Hasegawa A, Yasukawa M, Sakai I, Fujita S
First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Japan.
J Immunol. 2001 Jan 15;166(2):1125-31. doi: 10.4049/jimmunol.166.2.1125.
We have recently reported that down-regulation of CXC chemokine receptor (CXCR) 4 in CD4(+) T lymphocytes is induced by human herpesvirus (HHV) 6 infection. In this study, we further studied the mechanisms of HHV-6-induced CXCR4 down-regulation, focusing on the regulation of CXCR4 transcription. Down-regulation of CXCR4 transcription was detected in HHV-6A-infected JJHAN and HHV-6B-infected MT-4 cell lines, as we had previously reported for HHV-6-infected peripheral blood CD4(+) T lymphocytes. Luciferase assays revealed that a YY1-binding site around -320 relative to the transcription start site is important for down-regulation of CXCR4 transcription in HHV-6-infected cells. The binding activity of YY1, which is a repressor of CXCR4 transcription, to the CXCR4 promoter appeared to significantly increase in HHV-6-infected cells compared with the binding activity in mock-infected cells. Immunoprecipitation assays showed that in HHV-6-infected cells association of c-Myc with YY1 was decreased and that of Max with c-Myc was increased, whereas association of Mad with Max appeared to be decreased. The amounts of each of YY1, c-Myc, Max, and Mad proteins synthesized in cells were not altered by HHV-6 infection. These data indicate that the decreased association of YY1 with c-Myc that is caused by impaired interaction in the c-Myc/Max/Mad network results in increased binding activity of YY1 to the CXCR4 promoter, mediating down-regulation of CXCR4 production in HHV-6-infected cells.
我们最近报道，人类疱疹病毒（HHV）6感染可诱导CD4(+) T淋巴细胞中CXC趋化因子受体（CXCR）4的下调。在本研究中，我们进一步研究了HHV-6诱导CXCR4下调的机制，重点关注CXCR4转录的调控。正如我们之前报道的HHV-6感染外周血CD4(+) T淋巴细胞一样，在HHV-6A感染的JJHAN和HHV-6B感染的MT-4细胞系中检测到CXCR4转录下调。荧光素酶检测显示，相对于转录起始位点约-320处的YY1结合位点对于HHV-6感染细胞中CXCR4转录的下调很重要。与模拟感染细胞中的结合活性相比，作为CXCR4转录抑制因子的YY1与CXCR4启动子的结合活性在HHV-6感染细胞中似乎显著增加。免疫沉淀分析表明，在HHV-6感染的细胞中，c-Myc与YY1的结合减少，Max与c-Myc的结合增加，而Mad与Max的结合似乎减少。HHV-6感染并未改变细胞中合成的YY1、c-Myc、Max和Mad蛋白各自的量。这些数据表明，c-Myc/Max/Mad网络中相互作用受损导致YY1与c-Myc的结合减少，从而导致YY1与CXCR4启动子的结合活性增加，介导HHV-6感染细胞中CXCR4产生的下调。
