BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon De Novo Infection.
BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon De Novo Infection.
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DOI：
10.1128/msphere.00138-18
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发表时间：
2018-04-25
期刊：
影响因子：
4.8
通讯作者：
Murata T
中科院分区：
文献类型：
--
作者：
Konishi N;Narita Y;Hijioka F;Masud HMAA;Sato Y;Kimura H;Murata T
EB病毒（EBV）是一种致癌的γ疱疹病毒，携带约80个基因。虽然一些基因已被广泛研究，但大多数裂解基因仍在很大程度上未被探索。因此，我们将71个EBV裂解基因克隆到表达载体中，并使用报告基因测定来筛选激活信号转导途径、病毒和细胞启动子的因子。BGLF 2可能通过与p38和c-Jun N-末端激酶（JNK）相互作用激活AP-1信号通路，并增加病毒的感染性。我们还发现BKRF 4可以负调控AP-1活性。因此，它表明，EBV利用和修改AP-1信号通路的复制和生存。EB病毒（Epstein-Barr virus，EBV）是一种引起传染性单核细胞增多症和几种恶性肿瘤（如地方性伯基特淋巴瘤和鼻咽癌）的人类γ疱疹病毒。疱疹病毒携带可以改变细胞功能的基因，包括转录和泛素化，从而促进病毒在感染细胞中的生长和存活。使用报告筛选系统，我们揭示了参与这些过程中的几个EBV基因产物。其中，BGLF 2通过磷酸化p38和c-Jun N-末端激酶（JNK）激活AP-1信号通路。BGLF 2基因的敲除不影响病毒基因表达和病毒基因组DNA复制，但导致子代滴度显著降低。我们还发现，BGLF 2破坏导致从头感染后感染性显著丧失。有趣的是，结合伴侣BKRF 4的表达抑制了BGLF 2对AP-1的激活。这些结果揭示了皮层蛋白BGLF 2的生理作用。重要性EB病毒（EBV）是一种致癌的γ疱疹病毒，携带约80个基因。虽然一些基因已被广泛研究，但大多数裂解基因仍在很大程度上未被探索。因此，我们将71个EBV裂解基因克隆到表达载体中，并使用报告基因测定来筛选激活信号转导途径、病毒和细胞启动子的因子。BGLF 2可能通过与p38和c-Jun N-末端激酶（JNK）相互作用激活AP-1信号通路，并增加病毒的感染性。我们还发现BKRF 4可以负调控AP-1活性。因此，它表明，EBV利用和修改AP-1信号通路的复制和生存。
Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, carries ~80 genes. While several genes have been investigated extensively, most lytic genes remain largely unexplored. Therefore, we cloned 71 EBV lytic genes into an expression vector and used reporter assays to screen for factors that activate signal transduction pathways, viral and cellular promoters. BGLF2 activated the AP-1 signaling pathway, likely by interacting with p38 and c-Jun N-terminal kinase (JNK), and increased infectivity of the virus. We also revealed that BKRF4 can negatively regulate AP-1 activity. Therefore, it is suggested that EBV exploits and modifies the AP-1 signaling pathway for its replication and survival. Epstein-Barr virus (EBV) is a human gammaherpesvirus that causes infectious mononucleosis and several malignancies, such as endemic Burkitt lymphoma and nasopharyngeal carcinoma. Herpesviruses carry genes that can modify cell functions, including transcription and ubiquitination, thereby facilitating viral growth and survival in infected cells. Using a reporter screening system, we revealed the involvement of several EBV gene products in such processes. Of these, BGLF2 activated the AP-1 signaling pathway through phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Knockout of the BGLF2 gene did not affect viral gene expression and viral genome DNA replication, but resulted in marked reduction of progeny titer. We also found that the BGLF2 disruption resulted in significant loss of infectivity upon de novo infection. Interestingly, expression of a binding partner, BKRF4, repressed the activation of AP-1 by BGLF2. These results shed light on the physiological role of the tegument protein BGLF2. IMPORTANCE Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, carries ~80 genes. While several genes have been investigated extensively, most lytic genes remain largely unexplored. Therefore, we cloned 71 EBV lytic genes into an expression vector and used reporter assays to screen for factors that activate signal transduction pathways, viral and cellular promoters. BGLF2 activated the AP-1 signaling pathway, likely by interacting with p38 and c-Jun N-terminal kinase (JNK), and increased infectivity of the virus. We also revealed that BKRF4 can negatively regulate AP-1 activity. Therefore, it is suggested that EBV exploits and modifies the AP-1 signaling pathway for its replication and survival.