Lista María José, Martins Rodrigo Prado, Angrand Gaelle, Quillévéré Alicia, Daskalogianni Chrysoula, Voisset Cécile, Teulade-Fichou Marie-Paule, Fåhraeus Robin, Blondel Marc
Institut National de la Santé et de la Recherche Médicale UMR1078; Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé; Etablissement Français du Sang (EFS) Bretagne; CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, 22 avenue Camille Desmoulins, F-29200 Brest, France.
Cibles Thérapeutiques, Institut National de la Santé et de la Recherche Médicale UMR1162, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 27 rue Juliette Dodu, F-75010 Paris, France.
Microb Cell. 2017 Aug 31;4(9):305-307. doi: 10.15698/mic2017.09.590.
The oncogenic Epstein-Barr virus (EBV) evades the immune system but has an Achilles heel: its genome maintenance protein EBNA1. Indeed, EBNA1 is essential for viral genome replication and maintenance but also highly antigenic. Hence, EBV evolved a system in which the glycine-alanine repeat (GAr) of EBNA1 limits the translation of its own mRNA at a minimal level to ensure its essential function thereby, at the same time, minimizing immune recognition. Defining intervention points where to interfere with EBNA1 immune evasion is an important step to trigger an immune response against EBV-carrying cancers. Thanks to a yeast-based assay that recapitulates all the aspects of EBNA1 self-limitation of expression, a recent study by Lista [Nature Communications (2017) 7, 435-444] has uncovered the role of the host cell nucleolin (NCL) in this process via a direct interaction of this protein with G-quadruplexes (G4) formed in GAr-encoding sequence of EBNA1 mRNA. In addition, the G4 ligand PhenDC3 prevents NCL binding on EBNA1 mRNA and reverses GAr-mediated repression of translation and antigen presentation. This shows that the NCL-EBNA1 mRNA interaction is a relevant therapeutic target to unveil EBV-carrying cancers to the immune system and that the yeast model can be successfully used for uncovering drugs and host factors that interfere with EBV stealthiness.
致癌性爱泼斯坦-巴尔病毒（EBV）可逃避免疫系统，但有一个致命弱点：其基因组维持蛋白EBNA1。事实上，EBNA1对病毒基因组的复制和维持至关重要，但也具有高度抗原性。因此，EBV进化出一种系统，其中EBNA1的甘氨酸-丙氨酸重复序列（GAr）将其自身mRNA的翻译限制在最低水平，以确保其基本功能，从而同时将免疫识别降至最低。确定干扰EBNA1免疫逃逸的干预点是引发针对携带EBV癌症的免疫反应的重要一步。得益于一种基于酵母的检测方法，该方法概括了EBNA1自我限制表达的所有方面，Lista最近的一项研究[《自然通讯》（2017年）7，435 - 444]通过宿主细胞核仁素（NCL）与EBNA1 mRNA编码GAr序列中形成的G-四链体（G4）的直接相互作用，揭示了宿主细胞NCL在此过程中的作用。此外，G4配体PhenDC3可阻止NCL与EBNA1 mRNA结合，并逆转GAr介导的翻译抑制和抗原呈递。这表明NCL-EBNA1 mRNA相互作用是将携带EBV的癌症暴露于免疫系统的一个相关治疗靶点，并且酵母模型可成功用于发现干扰EBV隐匿性的药物和宿主因子。
