Tumor suppressor reprogramming by EBV through post-translational modification

摘要： 免疫功能低下的HIV阳性患者有严重的机会主义并发症 可能导致B细胞淋巴瘤的致癌性病毒感染。EB病毒(EBV)和 卡波西肉瘤相关病毒(KSHV)是两种人类致癌性伽马疱疹病毒 与B细胞淋巴瘤有关的单独或混合感染。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出来。 作为小的非编码RNA。EB病毒转化的B细胞驱动潜伏期III，也见于HIV 相关的EBV阳性淋巴瘤。EBV还与其他淋巴瘤有关，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患者中的相关淋巴瘤。EBV还可以高效地转化为 体外培养人原代B细胞，分化为永生化的淋巴母细胞系(LCLS)。这些 新生的转化的B细胞表达潜伏基因，其中之一是Epstein-Barr核 EBNA3C抗原，B细胞永生所必需的。EBNA3C调节细胞和病毒 通过与转录抑制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和干细胞因子蛋白小体的组成部分 降解途径。我们的长期目标是确定EBNA3C在重新编程中的作用 病毒和感染细胞基因组通过与肿瘤抑制因子Rb和 这些相互作用的调控后果与细胞存活、细胞周期调控有关 和扩散。我们将通过特定的POST来研究RB的调节机制 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 Rb的发生是通过对细胞重要的EBNA3C募集CyclinD/CDK4/6复合体来实现的 循环递增。这会通过泛素化导致Rb的丢失，从而导致细胞和病毒 通过激活细胞E2F途径、细胞周期进程、 存活率和恶变率增加。这些研究将考察 EBNA3C在调节B细胞永生化重要的Rb/Cyclin D/E2F网络中的作用 对KSHV和EBV在HIV潜伏期III淋巴瘤中作用的新见解的启示 病人。

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.