Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation.
Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation.
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DOI：
10.1038/mi.2017.117
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发表时间：
2018-05
影响因子：
8
通讯作者：
Tesfaigzi Y
中科院分区：
文献类型：
--
作者：
Zhang C;Jones JT;Chand HS;Wathelet MG;Evans CM;Dickey B;Xiang J;Mebratu YA;Tesfaigzi Y
IFN-γ被认为是一种促炎细胞因子，但也可以阻断某些慢性疾病的炎症，尽管其潜在机制尚不清楚。我们发现IFN-γ快速诱导Noxa表达，并且与Noxa +/+小鼠相比，Noxa -/-小鼠反复暴露于屋尘螨后的炎症程度增强。Noxa的表达阻断了TNF-α-诱导的NF-κB核易位和促炎细胞因子的产生。Noxa不影响TNF-α诱导的i - κ b α磷酸化，但影响48链泛素化i - κ b α的降解。Noxa的Cys25与phospho-HSP27的Cys137交联，这两个蛋白都是阻断泛素化i - κ b α降解所必需的。由于phospho-HSP27存在于气道上皮细胞中，而不存在于成纤维细胞或胸腺细胞中，因此我们产生了在气道上皮中诱导表达Noxa的转基因小鼠。这些小鼠通过阻断NF-κB核易位显示出对过敏原诱导的炎症和粘膜细胞化生的保护作用。此外，我们发现了一种noxa衍生的肽，它可以延长48链泛素化i -κB α的降解，阻断NF-κB的核易位，并减少过敏原诱导的小鼠炎症。这些结果表明，Noxa蛋白的抗炎作用可能仅限于气道上皮细胞，使用Noxa治疗慢性肺部疾病可能与减少副作用有关。
IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa-/- compared with noxa+/+ mice. Noxa expression blocked TNF-α-induced nuclear translocation of NF-κB and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because, phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.
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