泛素-蛋白酶体系统介导自噬清除幽门螺杆菌感染的功能与机制研究

传统抗生素难以杀灭细胞内幽门螺杆菌（H.pylori）感染，是治疗失败的重要原因之一。泛素-蛋白酶体系统（UPS）是宿主的重要防御机制，但在清除H.pylori感染中如何发挥作用尚不清楚。我们前期发现，H.pylori入侵细胞后与泛素及蛋白酶体均存在共定位，且蛋白酶体激动剂可以抑制胞内H.pylori增殖，而抑制蛋白酶体可促进胞内H.pylori增殖；此外，我们还发现敲减蛋白酶体亚基后H.pylori与自噬标记分子LC3B共定位明显减少，推测H.pylori侵入细胞后可以被泛素和蛋白酶体识别，并通过介导自噬被宿主清除。本研究将在前期基础上，进一步明确UPS对胞内H.pylori感染的清除作用，鉴定参与泛素化过程的H.pylori外膜蛋白和E3连接酶，并揭示UPS介导自噬清除H.pylori的分子机制。研究结果将揭示宿主防御微生物的新机制，为开发新的H.pylori治疗方案提供理论依据。

Traditional antibiotics could not effectively eliminate intracellular Helicobacter pylori (H.pylori) infection, which is one of the important reasons for the failure of clinical eradication therapy. Ubiquitin proteasome system (UPS) is an important defense mechanism in the host innate immune system, but its role in eliminating H.pylori infection remains unclear. Our previous study found that H.pylori colocalizated with ubiquitin and proteasome after invading cells. Post-treated with proteasome agonists could significantly reduce the number of intracellular H.pylori, while inhibition of proteasome function could promote the proliferation of intracellular H.pylori. In addition, we also observed that the decreased colocalization of H.pylori and LC3B after the proteasome subunit was knocked down, which implied that UPS could eliminate intracellular H.pylori via mediate autophagy. Therefore, this study will further confirm the eliminating effect of UPS on intracellular H.pylori infection, identify H.pylori outer membrane protein and host E3 ubiquitin ligase involved in the ubiquitination process, and clarify the molecular mechanism of UPS eliminating H.pylori. The results are expected to further reveal the molecular mechanism of host defense against pathogenic microorganisms, and provide a theoretical basis for the clinical development of new H.pylori treatment regimens.