Tumor suppressor reprogramming by EBV through post-translational modification

摘要： 免疫功能低下的艾滋病毒阳性患者有严重的并发症， 可能导致B细胞淋巴瘤的致癌病毒感染。EB病毒（EBV）和 卡波西肉瘤相关病毒（Kaposi's sarcoma associated virus，KSHV）是两种人类致癌性γ疱疹病毒 与B细胞淋巴瘤相关，无论是单独感染还是合并感染。EB病毒相关B细胞 淋巴瘤被确定为潜伏期III感染，主要潜伏基因也表达 小的非编码RNA。EBV转化的B细胞驱动潜伏期III，也见于HIV 相关的EBV阳性淋巴瘤。EBV也与其他淋巴瘤有关，包括 伯基特淋巴瘤，霍奇金淋巴瘤和非霍奇金淋巴瘤，以及移植后和艾滋病 免疫功能低下的HIV患者的相关淋巴瘤。EB病毒也有效地转化为 体外人原代B细胞转化为永生化淋巴母细胞样细胞系（LCL）。这些 新生的转化B细胞表达潜伏基因，其中之一是EB病毒核 抗原EBNA 3C，B细胞永生化所必需的。EBNA 3C调节细胞和病毒 通过与转录阻遏物相互作用的基因表达，以及 哺乳动物细胞周期，包括细胞周期蛋白A和SCF蛋白体的组分 降解途径我们的长期目标是确定EBNA 3C在重编程中的作用。 病毒和感染细胞基因组通过与肿瘤抑制基因Rb和 这些相互作用的调节结果与细胞存活、细胞周期调节 和扩散。我们将通过特异性的后- EBV感染后的翻译修饰，包括磷酸化和乙酰化 对靶向泛素化很重要。我们将确定增强的磷酸化/乙酰化 通过EBNA 3C募集CyclinD/Cdk 4/6复合物，Rb的表达对细胞增殖和分化起重要作用。 循环进展这导致Rb通过泛素化而丢失，从而导致细胞和病毒的凋亡。 通过激活细胞E2 F途径的基因组重编程，细胞周期进程， 增加存活率和恶性转化。这些研究将探讨 EBNA 3C在调节Rb/CyclinD/E2 F网络中对B细胞永生化具有重要意义 KSHV和EBV对HIV潜伏期III淋巴瘤的贡献的新见解的意义 患者

Abstract: Immunocompromised HIV-positive patients have serious complications with opportunistic oncogenic viral infections that can lead B-cell lymphomas. Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated virus (KSHV) are two human oncogenic gammaherpesviruses associated with B-cell lymphomas either individually or as co-infections. EBV-associated B-cell lymphomas are established as latency III infection with the major latent genes expressed as well as the small non-coding RNAs. EBV transformed B cells drive latency III, also seen in HIV associated EBV-positive lymphomas. EBV is also associated with other lymphomas including Burkitt’s lymphoma, Hodgkin’s and non-Hodgkin’s lymphoma, and post-transplant and AIDS associated lymphomas in immunocompromised HIV-patients. EBV also efficiently transforms human primary B-cells in vitro, into immortalized lymphoblastoid cell lines (LCLs). These nascent transformed B cells express latent genes, one of which is the Epstein-Barr nuclear antigen EBNA3C, essential for immortalization of B-cells. EBNA3C regulates cellular and viral gene expression through interaction with transcription repressors, and complexes of the mammalian cell cycle which include CyclinA, and components of the SCF proteosome degradation pathway. Our long term goal is to determine the role of EBNA3C in reprogramming viral and infected cell genomes through interactions with the tumor suppressor Rb and the regulatory consequences of these interactions as related to cell survival, cell cycle regulation and proliferation. We will investigate the mechanism of Rb regulation through specific post- translation modifications after infection by EBV, which includes phosphorylation and acetylation important for targeted ubiquitination. We will determine if enhanced phosphorylation/acetylation of Rb occurs through recruitment of CyclinD/Cdk4/6 complexes by EBNA3C important for cell cycle progression. This results in loss of Rb through ubiquitination which leads to cell and viral genome reprogramming by activation of the cellular E2F pathway, cell cycle progression, increased survival and malignant transformation. These studies will examine the role of EBNA3C in regulating the Rb/CyclinD/E2F network important for B-cell immortalization with implications for novel insights into KSHV and EBV contributions to latency III lymphomas in HIV patients.