QQ客服 官方微博 反馈留言

	Impeding the interaction between ​Nur77 and p38 reduces LPS-induced inflammation
	Li Li ; Yuan Liu ; Hang-zi Chen ; Feng-wei Li ; Jian-feng Wu ; Hong-kui Zhang ; Jian-ping He ; Yong-zhen Xing ; Yan Chen ; Wei-jia Wang ; Xu-yang Tian ; An-zhong Li ; Qian Zhang ; Pei-qiang Huang ; Jiahuai Han ; Tianwei Lin ; Lin TW(林天伟) ; Qiao Wu ; Wu Q(吴乔)
	2015-03-30
英文摘要	该成果阐明了一条孤儿核受体Nur77通过p38-NF-κB信号通路参与炎症反应调控的新途径，为新的抗炎药物的筛选提供了新的靶标和理论基础。 吴乔课题组长期以来一直致力于孤儿核受体Nur77作用机理和生物学功能研究。该成果是吴乔课题组近年来在NatureChemicalBiology发表的第四篇系列研究论文，也是与不同学科领域相关课题组（包括结构生物学、化学生物学、天然产物药物研究等）合作的原创性成果。这些研究成果充分体现了学科交叉的优势，代表了相关研究的发展趋势。他们从分子机制、信号调控网络、共晶结构、小分子探针、药物靶点和疾病治疗等角度全面系统地阐明了Nur77作为临床重要的靶标，调控不同疾病的重要生物学功能，丰富和发展了孤儿核受体的理论知识，并且找到了能够降低血糖、抑制黑色素瘤生长和抗炎反应的小分子化合物，为治疗相关疾病提供了重要的先导化合物。该系列研究先后得到了多个国家自然科学基金重点项目和科技部“973”项目的长期支持。; Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor ​Nur77 (also known as ​TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. ​Nur77 directly associates with ​p65 to block its binding to the κB element. However, this function of ​Nur77 is countered by the LPS-activated ​p38α phosphorylation of ​Nur77. Dampening the interaction between ​Nur77 and ​p38α would favor ​Nur77 suppression of the hyperinflammatory response. A compound, ​n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a ​Nur77-biased library, blocked the ​Nur77-​p38α interaction by targeting the ligand-binding domain of ​Nur77 and restored the suppression of the hyperinflammatory response through ​Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a ​p38α substrate to modulate ​p38α-regulated functions.; This work was supported by grants from the National Natural Science Fund of China, the '973' Project of the Ministry of Science and Technology (91413113, 2014CB910602, 31370724, 31221065) and the Program of Introducing Talents of Discipline to Universities (B12001). The crystallographic data collection at Beamline BL17U1 at Shanghai Synchrotron Radiation Facility is gratefully acknowledged.
语种	英语
出版者	Nature Publishing Group
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1038/nchembio.1788]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Li Li,Yuan Liu,Hang-zi Chen,et al. Impeding the interaction between ​Nur77 and p38 reduces LPS-induced inflammation[J],2015.
APA	Li Li.,Yuan Liu.,Hang-zi Chen.,Feng-wei Li.,Jian-feng Wu.,...&吴乔.(2015).Impeding the interaction between ​Nur77 and p38 reduces LPS-induced inflammation..
MLA	Li Li,et al."Impeding the interaction between ​Nur77 and p38 reduces LPS-induced inflammation".(2015).

个性服务

查看访问统计

相关权益政策

暂无数据

收藏/分享

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。