HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling.
HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling.
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HMBA 通过抑制 NF-κB 信号传导中负反馈调节器 A20/TNFAIP3 的表达来增强前列腺素诱导的潜在 HIV-1 激活
DOI：
10.1155/2016/5173205
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发表时间：
2016
影响因子：
--
通讯作者：
Liu M
中科院分区：
文献类型：
--
作者：
Chen D;Wang H;Aweya JJ;Chen Y;Chen M;Wu X;Chen X;Lu J;Chen R;Liu M
在过去的十年中，HIV-1的转录激活被认为是根除潜伏HIV-1前病毒的一种有希望的策略。两种药物，前列腺素和六亚甲基双乙酰胺（HMBA），已经显示出在单独使用或联合使用时作为释放HIV-1潜伏期的诱导剂的强大作用，尽管它们的细胞靶点目前还不清楚，特别是在药物联合使用时。在这里，我们已经证明HMBA和prostratin通过不同的机制协同释放HIV-1潜伏期。prostratin通过改善P-TEFb激活，强烈刺激HMBA诱导的HIV-1转录，而HMBA能够通过抑制prostratin诱导的去泛素酶A20的表达，促进NF-κB依赖性转录的启动。去泛素酶A20是NF-κB信号通路中的负反馈调节因子。此外，HMBA能够增加前列腺素诱导的NF-κB抑制剂i -κB α的磷酸化和降解，从而增强和延长前列腺素诱导的NF-κB核易位，这是刺激转录起始的先决条件。因此，通过阻断负反馈回路，HMBA作为NF-κB信号通路的信号增强剂发挥作用。
In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.