Regulation of NF-κB Circuitry by a Component of the Nucleosome Remodeling and Deacetylase Complex Controls Inflammatory Response Homeostasis (Publication with Expression of Concern. See vol. 191, pg. 1198, 2016) (Withdrawn Publication. See vol. 292, pg. 4764, 2017)
Regulation of NF-κB Circuitry by a Component of the Nucleosome Remodeling and Deacetylase Complex Controls Inflammatory Response Homeostasis (Publication with Expression of Concern. See vol. 191, pg. 1198, 2016) (Withdrawn Publication. See vol. 292, pg. 4764, 2017)
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DOI：
10.1074/jbc.m110.139469
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发表时间：
2010-07-30
影响因子：
4.8
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Pakala, Suresh B.;Bui-Nguyen, Tri M.;Kumar, Rakesh
MTA1辅助调节因子(转移性肿瘤抗原1)是核小体重塑和脱乙酰酶(NuRD)复合体的一个组成部分，与人类癌症密切相关，但其在炎症反应中的作用尚不清楚。在这里，我们发现MTA1是炎症的靶点，而巨噬细胞被大肠杆菌脂多糖(LPS)刺激后，通过核因子-kappaB途径刺激MTA1的转录。出乎意料的是，我们发现内毒素刺激的巨噬细胞中MTA1的缺失会损害核因子-kappaB信号和炎性分子的表达。MTA1本身在内毒素刺激的巨噬细胞中作为炎性细胞因子的转录辅助激活因子，相反，它在其耗竭诱导的细胞因子表达时，在静息原代巨噬细胞中扮演辅助抑制因子的角色。脂多糖刺激组蛋白脱乙酰基酶2(HDAC2)的S亚硝化，干扰其与MTA1的结合，进而导致MTA1在激活的巨噬细胞中失去辅阻遏物行为。因此，与野生型小鼠相比，MTA1(-/-)小鼠在内毒素刺激下的巨噬细胞中炎性细胞因子的净水平更高。因此，MTA1(-/-)小鼠比对照组小鼠更容易受到内毒素诱导的感染性休克的影响，这表明MTA1保护小鼠免受解除调节的宿主炎症反应的影响。这些发现揭示了MTA1作为核因子-kappa B通路的靶点和组件，在调节炎症反应中的一个先前未被认识的关键的动态平衡作用。
The MTA1 coregulator (metastatic tumor antigen 1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, has been intimately linked with human cancer, but its role in inflammatory responses remains unknown. Here, we discovered that MTA1 is a target of inflammation, and stimulation of macrophages with Escherichia coli lipopolysaccharide (LPS) stimulates MTA1 transcription via the NF-kappa B pathway. Unexpectedly, we found that MTA1 depletion in LPS-stimulated macrophages impairs NF-kappa B signaling and expression of inflammatory molecules. MTA1 itself acts as a transcriptional coactivator of inflammatory cytokines in LPS-stimulated macrophages, and in contrast, it acts as a corepressor in resting primary macrophages as its depletion induced cytokine expression. LPS stimulates S-nitrosylation of histone deacetylase 2 (HDAC2) and interferes with its binding to MTA1, which, in turn, resulted in the loss of corepressor behavior of MTA1.HDAC complex in activated macrophages. Consequently, the net levels of inflammatory cytokines in LPS-stimulated macrophages from MTA1(-/-) mice were high compared with wild-type mice. Accordingly, MTA1(-/-) mice were much more susceptible than control mice to septic shock induced by LPS, revealing that MTA1 protects mice from deregulated host inflammatory response. These findings reveal a previously unrecognized, critical homeostatic role of MTA1, both as a target and as a component of the NF-kappa B circuitry, in the regulation of inflammatory responses.