USP14调节免疫蛋白酶体的形成及活性在LPS诱导肺炎模型中的作用机制研究

Promoting inflammation retrogression is the key to the treatment of pneumonia. For a long time, people have taken various measures to fight against infection and eliminate the pathogenic bacteria. However, the drug-resistant strains have increased and the process of pneumonia has been delayed with the extensive application of various antibiotic. Recent research reported that Ubiquitin-specific protease 14 (USP14) promotes the release of inflammatory cytokines through regulating NF-κB pathway, but the exact mechanisms are still obscure thus far. In our preliminary studies, we found that USP14 phosphorylation promoted the formation of immunoproteasome, leading to an enlarged inflammatory response. Conversely, inhibition of USP14 inhibited the formation of immunoproteasome and had an inflammation retrogression effect. However, the mechanism is not clear. Based on our preliminary studies, this research is plan to study LPS mediated phosphorylated USP14 to promote the formation of immunoproteasome and increase the deubiquitination activity of USP14 and enhance the ability of proteasome to degrade proteins, and to illuminate the relationship between USP14-immunoproteasome and NF-κB·IκB pathway. Meanwhile, the therapeutic effect of IU1 on gram-negative bacillus pneumonia is proposed in the clinical, which provides a new basis for the treatment and prognosis of pneumonia.

阻断并促进炎性消退是治疗肺炎的关键环节。抗生素是目前治疗肺炎主要手段。但由于抗生素的大量使用，耐药细菌逐渐增多，应用抗生素治疗肺炎疗效变差，甚至长期不愈。近期研究表明，肺炎可致使泛素特异性蛋白酶14（USP14）通过去泛素化作用调节NF-κB·IκB通路促进炎症因子的释放，使炎性反应加重，但具体机制尚不明确。我们发现USP14磷酸化可促进免疫蛋白酶体的形成，导致炎症反应加重；而抑制USP14磷酸化可减少免疫蛋白酶体的形成，使炎症反应减弱。本研究目的是采用动物实验肺炎模型，进一步证实脂多糖（LPS）介导的肺炎可使 USP14磷酸化促进免疫蛋白酶体的形成，加重炎性反应；并明确USP14在肺炎的炎性反应调节作用的分子学机制，阐明USP14-免疫蛋白酶体与NF-κB·IκB信号通路的关系。同时观察IU1对革兰阴性杆菌肺炎患者肺灌洗液炎性反应细胞的炎性消退作用，为肺炎的治疗及预后提供新的途经。

促进炎症的消退是治疗肺炎的关键。长期以来，人们采取种种措施抗感染，清除病原菌，然而随着各种抗生素的大量应用，耐药细菌增多，肺部炎症迁延不愈。我们的前期研究发现敲除USP14基因下调USP14的表达显著降低LPS所引起的炎性因子的释放；同时我们还发现在LPS介导下磷酸化的USP14促进免疫蛋白酶体的形成，并增加USP14的去泛素化活性及蛋白酶体降解底物的能力。本研究在前期的工作基础上，研究发现抑制USP14的表达阻止了LPS所诱导的免疫蛋白酶体的形成，具有炎症消退作用。同时，还发现USP14小分子抑制剂IU1显著抑制LPS所引起的炎性反应，为临床上革兰阴性杆菌肺炎患者的治疗及预后提供新的依据。