DNMT1介导EBV编码瘤蛋白LMP1抑制细胞程序性坏死的分子机制研究

程序性坏死是一种不同于凋亡的新的细胞死亡方式，受体相互作用蛋白RIPK3是程序性坏死的特异性激活蛋白。研究认为病毒抑制程序性坏死有利于其在宿主细胞内存活以维持其持续感染。我们新近研究发现，EBV可通过其编码的潜伏膜蛋白LMP1下调程序性坏死关键分子RIPK3表达，从而抑制细胞程序性坏死的发生；EBV-LMP1可能通过DNA甲基转移酶DNMT1造成RIPK3甲基化沉默；天然小分子Grifolin可显著抑制DNMT1表达。基于此，本项目拟以鼻咽癌为主要研究模型，以程序性坏死的关键调控因子RIPK3为重点，发现EBV-LMP1通过DNMT1促进RIPK3甲基化沉默抑制肿瘤细胞程序性坏死的新机制，探讨天然小分子Grifolin诱导细胞程序性坏死的新功能，为阐明EBV抑制程序性坏死提供新的实验证据，为进一步诠释病毒感染肿瘤中程序性坏死的作用提供新的理论依据。

Necroptosis is a caspase-independent, but receptor interacting protein kinase (RIPK)-dependent form of programmed cell death. Viruses suppress necroptosis to assure sustained infection in their natural hosts. In our previous study, we found that EBV encoded latent membrane protein 1 (LMP1) inhibited necroptosis through down-regulating RIPK3 expression. EBV-LMP1 activated DNA methyltransferase 1 (DNMT1), resulting in promoter methylation and silencing of RIPK3. Grifolin, a novel small-molecular compound isolated from the fungus, Albatrellus confluens, could significantly repress DNMT1 expression. Basis on the preliminary findings, we will clarity the importance of the necroptosis specific activator RIPK3 in EBV-LMP1-positive nasopharyngeal carcinoma tumorigenesis. Thus, this project can demonstrate the molecular mechanisms that EBV inhibits RIPK3 expression and necroptosis via DNMT1, reveal a new function of Grifolin in inducing necroptosis, and provide novel evidences for necroptosis in the viruses-associated carcinogenesis.