乙肝病毒糖基化位点突变型S蛋白通过抑制ERAD介导的IRE1α降解在隐匿性乙型肝炎发病机制中的作用

S蛋白糖基化位点突变引起HBsAg分泌障碍是隐匿性乙型肝炎的重要致病机制，前期研究发现该突变型S蛋白可能通过抑制ERAD介导的IRE1α降解引起肝脏炎症。本项目拟通过构建表达糖基化位点突变型及逆转突变型S蛋白肝细胞模型，比较分析该突变型S蛋白对IL-6和TGF-β等炎症因子、NF-κB炎症通路以及IRE1α水平和活性的影响。对IRE1α进行基因干扰和异位过表达，揭示IRE1α在隐匿性乙型肝炎发病中的作用。进一步建立Sel1L缺陷细胞模型，分析突变型S蛋白或IRE1α与Sel1L间的相互作用，阐明该突变型S蛋白通过与IRE1α竞争ERAD体系导致IRE1α过激活。构建SEL1L基因敲除小鼠模型，进一步验证IRE1α及其ERAD在该突变型S蛋白介导肝脏炎症中的作用和机制。旨在揭示糖基化位点突变型S蛋白导致隐匿性乙型肝炎的致病机制，为开拓治疗靶点提供新思路。

N-glycosylation mutations within S region leading to impaired HBsAg secretion, which is an important mechanism of occult hepatitis B occurrence. Preliminary studies have found that S protein carrying N-glycosylation mutations may lead to liver inflammation through competing with IRE1α for ERAD. This project aims to establish a model of expressing S protein carrying N-glycosylation mutations in huh-7 cells and analyze the impact of S protein carrying N-glycosylation mutations on IL-6 and TGF-βlevel, NF-κB pathway and IRE1α and its activity. By using siRNA and ectopic expression to interfere with or over-express IRE1α, analyze the crucial role of IRE1α in occult hepatitis B occurrence. We would like to clarify S protein carrying N-glycosylation mutations led to IRE1αover-activation through competing with IRE1α for ERAD, by establishing Sel1L-deficient cell model and analyze the interaction between the mutant S protein or IRE1α and Sel1L. At the same time,we would construct wild-type and SEL1L knockout mouse models to verify the role of IRE1α and its ERAD in the process of the mutant S protein leading to liver inflammation. Our study explores the key molecular mechanisms of occult hepatitis B mediated by S protein carrying N-glycosylation mutations, providing new ideas and strategies for occult hepatitis B.