NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation.
NQO1 inhibits the TLR-dependent production of selective cytokines by promoting IκB-ζ degradation.
复制标题
DOI：
10.1084/jem.20172024
复制
发表时间：
2018-08-06
期刊：
影响因子：
--
通讯作者：
Suzuki H
中科院分区：
文献类型：
--
作者：
Kimura A;Kitajima M;Nishida K;Serada S;Fujimoto M;Naka T;Fujii-Kuriyama Y;Sakamato S;Ito T;Handa H;Tanaka T;Yoshimura A;Suzuki H
Kimura等证明NQO 1通过与PDLIM 2形成复合物在降解IκB-κ B蛋白中起关键作用，并选择性抑制TLR配体诱导的IL-6和IL-12产生。NAD（P）H：醌氧化还原酶1（NQO 1）保护细胞免受氧化应激和有毒醌类的伤害。在这项研究中，我们发现NQO 1在抑制Toll样受体（TLR）介导的先天免疫反应中的新作用。NQO 1缺陷型巨噬细胞在LPS刺激下选择性地产生过量的IL-6、IL-12和GM-CSF，并且巨噬细胞中NQO 1的缺失加剧了LPS诱导的脓毒性休克。NQO 1与核IκB蛋白IκB-κ B相互作用，这是TLR介导的诱导包括IL-6在内的次级应答基因子集所必需的，并以泛素依赖性方式促进IκB-κ B降解。我们证明了PDLIM 2，即泛素E3连接酶，参与NQO 1依赖的IκB-κ B降解。NQO 1增强了PDLIM 2与IκB-κ B的结合，导致IκB-κ B降解增加。总的来说，本研究描述了NQO 1-PDLIM 2复合物作为先天免疫信号传导中的新的重要调节剂的机制，并表明NQO 1在TLR介导的炎症和疾病中的治疗潜力。
Kimura et al. demonstrate that NQO1 plays a crucial role in degrading IκB-ζ protein through forming the complex together with PDLIM2 and selectively suppresses IL-6 and IL-12 production induced by TLR ligands. NAD(P)H:quinone oxidoreductase 1 (NQO1) protects cells against oxidative stress and toxic quinones. In this study, we found a novel role of NQO1 in suppressing Toll-like receptor (TLR)–mediated innate immune responses. NQO1-deficient macrophages selectively produced excessive amounts of IL-6, IL-12, and GM-CSF on LPS stimulation, and the deletion of NQO1 in macrophages exacerbated LPS-induced septic shock. NQO1 interacted with the nuclear IκB protein IκB-ζ, which is essential for the TLR-mediated induction of a subset of secondary response genes, including IL-6, and promoted IκB-ζ degradation in a ubiquitin-dependent manner. We demonstrated that PDLIM2, known as the ubiquitin E3 ligase, participates in NQO1-dependent IκB-ζ degradation. NQO1 augmented the association between PDLIM2 and IκB-ζ, resulting in increased IκB-ζ degradation. Collectively, this study describes a mechanism of the NQO1–PDLIM2 complex as a novel and important regulator in the innate immune signaling and suggests the therapeutic potential of NQO1 in TLR-mediated inflammation and disorders.
登录
查看更多内容
DOI：
10.1084/jem.20090560
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kimura A;Naka T;Nakahama T;Chinen I;Masuda K;Nohara K;Fujii-Kuriyama Y;Kishimoto T
通讯作者：
Kishimoto T
影响因子：
120.7
作者：
FISHER, CJ;DHAINAUT, JFA;STABLEIN, D
通讯作者：
STABLEIN, D
影响因子：
10.5
作者：
Asher, G;Tsvetkov, P;Shaul, Y
通讯作者：
Shaul, Y
影响因子：
5.7
作者：
Huang, Jing;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
通讯作者：
Kupiec-Weglinski, Jerzy W.
DOI：
10.1016/j.bbrc.2004.06.177
发表时间：
2004-08-27
影响因子：
3.1
作者：
Boutros, PC;Moffat, ID;Okey, AB
通讯作者：
Okey, AB