Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1.
Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1.
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DOI：
10.1371/journal.ppat.1007394
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发表时间：
2018-11
期刊：
影响因子：
6.7
通讯作者：
Tempera I
中科院分区：
文献类型：
--
作者：
Hulse M;Caruso LB;Madzo J;Tan Y;Johnson S;Tempera I
潜伏膜蛋白1（LMP 1）是EB病毒（EBV）的主要转化蛋白，在EBV体外诱导的B细胞转化中起重要作用。多聚腺苷二磷酸核糖聚合酶1（Poly（ADP-ribose）polymerase 1，PARP 1）调节染色质的可接近性，改变转录激活因子和抑制因子的功能，并直接参与转录激活。以前我们发现LMP 1激活PARP 1并通过PARP 1增加聚（ADP-核糖）化（PAR化）。因此，为了鉴定通过PARP 1调节的LMP 1的靶标，LMP 1在EBV阴性伯基特淋巴瘤细胞系中异位表达。然后用PARP抑制剂奥拉帕尼处理这些表达LMP 1的细胞，并准备进行RNA测序。通过该RNA-seq实验鉴定的LMP 1/PARP靶标主要涉及代谢和信号传导。有趣的是，RNA-seq数据的Inflamity Pathway分析表明，缺氧诱导因子1-α（HIF-1α）是通过PARP 1介导的LMP 1靶标。PARP 1是B细胞中HIF-1α依赖性基因表达的共激活因子，LMP 1介导的PARP 1激活可增强这种共激活作用。HIF-1α与PARP 1形成PAR化复合物，HIF-1α和PARP 1均存在于HIF-1α下游靶点的启动子区域，导致阳性组蛋白标记在这些区域积累。PARP 1抑制剂可减弱PARP 1和HIF-1α在HIF-1α下游靶点启动子区的复合物形成、PAR化和结合，随后导致抑制性组蛋白标记物的积累和阳性组蛋白标记物的丢失。此外，LMP 1将细胞转换为糖酵解“瓦尔堡”代谢，优先使用有氧糖酵解而不是线粒体呼吸。最后，LMP 1+细胞对PARP 1抑制更敏感，因此，靶向PARP 1活性可能是LMP 1 + EBV相关恶性肿瘤的有效治疗。EB病毒（Epstein-Barr virus，EBV）是最普遍存在的人类病毒之一，全世界超过90%的成年人在其B淋巴细胞的一小部分中具有终身潜伏的EBV感染。已知EBV引起淋巴组织增生性疾病，并且与几种其他类型的癌症相关，包括霍奇金淋巴瘤、伯基特淋巴瘤和鼻咽癌。然而，在大多数情况下，EBV阳性淋巴瘤的方法与相同组织学的EBV阴性淋巴瘤没有区别。潜伏膜蛋白1（LMP 1）是EB病毒的主要转化蛋白，在体外EB病毒诱导的B细胞转化中起关键作用。LMP 1激活几种表观遗传调节因子以改变宿主基因表达，包括染色质修饰酶聚（ADP-核糖）聚合酶1或PARP 1。在目前的研究中，我们已经确定LMP 1可以激活PARP 1，以增加缺氧诱导因子1-α（HIF-1α）依赖性基因表达，导致宿主细胞代谢的变化，表明“瓦尔堡效应”（有氧糖酵解）。这随后为表达LMP 1的细胞提供了增殖优势。LMP 1诱导的HIF-1α依赖性基因表达增加、细胞代谢改变和细胞增殖加速可被PARP抑制剂奥拉帕尼抵消。因此，靶向PARP 1活性可能是LMP 1 + EBV相关恶性肿瘤的有效治疗方法。
Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Poly(ADP-ribose) polymerase 1 (PARP1) regulates accessibility of chromatin, alters functions of transcriptional activators and repressors, and has been directly implicated in transcriptional activation. Previously we showed that LMP1 activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. Therefore, to identify targets of LMP1 that are regulated through PARP1, LMP1 was ectopically expressed in an EBV-negative Burkitt’s lymphoma cell line. These LMP1-expressing cells were then treated with the PARP inhibitor olaparib and prepared for RNA sequencing. The LMP1/PARP targets identified through this RNA-seq experiment are largely involved in metabolism and signaling. Interestingly, Ingenuity Pathway Analysis of RNA-seq data suggests that hypoxia-inducible factor 1-alpha (HIF-1α) is an LMP1 target mediated through PARP1. PARP1 is acting as a coactivator of HIF-1α-dependent gene expression in B cells, and this co-activation is enhanced by LMP1-mediated activation of PARP1. HIF-1α forms a PARylated complex with PARP1 and both HIF-1α and PARP1 are present at promoter regions of HIF-1α downstream targets, leading to accumulation of positive histone marks at these regions. Complex formation, PARylation and binding of PARP1 and HIF-1α at promoter regions of HIF-1α downstream targets can all be attenuated by PARP1 inhibition, subsequently leading to a buildup of repressive histone marks and loss of positive histone marks. In addition, LMP1 switches cells to a glycolytic ‘Warburg’ metabolism, preferentially using aerobic glycolysis over mitochondrial respiration. Finally, LMP1+ cells are more sensitive to PARP1 inhibition and, therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies. Epstein-Barr virus (EBV) is one of the most ubiquitous human viruses, with over 90% of adults worldwide harboring lifelong latent EBV infection in a small fraction of their B-lymphocytes. EBV is known to cause lymphoproliferative disorders and is associated with several other types of cancer, including Hodgkin's lymphoma, Burkitt's lymphoma and Nasopharyngeal carcinoma. However, in most cases, the approach to EBV-positive lymphomas does not differ from EBV-negative lymphomas of the same histology. Latent membrane protein 1 (LMP1) is the major transforming protein of EBV and is critical for EBV-induced B-cell transformation in vitro. LMP1 activates several epigenetic regulators to modify host gene expression, including the chromatin-modifying enzyme Poly(ADP-ribose) polymerase 1, or PARP1. In the current study we have determined that LMP1 can activate PARP1 to increase hypoxia-inducible factor 1-alpha (HIF-1α)-dependent gene expression, leading to a change in host cell metabolism indicative of a ‘Warburg effect’ (aerobic glycolysis). This subsequently provides a proliferative advantage to LMP1-expressing cells. The LMP1-induced increase in HIF-1α-dependent gene expression, alteration of cellular metabolism, and accelerated cellular proliferation, can be offset with the PARP inhibitor olaparib. Therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies.
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