Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex.
Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex.
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DOI：
10.3389/fcimb.2017.00094
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发表时间：
2017
影响因子：
5.7
通讯作者：
Lee KY
中科院分区：
文献类型：
--
作者：
Min Y;Wi SM;Shin D;Chun E;Lee KY
TRAF 6-ECSIT复合物对于Toll样受体4（TLR 4）诱导的线粒体活性氧（mROS）和核因子-κ B（NF-κB）活化的产生至关重要。过氧化物氧还蛋白-6（Peroxiredoxin-6，Prdx 6）是过氧化物氧还蛋白家族中的一员，参与抗氧化保护和细胞信号转导。在这里，我们报告了Prdx 6在mROS产生和NF-κB活化中的调节作用。Prdx 6通过TLR 4刺激易位到线粒体中，并且Prdx 6敲低（Prdx 6 KD）的THP-1细胞具有增加的线粒体活性氧水平，并且对鼠伤寒沙门氏菌感染具有抗性。生物化学研究揭示了Prdx 6与TRAF 6的C-末端TRAF-C结构域的相互作用，其驱动易位到线粒体中。有趣的是，Prdx 6通过其C-末端TRAF-C结构域与ECSIT竞争性地相互作用于TRAF 6，导致TRAF 6-ECSIT相互作用的中断。抑制作用与TLR 4诱导的NF-κB活化密切相关。Prdx 6过表达可抑制TLR 4诱导的NF-κB表达，而Prdx 6 KD THP-1细胞则可诱导IL-6和IL-1 β等促炎细胞因子的产生，并上调TLR 4诱导的NF-κ B依赖基因表达。综上所述，数据表明Prdx 6中断了由TLR 4刺激诱导的TRAF 6-ECSIT复合物的形成，由于抑制线粒体中的mROS产生和抑制细胞质中的NF-κB活化而导致杀菌活性的抑制。
A TRAF6-ECSIT complex is crucial for the generation of mitochondrial reactive oxygen species (mROS) and nuclear factor-kappa B (NF-κB) activation induced by Toll-like receptor 4 (TLR4). Peroxiredoxin-6 (Prdx6) as a member of the peroxiredoxin family of antioxidant enzymes is involved in antioxidant protection and cell signaling. Here, we report on a regulatory role of Prdx6 in mROS production and NF-κB activation by TLR4. Prdx6 was translocated into the mitochondria by TLR4 stimulation and Prdx6-knockdown (Prdx6KD) THP-1 cells had increased level of mitochondrial reactive oxygen species levels and were resistant to Salmonella typhimurium infection. Biochemical studies revealed Prdx6 interaction with the C-terminal TRAF-C domain of TRAF6, which drove translocation into the mitochondria. Interestingly, Prdx6 competitively interacted with ECSIT to TRAF6 through its C-terminal TRAF-C domain, leading to the interruption of TRAF6-ECSIT interaction. The inhibitory effect was critically implicated in the activation of NF-κB induced by TLR4. Overexpression of Prdx6 led to the inhibition of NF-κB induced by TLR4, whereas Prdx6KD THP-1 cells displayed enhanced production of pro-inflammatory cytokines including interleukin-6 and -1β, and the up-regulation of NF-κB-dependent genes induced by TLR4 stimulation. Taken together, the data demonstrate that Prdx6 interrupts the formation of TRAF6-ECSIT complex induced by TLR4 stimulation, leading to suppression of bactericidal activity because of inhibited mROS production in mitochondria and the inhibition of NF-κB activation in the cytoplasm.