RETINOIC ACID IS A NEGATIVE REGULATOR OF THE EPSTEIN-BARR-VIRUS PROTEIN (BZLF1) THAT MEDIATES DISRUPTION OF LATENT INFECTION
RETINOIC ACID IS A NEGATIVE REGULATOR OF THE EPSTEIN-BARR-VIRUS PROTEIN (BZLF1) THAT MEDIATES DISRUPTION OF LATENT INFECTION
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DOI：
10.1073/pnas.90.9.3894
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发表时间：
1993-05-01
影响因子：
11.1
通讯作者：
KENNEY, S
中科院分区：
文献类型：
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作者：
SISTA, ND;PAGANO, JS;KENNEY, S
EB病毒潜伏感染的阻断是由关键的即刻早期蛋白BZLF1(或Z，碱性亮氨酸拉链家族的成员)诱导的，它反式激活病毒早期启动子。病毒重新激活的标志是早期基因产物的重新合成，如EBV早期抗原扩散(EA-D)。维甲酸此前已被证明可抑制EBV感染的重新激活。维甲酸反应受体是已知的正向调节转录因子，但也可以负向调节AP-1反应基因。在这里，我们证明了维甲酸受体α(RARpha)和维甲酸X受体α(RXRpha)抑制Z蛋白反式激活病毒早期启动子BMRF1的能力，BMRF1指导EA-D的转录。Z还可以通过非DNA结合机制相互抑制RARpha和RXRpha诱导的RARbeta基因(BRE)自动调节细胞启动子的激活。RXRpha抑制Z与BMRF1启动子中的AP-1基序结合，Z反过来抑制RARpha与BRE启动子中的维甲酸反应元件结合。此外，谷胱甘肽-S-转移酶-RXRα融合蛋白可以直接与Z蛋白相互作用。这些结果表明，Z(病毒蛋白)和RARpha和RXRpha(细胞蛋白)之间的直接蛋白质-蛋白质相互作用可以调节潜伏的EBV感染的重新激活。
Disruption of latent Epstein-Barr virus (EBV) infection is induced by the key immediate-early protein BZLF1 (or Z, a member of the basic leucine-zipper family), which transactivates the viral early promoters. Viral reactivation is marked by renewed synthesis of early gene products such as EBV early antigen-diffuse (EA-D). Retinoic acid has been previously shown to inhibit reactivation of EBV infection. Retinoic acid responsive receptors are known to act as positively regulating transcription factors but can also negatively regulate AP-1 responsive genes. Here we demonstrate that the retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha) inhibit the ability of the Z protein to transactivate the viral early promoter BMRF1, which directs transcription of EA-D. Z can also reciprocally inhibit RARalpha- and RXRalpha-induced activation of an autoregulated cellular promoter for the RARbeta gene (BRE) through a non-DNA binding mechanism. RXRalpha inhibits Z from binding to the AP-1 motif in the BMRF1 promoter and, reciprocally, Z inhibits RARalpha from binding to its retinoic acid response element in the BRE promoter. Furthermore, a glutathione-S-transferase-RXRalpha fusion protein can interact directly with the Z protein. These results suggest that a direct protein-protein interaction between Z (the viral protein) and RARalpha and RXRalpha (cellular proteins) can modulate the reactivation of latent EBV infection.