PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.
PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.
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DOI：
10.15252/embr.201949305
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发表时间：
2020-11-05
期刊：
影响因子：
7.7
通讯作者：
Zhu H
中科院分区：
文献类型：
--
作者：
Yang X;Wang Y;Lu P;Shen Y;Zhao X;Zhu Y;Jiang Z;Yang H;Pan H;Zhao L;Zhong Y;Wang J;Liang Z;Shen X;Lu D;Jiang S;Xu J;Wu H;Lu H;Jiang G;Zhu H
潜伏的HIV-1储库是病毒根除的主要障碍。然而，我们对HIV-1如何建立潜伏期的理解是不完整的。在这里，通过进行全基因组CRISPR-Cas9敲除文库筛选，我们鉴定出磷脂酰乙醇胺结合蛋白1（PEBP 1），也称为Raf激酶抑制蛋白（RKIP），作为诱导HIV潜伏期的新基因。PEBP 1的消耗导致HIV-1在多种潜伏期模型中重新激活。从机制上讲，PEBP 1使Raf 1/ERK/IκB和IKK/IκB信号通路去磷酸化，将NF-κB隔离在细胞质中，从而使HIV-1转录失活，诱导潜伏期。重要的是，由绿色茶化合物表没食子儿茶素-3-没食子酸酯（EGCG）诱导的PEBP 1表达通过抑制NF-κB的核转位来防止潜伏期逆转，从而抑制从接受抗逆转录病毒治疗（ART）的患者分离的原代CD 4 + T细胞中的HIV-1转录。这些结果表明PEBP 1在调控HIV转录的上游NF-κB信号通路中起关键作用。靶向这一途径可能是未来控制患者体内HIV宿主的一种选择。潜伏的HIV-1储库阻止了有效的病毒根除。磷酸酶PEBP 1在调控HIV-1转录的NF-κB依赖性途径中起着关键作用，其靶向作用可以控制患者体内的HIV储库。
The latent HIV‐1 reservoir is a major barrier to viral eradication. However, our understanding of how HIV‐1 establishes latency is incomplete. Here, by performing a genome‐wide CRISPR‐Cas9 knockout library screen, we identify phosphatidylethanolamine‐binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein (RKIP), as a novel gene inducing HIV latency. Depletion of PEBP1 leads to the reactivation of HIV‐1 in multiple models of latency. Mechanistically, PEBP1 de‐phosphorylates Raf1/ERK/IκB and IKK/IκB signaling pathways to sequestrate NF‐κB in the cytoplasm, which transcriptionally inactivates HIV‐1 to induce latency. Importantly, the induction of PEBP1 expression by the green tea compound epigallocatechin‐3‐gallate (EGCG) prevents latency reversal by inhibiting nuclear translocation of NF‐κB, thereby suppressing HIV‐1 transcription in primary CD4+ T cells isolated from patients receiving antiretroviral therapy (ART). These results suggest a critical role for PEBP1 in the regulation of upstream NF‐κB signaling pathways governing HIV transcription. Targeting of this pathway could be an option to control HIV reservoirs in patients in the future. The latent HIV‐1 reservoir prevents efficient viral eradication. The phosphatase PEBP1 plays a critical role in the regulation of NF‐κB‐dependent pathways governing HIV‐1 transcription, and its targeting could control HIV reservoirs in patients.