CBX4形成液相分离小体并SUMO化EZH2促进HIV-1潜伏感染的机制研究

HIV-1潜伏感染是艾滋病功能性治愈的主要障碍。为了根除病毒储藏库，受感染的细胞必须被特异性激活和清除。然而当前所开发出的潜伏感染激活剂（LRA）均收效甚微。因此我们试图寻找新靶点用于开发高效安全的LRA。我们在多种模型中均发现：多梳蛋白家族成员CBX4可以促进HIV-1的潜伏感染，并招募H3K27me3修饰蛋白EZH2。为此，我们提出了CBX4介导HIV-1潜伏感染的新机制，即：CBX4招募EZH2形成抑制性蛋白复合体富集于HIV-1启动子附近，建立并维持抑制性表观遗传学修饰H3K27me3，从而促进HIV-1的潜伏感染。进一步的预实验显示：CBX4复合体为一种新的核内液相分离（LLPS）小体，并对EZH2进行SUMO化修饰。本项目拟进一步评价和证实CBX4通过形成液相分离小体和SUMO化EZH2促进HIV-1潜伏感染的调控机制。为确立CBX4作为LRA研发的新靶点提供更充分的科学依据。

HIV-1 latency is the major obstacle to achieve a functional cure of AIDS. To eradicate viral reservoirs, HIV-1-infected cells must be specifically reactivated and eliminated. However, present latency-reversing agents (LRAs) are quite dissatisfactory. Thus, we try to find new targets to develop LRAs with high efficiency and low toxicity. In several latency models, we found that polycomb-group (PcG) protein CBX4 promoted HIV-1 latency and recruited H3K27me3 modifier EZH2. Here, we propose the novel mechanism of CBX4-mediated HIV-1 latency, which is: CBX4 recruits EZH2 to the HIV-1 promoter and forms suppressive protein complex, followed by the establishment and maintenance of suppressive epigenetic modification H3K27me3, resulting in the formation of HIV-1 latency. Further preliminary experiments indicated that CBX4 complexes were novel liquid-liquid phase-separated (LLPS) nuclear bodies. CBX4 SUMOylated EZH2 utilizing its SUMO E3 ligase activity. Our study will further evaluate and confirm the mechanisms of CBX4-mediated HIV-1 latency by forming LLPS bodies and SUMOylating EZH2, which will provide more sufficient scientific evidences to ascertain that CBX4 could be the novel target to develop LRAs.