC作用。结论：Merm 1是一种新的GR共调节因子。意义：Merm 1介导GC作用的炎症调节。糖皮质激素（GC）调节细胞命运和免疫功能。我们确定了促进转移的甲基转移酶，转移相关的甲基转移酶1（WBSCR 22/Merm 1）作为一种新的糖皮质激素受体（GR）调节剂相关的人类疾病。Merm 1结合GR共激活剂GRIP 1，但不GR。Merm 1的损失损害GR反式激活和反式阻遏通过减少GR招聘到其结合位点。这是伴随着损失的GR依赖性H3 K4 Me 3在一个良好的特征启动子。炎症促进GC抗性，部分通过TNFα和IFNγ的作用。这些细胞因子通过驱动两个保守的赖氨酸残基的泛素化来抑制Merm 1蛋白的表达。Merm 1表达的恢复挽救了GR反式激活。在人肺外植体中也观察到Merm 1和GR功能的细胞因子抑制。此外，在炎性和肿瘤性人类肺部病变中均观察到Merm 1蛋白的显著丢失。总之，Merm 1是影响GR募集和功能的染色质结构的新型调节剂，有助于炎症中GC敏感性的丧失，并抑制肺部疾病中的表达。
Background: Glucocorticoid (GC) action in inflammation is important but poorly understood. Results: Merm1 regulates glucocorticoid receptor (GR) recruitment to the genome and mediates subsequent histone modification. Proinflammatory cytokine induction of GC resistance is accompanied by Merm1 degradation; restoration of Merm1 expression rescues GC action. Conclusion: Merm1 is a novel GR co-modulator. Significance: Merm1 mediates inflammation regulation of GC action. Glucocorticoids (GC) regulate cell fate and immune function. We identified the metastasis-promoting methyltransferase, metastasis-related methyltransferase 1 (WBSCR22/Merm1) as a novel glucocorticoid receptor (GR) regulator relevant to human disease. Merm1 binds the GR co-activator GRIP1 but not GR. Loss of Merm1 impaired both GR transactivation and transrepression by reducing GR recruitment to its binding sites. This was accompanied by loss of GR-dependent H3K4Me3 at a well characterized promoter. Inflammation promotes GC resistance, in part through the actions of TNFα and IFNγ. These cytokines suppressed Merm1 protein expression by driving ubiquitination of two conserved lysine residues. Restoration of Merm1 expression rescued GR transactivation. Cytokine suppression of Merm1 and of GR function was also seen in human lung explants. In addition, striking loss of Merm1 protein was observed in both inflammatory and neoplastic human lung pathologies. In conclusion, Merm1 is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease.