HIV-1 Tat represses transcription from the mannose receptor promoter
HIV-1 Tat represses transcription from the mannose receptor promoter
复制标题
DOI：
10.4049/jimmunol.165.12.7035
复制
发表时间：
2000-12-15
影响因子：
4.4
通讯作者：
Shepherd, VL
中科院分区：
文献类型：
--
作者：
Caldwell, RL;Egan, BS;Shepherd, VL
甘露糖受体在成熟的巨噬细胞和未成熟的树突细胞上表达，并起到介导病原体的吞噬作用和捕获Ag以递送至含有MHC II类的细胞内区室的作用。先前已经报道，HIV-1感染的巨噬细胞与甘露糖受体相关的功能降低，包括卡氏肺孢子虫吞噬作用和甘露糖基化白蛋白摄取受损。包括达特蛋白在内的几种HIV-1衍生蛋白已显示转录抑制宿主细胞基因。本研究旨在确定HIV-1衍生蛋白达特在HIV介导的甘露糖受体下调中的作用。用达特表达载体和甘露糖受体启动子-荧光素酶报告基因构建体共转染人巨噬细胞系U937，导致甘露糖受体启动子活性下调。这种抑制作用靶向于基础启动子。单外显子或双外显子达特的表达均导致启动子活性降低，转录激活反应元件（TAR）序列的加入增强了Tat介导的抑制作用。当转染的细胞用外源添加的达特蛋白处理时，也观察到下调。这些结果与焦油通过干扰宿主转录起始机制降低甘露糖受体启动子活性的机制一致，可能导致可用于Ag或病原体捕获的表面甘露糖受体水平降低。
The mannose receptor is expressed on mature macrophages and immature dendritic cells, and functions to mediate phagocytosis of pathogens and capture of Ags for delivery to MHC class II-containing intracellular compartments. It has been previously reported that HIV-1-infected macrophages have reduced functions associated with the mannose receptor, including impaired Pneumocystis carinii phagocytosis and mannosylated albumin uptake. Several HIV-1-derived proteins including the Tat protein have been shown to transcriptionally repress host cell genes. The present study was undertaken to define the role of the HIV-1-derived protein Tat in HIV-mediated mannose receptor down-regulation. Cotransfection of the human macrophage cell line U937 with a Tat expression vector and a mannose receptor promoter-luciferase reporter construct resulted in down-regulation of mannose receptor promoter activity. This repression was targeted to the basal promoter. Expression of either one- or two-exon Tat resulted in decreased promoter activity, The addition of the transactivation response element (TAR) sequence enhanced the Tat-mediated repression. Down-regulation was also seen when transfected cells were treated with exogenously added Tat protein, These results are consistent with a mechanism whereby Tar reduces mannose receptor promoter activity by interfering with the host transcriptional initiation machinery, potentially resulting in decreased levels of surface mannose receptor available for Ag or pathogen capture.