Department of Pathology, University of Pittsburgh and Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Blood. 2011 Nov 17;118(20):5528-39. doi: 10.1182/blood-2011-04-347112. Epub 2011 Aug 17.
Endoplasmic reticulum (ER) stress triggers a homeostatic cellular response in mammalian cells to ensure efficient folding, sorting, and processing of client proteins. In lytic-permissive lymphoblastoid cell lines (LCLs), pulse exposure to the chemical ER-stress inducer thapsigargin (TG) followed by recovery resulted in the activation of the EBV immediate-early (BRLF1, BZLF1), early (BMRF1), and late (gp350) genes, gp350 surface expression, and virus release. The protein phosphatase 1 a (PP1a)-specific phosphatase inhibitor Salubrinal (SAL) synergized with TG to induce EBV lytic genes; however, TG treatment alone was sufficient to activate EBV lytic replication. SAL showed ER-stress-dependent and -independent antiviral effects, preventing virus release in human LCLs and abrogating gp350 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated B95-8 cells. TG resulted in sustained BCL6 but not BLIMP1 or CD138 expression, which is consistent with maintenance of a germinal center B-cell, rather than plasma-cell, phenotype. Microarray analysis identified candidate genes governing lytic replication in LCLs undergoing ER stress.
内质网（ER）应激会在哺乳动物细胞中引发一种稳态的细胞反应，以确保客户蛋白的有效折叠、分类和处理。在裂解型允许的淋巴母细胞系（LCL）中，用化学 ER 应激诱导剂他普西龙（TG）脉冲处理，然后恢复，会导致 EBV 即刻早期（BRLF1、BZLF1）、早期（BMRF1）和晚期（gp350）基因、gp350 表面表达和病毒释放的激活。蛋白磷酸酶 1a（PP1a）特异性磷酸酶抑制剂 Salubrinal（SAL）与 TG 协同诱导 EBV 裂解基因；然而，TG 单独处理足以激活 EBV 裂解复制。SAL 表现出 ER 应激依赖性和非依赖性的抗病毒作用，防止人 LCL 中的病毒释放，并在 TPA 处理的 B95-8 细胞中阻断 gp350 的表达。TG 导致 BCL6 的持续表达，但不导致 BLIMP1 或 CD138 的表达，这与维持生发中心 B 细胞而不是浆细胞表型一致。微阵列分析确定了在经历 ER 应激的 LCL 中控制裂解复制的候选基因。
