Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress-induced transcription factors ATF4 and CHOP
Regulation of gammaherpesvirus lytic replication by endoplasmic reticulum stress-induced transcription factors ATF4 and CHOP
复制标题
内质网应激诱导转录因子 ATF4 和 CHOP 对伽玛疱疹病毒裂解性复制的调节
DOI：
10.1074/jbc.m117.813675
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发表时间：
2018
影响因子：
4.8
通讯作者：
Xiao-zhen Liang
中科院分区：
文献类型：
--
作者：
Xingchen-Zhou;Sihan-Dong;Zhongshun-Liu;Shuai Liu;Chao-can Zhang;Xiao-zhen Liang
内质网(ER)中的应激诱导未折叠蛋白反应(UPR)涉及多种信号通路，控制着细胞的命运。B细胞受体(BCR)信号可以触发UPR，诱导伽玛疱疹病毒裂解复制，是体内伽马疱疹病毒重新激活的生理机制。然而，UPR如何调控BCR介导的伽马疱疹病毒感染尚不清楚。在这里，我们证明了内质网应激源衣霉素和thapsigargin通过诱导UPR介导物Bip的表达和阻断Akt、ERK和JNK的激活来抑制BCR介导的小鼠伽马疱疹病毒68(MHV68)的裂解复制。Bip和下游转录因子ATF4均抑制BCR介导的MHV68裂解基因的表达，而UPR诱导的C/EBP同源蛋白(CHOP)通过抑制上游Bip和ATF4的表达而促进BCR介导的MHV68裂解复制。BIP基因敲除足以挽救BCR介导的MHV68裂解基因在CHOP基因敲除细胞中的表达，这种挽救被异位ATF4表达阻断。此外，ATF4还直接抑制了MHV68裂解开关反式激活子RTA的启动子活性。综上所述，我们表明内质网应激诱导的CHOP抑制BiP和ATF4的表达，而ATF4反过来在CHOP介导的BCR控制的MHV68裂解复制的调节中发挥关键作用。我们认为，内质网应激介导的UPR和BCR信号通路是相互联系的，并形成一个复杂的网络来调节伽马疱疹病毒的感染周期。
The stress-induced unfolded protein response (UPR) in the endoplasmic reticulum (ER) involves various signaling cross-talks and controls cell fate. B-cell receptor (BCR) signaling, which can trigger UPR, induces gammaherpesvirus lytic replication and serves as a physiological mechanism for gammaherpesvirus reactivationin vivo. However, how the UPR regulates BCR-mediated gammaherpesvirus infection is unknown. Here, we demonstrate that the ER stressors tunicamycin and thapsigargin inhibit BCR-mediated murine gammaherpesvirus 68 (MHV68) lytic replication by inducing expression of the UPR mediator Bip and blocking activation of Akt, ERK, and JNK. Both Bip and the downstream transcription factor ATF4 inhibited BCR-mediated MHV68 lytic gene expression, whereas UPR-induced C/EBP homologous protein (CHOP) was required for and promoted BCR-mediated MHV68 lytic replication by suppressing upstream Bip and ATF4 expression. Bip knockout was sufficient to rescue BCR-mediated MHV68 lytic gene expression in CHOP knockout cells, and this rescue was blocked by ectopic ATF4 expression. Furthermore, ATF4 directly inhibited promoter activity of the MHV68 lytic switch transactivator RTA. Altogether, we show that ER stress–induced CHOP inhibits Bip and ATF4 expression and that ATF4, in turn, plays a critical role in CHOP-mediated regulation of BCR-controlled MHV68 lytic replication. We conclude that ER stress–mediated UPR and BCR signaling pathways are interconnected and form a complex network to regulate the gammaherpesvirus infection cycle.