EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1:: role of NF-κB, STAT1, and p53
EBV latency III immortalization program sensitizes B cells to induction of CD95-mediated apoptosis via LMP1:: role of NF-κB, STAT1, and p53
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DOI：
10.1182/blood-2005-05-2053
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Feuillard, J
中科院分区：
文献类型：
--
作者：
Le Clorennec, C;Youlyouz-Marfak, I;Feuillard, J
EB病毒（EBV）诱导CD 95表达，并且CD 95基因（FAS）受NF-κ B、STAT 1和/或p53调节。为了了解这些因子在淋巴母细胞系（LCL）中EBV对CD 95的调节中的作用，我们克隆了显性活性I κ B α，活性I κ B α，（STAT 1 α）和非活性将STAT 11、p53（LMP 1的显性负突变体）和野生型LMP 1的STAT 1 β形式转化到新的双诱导型附加型载体中，pRT-1将这些质粒稳定转染到野生型LCL或EREB 2 -5细胞中，EREB 2 -5细胞是具有雌激素可调节的EBNA 2蛋白的LCL。抑制LMP 1信号转导降低了CD 95的表达，而过表达LMP 1则显著增加了CD 95的表达。EREB 2 -5细胞中潜伏期III程序的诱导与NF-κ B B、STAT 1和p53的激活相关。CD 95的表达受这3个转录系统的调控。STAT 1和p53的活化是继发于NF-κ B B活化。CD 95表面表达使EBV感染的B细胞对CD 95介导的凋亡的诱导敏感。发现体外抑制CD 95-CD 95配体相互作用可逆转EBV感染的B细胞的T细胞杀伤。因此，NF-κ B的LMP 1活化使受感染的B细胞对CD 95介导的凋亡敏感，并使EBV潜伏期III永生化的B细胞易于被免疫系统消除，有助于建立宿主/病毒平衡。
Epstein-Barr virus (EBV) induces CD95 expression and the CD95 gene (FAS) is regulated by NF-kappa B, STAT1, and/or p53. To understand the contribution of these factors in the regulation of CD95 by EBV in lymphoblastoid cell lines (LCLs), we cloned dominant-active I kappa B alpha, active (STAT1 alpha) and inactive (STAT1 beta) forms of STAT11, p53, a dominant-negative mutant of LMP1, and wild-type LMP1 into a novel double-inducible episomal vector, pRT-1 These plasmids were stably transfected either into wild-type LCLs or EREB2-5 cells, an LCL with an estrogen-regulatable EBNA2 protein. Inhibition of LMP1 signaling decreased expression of CD95, whereas overexpression of LMP1 markedly increased it. Induction of the latency III program in EREB2-5 cells correlated with activation of NF-kappa B, STAT1, and p53. CD95 expression was regulated by these 3 transcriptional systems. STAT1 and p53 activation were secondary to NF-kappa B activation. CD95 surface expression sensitized EBV-infected B cells to the induction of CD95-mediated apoptosis. In vitro inhibition of CD95-CD95 ligand interaction was found to reverse T-cell killing of EBV-Infected B cells. Therefore, LMP1 activation of NF-kappa B sensitizes infected B cells to CD95-mediated apoptosis and renders EBV latency III-immortalized B cells susceptible to elimination by the immune system, contributing to the establishment of a host/virus equilibrium.