NFκB and Cyclic AMP Response Element Sites Mediate the Valproic Acid and UL138 Responsiveness of the Human Cytomegalovirus Major Immediate Early Enhancer and Promoter.
NFκB and Cyclic AMP Response Element Sites Mediate the Valproic Acid and UL138 Responsiveness of the Human Cytomegalovirus Major Immediate Early Enhancer and Promoter.
复制标题
NFκB 和环 AMP 反应元件位点介导人类巨细胞病毒主要立即早期增强子和启动子的丙戊酸和 UL138 反应性。
DOI：
10.1128/jvi.00029-23
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发表时间：
2023
影响因子：
5.4
通讯作者：
Kalejta,RobertF
中科院分区：
文献类型：
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作者：
Albright,EmilyR;Walter,RyanM;Saffert,RyanT;Kalejta,RobertF
人巨细胞病毒（HCMV）的主要立即早期增强子和启动子（MIEP）驱动立即早期1（IE 1）和IE 2基因的转录，其编码的蛋白质刺激生产性裂解复制。MIEP在完全分化的细胞的去溶病毒感染开始时被病毒编码和被膜递送的pp 71蛋白激活。相反，MIEP在未完全分化的髓样细胞内的新生潜伏性感染开始时沉默，部分原因是被膜递送的pp 71被隔离在这些细胞的细胞质中，但也被抑制该位点转录的病毒因子，包括UL 138蛋白。在这两种感染模式中，MIEP活性可以通过组蛋白去乙酰化酶抑制剂丙戊酸（VPA）增加;然而，UL 138抑制MIEP的VPA反应性。在这里，我们发现，两个家族的细胞转录因子，NF-κB和cAMP反应元件结合蛋白（CREB），共同控制VPA介导的激活和UL 138介导的抑制HCMV MIEP. IMPORTANCEHCMV MIEP的人工调节，无论是激活或抑制，是一个有吸引力的潜在手段，针对潜伏的水库病毒，目前还没有可用的干预。MIEP可以被抑制以防止潜伏期再激活，或者被诱导以驱使病毒进入免疫系统可见的裂解阶段，并被多种小分子抗病毒药物抑制。了解MIEP是如何监管的是设计和实施这两种战略的关键部分。我们发现NF-κB和CREB控制MIEP对病毒UL 138蛋白的反应性，FDA批准的药物VPA可以帮助制定和执行针对潜伏HCMV的启动子调控策略。
The major immediate early enhancer and promoter (MIEP) of human cytomegalovirus (HCMV) drives the transcription of the immediate early one (IE1) and IE2 genes, whose encoded proteins stimulate productive, lytic replication. The MIEP is activated by the virally encoded and tegument-delivered pp71 protein at the start ofde novolytic infections of fully differentiated cells. Conversely, the MIEP is silenced at the start ofde novolatent infections within incompletely differentiated myeloid cells in part because tegument-delivered pp71 is sequestered in the cytoplasm in these cells, but also by viral factors that repress transcription from this locus, including the UL138 protein. During both modes of infection, MIEP activity can be increased by the histone deacetylase inhibitor valproic acid (VPA); however, UL138 inhibits the VPA-responsiveness of the MIEP. Here, we show that two families of cellular transcription factors, NF-κB and cAMP response element-binding protein (CREB), together control the VPA-mediated activation and UL138-mediated repression of the HCMV MIEP.IMPORTANCEArtificial regulation of the HCMV MIEP, either activation or repression, is an attractive potential means to target the latent reservoirs of virus for which there is currently no available intervention. The MIEP could be repressed to prevent latency reactivation or induced to drive the virus into the lytic stage that is visible to the immune system and inhibited by multiple small-molecule antiviral drugs. Understanding how the MIEP is regulated is a critical part of designing and implementing either strategy. Our revelation here that NF-κB and CREB control the responsiveness of the MIEP to the viral UL138 protein and the FDA-approved drug VPA could help in the formulation and execution of promoter regulatory strategies against latent HCMV.