The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1
The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1
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DOI：
10.1128/jvi.74.15.6790-6799.2000
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发表时间：
2000-08-01
影响因子：
5.4
通讯作者：
Margolis, DM
中科院分区：
文献类型：
--
作者：
Coull, JJ;Romerio, F;Margolis, DM
在人类免疫缺陷病毒1型（HIV - 1）感染后，神秘的机制使激活的淋巴细胞恢复静息状态，很少出现持续性非生产性感染。我们详细阐述了一种细胞因子可建立病毒潜伏的机制。转录因子YY1和LSF协同抑制HIV - 1长末端重复序列（LTR）的转录。LSF通过YY1的锌指结构将YY1募集到LTR。据观察，前两个锌指结构在体外足以进行这种相互作用。一种无法结合DNA的LSF突变体阻断了抑制作用。像其他转录抑制因子一样，YY1可通过募集组蛋白去乙酰化酶（HDAC）发挥作用。我们发现HDAC1与结合LTR的YY1 - LSF抑制复合物共纯化，YY1与HDAC1相互作用的结构域是抑制HIV - 1启动子所必需的，HDAC1的表达增强了YY1对LTR的抑制作用，而去乙酰化酶抑制剂曲古抑菌素A阻断了由YY1介导的抑制作用。在整合到染色体DNA中的病毒启动子的自然环境下，HDAC募集与YY1和LSF对HIV - 1表达的抑制之间的这种新联系，首次证明了HIV - 1抑制的分子机制。YY1和LSF可能建立HIV的转录和病毒潜伏状态，这种状态最近在体内已被确认，并且对艾滋病的长期治疗具有重要意义。
Enigmatic mechanisms restore the resting state in activated lymphocytes following human immunodeficiency virus type 1 (HIV-1) infection, rarely allowing persistent nonproductive infection. We detail a mechanism whereby cellular factors could establish virological latency. The transcription factors YY1 and LSF cooperate in repression of transcription from the HIV-1 long terminal repeat (LTR). LSF recruits YY1 to the LTR via the zinc fingers of YY1. The first two zinc fingers were observed to be sufficient for this interaction in vitro. A mutant of LSF incapable of binding DNA blocked repression. Like other transcriptional repressors, YY1 can function via recruitment of histone deacetylase (HDAC). We find that HDAC1 copurifies with the LTR-binding YY1-LSF repressor complex, the domain of YY1 that interacts with HDAC1 is required to repress the HIV-1 promoter, expression of HDAC1 augments repression of the LTR by YY1, and the deacetylase inhibitor trichostatin A blocks repression mediated by YYI. This novel link between HDAC recruitment and inhibition of HIV-1 expression by YY1 and LSF, in the natural context of a viral promoter integrated into chromosomal DNA, is the first demonstration of a molecular mechanism of repression of HUV-1. YY1 and LSF may establish transcriptional and virological latency of HIV, a state that has recently been recognized in vivo and has significant implications for the long-term treatment of AIDS.