CBX4 Regulates Long-Form Thymic Stromal Lymphopoietin-mediated Airway Inflammation through SUMOylation in House Dust Mite-induced Asthma
CBX4 Regulates Long-Form Thymic Stromal Lymphopoietin-mediated Airway Inflammation through SUMOylation in House Dust Mite-induced Asthma
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DOI：
10.1165/rcmb.2021-0301oc
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发表时间：
2022-06-01
影响因子：
6.4
通讯作者：
Cai, Shaoxi
中科院分区：
文献类型：
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作者：
Liang, Shixiu;Zhou, Zicong;Cai, Shaoxi
胸腺基质淋巴生成素有两种不同的亚型：短型（sfTSLP）和长型（lfTSLP）。在过敏性哮喘中，lfTSLP促进炎症，而sfTSLP抑制炎症。然而，哮喘气道上皮中lfTSLP和sfTSLP在过敏性发作中的调控作用尚不清楚。在这里，我们报告了小泛素样修饰因子（SUMOylation）在屋尘螨诱导的过敏性哮喘气道上皮中增强。抑制SUMOylation可显著减轻气道t辅助细胞2型炎症和lfTSLP的表达。从机制上说，染色体盒4 (CBX4)，一个summoylation E3连接酶，通过rna结合蛋白肌肉过剩(MEX)-3B，增强了lfTSLP mRNA的翻译，而不是sfTSLP。MEX-3B通过其K同源结构域结合lfTSLP mRNA，促进lfTSLP翻译。此外，CBX4通过提高转录因子TFII-I的SUMOylation浓度，调节人支气管上皮细胞中MEX-3B的转录。综上所述，我们证明了CBX4通过增强TFII-I - SUMOylation促进MEX-3B转录的重要机制，而MEX-3B通过结合lfTSLP mRNA并促进其翻译来增强lfTSLP的表达。我们的发现揭示了CBX4治疗lftslp介导哮喘的新靶点。
Thymic stromal lymphopoietin presents in two distinct isoforms: short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation, whereas sfTSLP inhibits inflammation, in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in the asthma airway epithelium. Here, we report that small ubiquitin-like modifier (SUMOylation) was enhanced in house dust mite-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway T-helper cell type 2 inflammation and lfTSLP expression. Mechanistically, chromobox 4 (CBX4), a SUMOylation E3 ligase, enhanced lfTSLP mRNA translation, but not sfTSLP, through the RNA-binding protein muscle excess (MEX)-3B. MEX-3B promoted lfTSLP translation by binding the lfTSLP mRNA through its K homology domains. Furthermore, CBX4 regulated MEX-3B transcription in human bronchial epithelial cells through enhancing SUMOylation concentrations of the transcription factor TFII-I. In conclusion, we demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents for lfTSLP-mediated asthma.