From the Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina 27710 and.
J Biol Chem. 2014 Jan 31;289(5):3066-72. doi: 10.1074/jbc.M113.503938. Epub 2013 Dec 12.
S-nitrosylation of nuclear factor κB (NF-κB) on the p65 subunit of the p50/p65 heterodimer inhibits NF-κB DNA binding activity. We have recently shown that p65 is constitutively S-nitrosylated in the lung and that LPS-induced injury elicits a decrease in SNO-p65 levels concomitant with NF-κB activation in the respiratory epithelium and initiation of the inflammatory response. Here, we demonstrate that TNFα-mediated activation of NF-κB in the respiratory epithelium similarly induces p65 denitrosylation. This process is mediated by the denitrosylase thioredoxin (Trx), which becomes activated upon cytokine-induced degradation of thioredoxin-interacting protein (Txnip). Similarly, inhibition of Trx activity in the lung attenuates LPS-induced SNO-p65 denitrosylation, NF-κB activation, and airway inflammation, supporting a pathophysiological role for this mechanism in lung injury. These data thus link stimulus-coupled activation of NF-κB to a specific, protein-targeted denitrosylation mechanism and further highlight the importance of S-nitrosylation in the regulation of the immune response.
核因子 κB（NF-κB）的 S-亚硝基化作用可抑制 p50/p65 异二聚体上的 p65 亚单位的 NF-κB DNA 结合活性。我们最近发现，p65 在肺部中持续发生 S-亚硝基化，而 LPS 诱导的损伤会导致 SNO-p65 水平降低，同时伴随着呼吸道上皮细胞中 NF-κB 的激活和炎症反应的启动。在这里，我们证明 TNFα 介导的呼吸道上皮细胞中的 NF-κB 激活同样会诱导 p65 的脱亚硝基化。这个过程是由脱亚硝基酶硫氧还蛋白（Trx）介导的，它在细胞因子诱导的硫氧还蛋白相互作用蛋白（Txnip）降解后被激活。同样，在肺部中抑制 Trx 活性会减弱 LPS 诱导的 SNO-p65 脱亚硝基化、NF-κB 激活和气道炎症，支持该机制在肺损伤中的病理生理作用。这些数据将 NF-κB 的刺激偶联激活与特定的、靶向蛋白质的脱亚硝基化机制联系起来，并进一步强调了 S-亚硝基化在免疫反应调节中的重要性。
