Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways
Reactivation of Kaposi's sarcoma-associated herpesvirus from latency requires MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways
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DOI：
10.1016/j.virol.2007.09.040
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发表时间：
2008-02-05
期刊：
影响因子：
3.7
通讯作者：
Gao, Shou-Jiang
中科院分区：
文献类型：
--
作者：
Xie, Jianping;Ajibade, Adetola Olalekan;Gao, Shou-Jiang
卡波西肉瘤相关疱疹病毒（KSHV）的裂解复制促进了卡波西肉瘤（KS）的进展，这是艾滋病患者的主要恶性肿瘤。虽然12- o -十四烷醇-13-醋酸酯（TPA）诱导的KSHV潜伏期再激活是由蛋白激酶C δ和MEK/ERK丝裂原激活蛋白激酶（MAPK）途径介导的，但我们最近发现MEK/ERK、JNK和p38 MAPK途径在人脐静脉内皮细胞的生产初级感染过程中调节KSHV裂解复制[Pan， H., Xie， J., Ye， F., Gao, sj ., 2006]。原发性感染期间MEK/ERK、JNK和p38多重丝裂原激活蛋白激酶途径对卡波西肉瘤相关疱疹病毒感染和复制的调节[j].中国生物医学工程学报，2016,32(2):444 - 444。在这里，我们报道，除了MEK/ERK途径，JNK和p38 MAPK途径也介导tpa诱导的潜伏期KSHV再激活。潜伏kshv感染的BCBL-1细胞中MEK/ERK、JNK和p38 MAPK通路组成性激活。TPA处理提高了活化ERK和p38的水平，但没有提高活化JNK的水平。所有三种MAPK途径的抑制剂以剂量依赖的方式减少tpa诱导的bccl -1细胞中KSHV感染性病毒粒子的产生。这些抑制剂在KSHV再激活的早期阶段阻断了病毒的裂解复制，并降低了病毒裂解基因的表达，包括RTA， RTA是病毒裂解复制的一个关键的即时早期反激活因子。激活MAPK通路是激活RTA启动子的必要和充分条件。此外，我们发现MAPK途径激活RTA启动子是由其下游靶点AP-1介导的。总之，这些发现表明，MAPK通路可能通过介导病毒感染和从病毒潜伏期到裂解复制的转换，在调节KSHV的生命周期中具有一般作用。(c) 2007爱思唯尔公司版权所有。
Lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV) promotes the progression of Kaposi's sarcoma (KS), a dominant malignancy in patients with AIDS. While 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced KSHV reactivation from latency is mediated by the protein kinase C delta and MEK/ERK mitogen-activated protein kinase (MAPK) pathways, we have recently shown that the MEK/ERK, JNK and p38 MAPK pathways modulate KSHV lytic replication during productive primary infection of human umbilical vein endothelial cells [Pan, H., Xie, J., Ye, F., Gao, S.J., 2006. Modulation of Kaposi's sarcoma-associated herpesvirus infection and replication by MEK/ERK, JNK, and p38 multiple mitogen-activated protein kinase pathways during primary infection. J. Virol. 80 (11), 5371-5382]. Here, we report that, besides the MEK/ERK pathway, the JNK and p38 MAPK pathways also mediate TPA-induced KSHV reactivation from latency. The MEK/ERK, JNK and p38 MAPK pathways were constitutively activated in latent KSHV-infected BCBL-1 cells. TPA treatment enhanced the levels of activated ERK and p38 but not those of activated JNK. Inhibitors of all three MAPK pathways reduced TPA-induced production of KSHV infectious virions in BCBL-1 cells in a dose-dependent fashion. The inhibitors blocked KSHV lytic replication at the early stage(s) of reactivation, and reduced the expression of viral lytic genes including RTA, a key immediate-early transactivator of viral lytic replication. Activation of MAPK pathways was necessary and sufficient for activating the promoter of RTA. Furthermore, we showed that the activation of RTA promoter by MAPK pathways was mediated by their downstream target AP-1. Together, these findings suggest that MAPK pathways might have general roles in regulating the life cycle of KSHV by mediating both viral infection and switch from viral latency to lytic replication. (c) 2007 Elsevier Inc. All rights reserved.