卡波氏肉瘤相关疱疹病毒ORF45介导ERK-RSK持续活化的新功能研究

项目名称： 卡波氏肉瘤相关疱疹病毒ORF45介导ERK-RSK持续活化的新功能研究

项目编号： No.81501740

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李晓娟

作者单位： 中山大学

项目金额： 18万元

中文摘要： 卡波氏肉瘤相关疱疹病毒KSHV在HIV患者和免疫功能低下的人群可显著诱发恶性肿瘤。KSHV持续感染和致病需要裂解复制，即早期蛋白ORF45诱导ERK-RSK持续活化，促进病毒的基因表达和复制，但该途径对宿主细胞的影响和机制尚不清楚。最近我们发现ORF45-RSK途径激活转录因子c-Fos和诱导Filamin A磷酸化，我们推测ORF45-RSK途径通过这些底物调控细胞基因表达和细胞活动。本项目将深入探讨ORF45-RSK途径通过c-Fos对宿主基因转录的调控作用和功能，以及通过Filamin A改变Integrin功能、降低细胞粘附和相关信号，调控KSHV裂解复制细胞的存活和锚定粘附性；阐明KSHV裂解复制如何利用ORF45介导的ERK-RSK持续活化改变宿主细胞形态和保护细胞存活以利于复制和子代病毒释放，进一步揭示RSK靶点对KSHV感染细胞的重要功能和在KSHV相关疾病治疗中的重要意义

中文关键词： 卡波氏肉瘤相关疱疹病毒；ORF45；基因表达调控；RSK；细胞存活

英文摘要： Infection of Kaposi's sarcoma associated herpesvirus (KSHV) causes severe malignancy in AIDS patients and immunosuppressive populations, and its persistent infection and pathogenesis require a continuous low level of lytic replication. Studies have revealed that KSHV immediate early protein ORF45 induces sustained activation of ERK-RSK pathway, promotes lytic gene expressions during late stage and viral lytic replication, however, the effects on cellular gene expression and activity of host cells remain unknown. Recently we found that ORF45-RSK pathway activates cellular transcription factor c-Fos to accelerate viral transcription during late lytic replication, and induces the phosphorylation of Filamin A. Based on our preliminary results, we hypothesized that the sustained ERK-RSK activation by ORF45 control the gene expression, cellular adhesion and survival of host cells through targeting specific substrates. This project is planning to study the regulation and important function of ORF45-RSK in cellular gene transcription through c-Fos (Aim 1), regulation in cell morphology and cell adhesion through Filamin A (Aim2), the protective effects of ORF45-RSK in cell survival (Aim3) during KSHV lytic replication. This project will expect to elucidate how KSHV lytic lifecycle utilize ORF45-mediated ERK-RSK activation to modulate cellular gene expression and cellular physiological processes to protect cell survival and facilitate viral replication, and to further reveal the novel function and significance of RSK in KSHV lytic infection and KSHV-related diseases.

英文关键词： KSHV;ORF45;gene expression;RSK; cell survival