Competition between PAF1 and MLL1/COMPASS confers the opposing function of LEDGF/p75 in HIV latency and proviral reactivation
Competition between PAF1 and MLL1/COMPASS confers the opposing function of LEDGF/p75 in HIV latency and proviral reactivation
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PAF1 和 MLL1/COMPASS 之间的竞争赋予 LEDGF/p75 在 HIV 潜伏期和前病毒再激活中相反的功能
DOI：
10.1126/sciadv.aaz8411
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发表时间：
2020-05-01
期刊：
影响因子：
13.6
通讯作者：
Hu, Deqing
中科院分区：
文献类型：
--
作者：
Gao, Ru;Bao, Jiaqian;Hu, Deqing
LEDGF/p75在HIV潜伏期和前病毒再激活期间差异调节病毒转录。转录状态决定了HIV在感染者体内的复制状态。然而，前病毒复制控制的转录机制仍不清楚。在这项研究中，我们表明，除了其在HIV整合的功能，LEDGF/p75差异调节HIV转录的潜伏期和前病毒再激活。在潜伏期，LEDGF/p75抑制前病毒转录通过启动子近端暂停RNA聚合酶II（Pol II）招募PAF 1复合物的前病毒。潜伏期逆转后，MLL 1复合物通过酪蛋白激酶II（CKII）依赖性与LEDGF/p75的结合，竞争性取代前病毒中的PAF 1。消耗或抑制CKII可防止PAF 1解离，并消除MLL 1和超延伸复合物（SEC）向原病毒的募集，从而削弱潜伏期逆转的转录再激活。因此，这些发现提供了一个机制的理解LEDGF/p75如何协调其独特的调节功能，在不同阶段的后整合的艾滋病毒生命周期。针对这些机制可能具有根除HIV感染的治疗潜力。
LEDGF/p75 differentially regulates viral transcription during HIV latency and proviral reactivation. Transcriptional status determines the HIV replicative state in infected patients. However, the transcriptional mechanisms for proviral replication control remain unclear. In this study, we show that, apart from its function in HIV integration, LEDGF/p75 differentially regulates HIV transcription in latency and proviral reactivation. During latency, LEDGF/p75 suppresses proviral transcription via promoter-proximal pausing of RNA polymerase II (Pol II) by recruiting PAF1 complex to the provirus. Following latency reversal, MLL1 complex competitively displaces PAF1 from the provirus through casein kinase II (CKII)–dependent association with LEDGF/p75. Depleting or pharmacologically inhibiting CKII prevents PAF1 dissociation and abrogates the recruitment of both MLL1 and Super Elongation Complex (SEC) to the provirus, thereby impairing transcriptional reactivation for latency reversal. These findings, therefore, provide a mechanistic understanding of how LEDGF/p75 coordinates its distinct regulatory functions at different stages of the post-integrated HIV life cycles. Targeting these mechanisms may have a therapeutic potential to eradicate HIV infection.