The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC.
The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC.
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DOI：
10.1007/s13365-016-0435-6
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发表时间：
2016-10
影响因子：
3.2
通讯作者：
White MK
中科院分区：
文献类型：
--
作者：
Wollebo HS;Bellizzi A;Cossari DH;Salkind J;Safak M;White MK
Brd4 是一种表观遗传读取蛋白，也是 BET（溴结构域和额外末端结构域）蛋白家族的成员，具有两个识别乙酰化赖氨酸残基的溴结构域。 Brd4 特异性结合乙酰化转录因子 NF-κB p65 并共激活转录。多瘤病毒 JC (JCV) 受非编码控制区 (NCCR) 调节，该非编码控制区包含用于病毒基因表达的启动子/增强子元件，包括 NF-κB 结合位点，可响应 TNF-α 等促炎细胞因子、DNA 损伤反应、钙信号传导以及赖氨酸残基 K218 和 K221 上 NF-κB p65 亚基的乙酰化。早期研究表明，NF-κB 参与神经胶质细胞中持续性/潜伏性 JCV 的重新激活，从而引起进行性多灶性白质脑病 (PML)，这是一种由神经胶质细胞中 JCV 复制引起的严重脑脱髓鞘疾病。为了研究 NF-κB 乙酰化对 JCV 转录的作用机制，我们检测了 Brd4，发现 Brd4 通过 JCV NF-κB 位点刺激 JCV 早期转录，并且涉及 p65 K218 和 K221。用 Brd4 抑制剂 JQ1(+) 或 K218 或 K221 突变为谷氨酰胺（K218R 或 K221）治疗可抑制这种刺激并降低细胞核中 p65 的比例。我们得出结论，Brd4参与神经胶质细胞中JCV激活状态的调节。
Brd4 is an epigenetic reader protein and a member of the BET (bromodomain and extra terminal domain) family of proteins with two bromodomains that recognize acetylated lysine residues. Brd4 specifically binds to acetylated transcription factor NF-κB p65 and coactivates transcription. Polyomavirus JC (JCV) is regulated by a noncoding control region (NCCR) containing promoter/enhancer elements for viral gene expression including a binding site for NF-κB, which responds to proinflammatory cytokines such as TNF-α, the DNA damage response, calcium signaling and acetylation of the NF-κB p65 subunit on lysine residues K218 and K221. Earlier studies indicated that NF-κB is involved in the reactivation of persistent/latent JCV in glial cells to cause progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the brain caused by replication of JCV in glial cells. To investigate the mechanism of action of NF-κB acetylation on JCV transcription, we examined Brd4 and found that JCV early transcription was stimulated by Brd4 via the JCV NF-κB site and that p65 K218 and K221 were involved. Treatment with the Brd4 inhibitor JQ1(+) or mutation of either K218 or K221 to glutamine (K218R or K221) inhibited this stimulation and decreased the proportion of p65 in the nucleus. We conclude that Brd4 is involved in the regulation of the activation status of JCV in glial cells.
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影响因子：
3.7
作者：
Mbonye, Uri;Karn, Jonathan
通讯作者：
Karn, Jonathan
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.3
作者：
Bellizzi, Anna;White, Martyn K.;Wollebo, Hassen S.
通讯作者：
Wollebo, Hassen S.
影响因子：
3.6
作者：
Devaiah, Ballachanda N.;Singer, Dinah S.
通讯作者：
Singer, Dinah S.
DOI：
10.1073/pnas.1120422109
发表时间：
2012-05-01
影响因子：
11.1
作者：
Devaiah, Ballachanda N.;Lewis, Brian A.;Singer, Dinah S.
通讯作者：
Singer, Dinah S.