CDK9 相互作用组的定量蛋白质组学揭示了 HSP90-CDC37-P-TEFb 复合物对 BETi 诱导的 HIV-1 潜伏期再激活的功能,Journal of Proteome Research

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CDK9 相互作用组的定量蛋白质组学揭示了 HSP90-CDC37-P-TEFb 复合物对 BETi 诱导的 HIV-1 潜伏期再激活的功能
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2023-08-04 , DOI: 10.1021/acs.jproteome.3c00162
Cong Wang _{1,

2} , Chunjing Chen ₁ , Zhenrui Pan ₁ , Yaohui He ₁ , Zhanming Zhang ₁ , Rongdiao Liu _{1,

3} , Yuhua Xue ₁ , Qiang Zhou _{3,

4} , Xiang Gao ₁

Affiliation

Brd4 作为一种有前途的药物靶点已被深入研究，因为它在肿瘤发生、炎症和 HIV-1 转录中发挥着重要作用。Brd4-P-TEFb (CDK9/Cyclin T1) 复合物的形成及其对转录延伸的调节对于 HIV 潜伏期重新激活和许多癌基因的表达至关重要。为了进一步研究 Brd4-P-TEFb 复合物控制伸长的机制，对 CDK9 相互作用组进行了基于质谱的定量蛋白质组学。使用选择性 BET 溴结构域抑制剂 JQ1 处理后，352 个蛋白质被成功鉴定为 CDK9 相互作用蛋白，且可信度较高。其中，HSP90和CDC37与CDK9的结合增加尤其引人注目，我们的数据表明HSP90-CDC37-P-TEFb复合物参与BETi诱导的HIV-1重新激活过程中控制P-TEFb复合物的动态平衡。 1 延迟。此外，HSP90-CDC37-P-TEFb 复合物直接调节 HIV-1 转录，并依赖热休克因子 1 (HSF1) 的募集来与 HIV-1 启动子结合。这些结果增进了对 HSP90-CDC37-P-TEFb 在 HIV-1 潜伏期逆转中的理解，并启发开发使用靶向药物组合来根除 HIV-1 的潜在策略。

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Quantitative Proteomics of the CDK9 Interactome Reveals a Function of the HSP90-CDC37-P-TEFb Complex for BETi-Induced HIV-1 Latency Reactivation

Brd4 has been intensively investigated as a promising drug target because of its implicated functions in oncogenesis, inflammation, and HIV-1 transcription. The formation of the Brd4-P-TEFb (CDK9/Cyclin T1) complex and its regulation of transcriptional elongation are critical for HIV latency reactivation and expression of many oncogenes. To further investigate the mechanism of the Brd4-P-TEFb complex in controlling elongation, mass spectrometry-based quantitative proteomics of the CDK9 interactome was performed. Upon treatment with the selective BET bromodomain inhibitor JQ1, 352 proteins were successfully identified with high confidence as CDK9-interacting proteins. Among them, increased bindings of HSP90 and CDC37 to CDK9 were particularly striking, and our data suggest that the HSP90-CDC37-P-TEFb complex is involved in controlling the dynamic equilibrium of the P-TEFb complex during BETi-induced reactivation of HIV-1 latency. Furthermore, the HSP90-CDC37-P-TEFb complex directly regulates HIV-1 transcription and relies on recruitment by heat shock factor 1 (HSF1) for binding to the HIV-1 promoter. These results advance the understanding of HSP90-CDC37-P-TEFb in HIV-1 latency reversal and enlighten the development of potential strategies to eradicate HIV-1 using a combination of targeted drugs.

更新日期：2023-08-04

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