Yang Yili, Dong Bei, Mittelstadt Paul R, Xiao Hua, Ashwell Jonathan D
Laboratory of Immune Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2002 May 31;277(22):19482-7. doi: 10.1074/jbc.M201687200. Epub 2002 Mar 21.
HIV Tat can enhance activation-induced up-regulation of Fas ligand (FasL), which may contribute to T cell apoptosis in human immune deficiency virus (HIV)-infected individuals. We have assessed functional and physical interactions between Tat and the Egr family of transcription factors (Egr-1, -2, and -3), the latter two of which are major participants in activation-induced FasL up-regulation. Here we report that whereas Tat itself has no effect on the FasL promoter, it binds to Egr-2 and -3 and synergizes with them to superinduce expression of a FasL promoter-driven reporter. A Tat molecule containing a single amino acid substitution that results in the loss of transactivation activity for the HIV long terminal repeat still binds Egr-3 but can no longer enhance Egr-mediated transactivation of the FasL promoter. Furthermore, the mutated Tat acts as a dominant negative inhibitor, blocking the superinduction of FasL caused by wild type Tat. Because Tat is present in virus-infected cells and in the serum of HIV-infected individuals, these results suggest that increased expression of FasL in these circumstances may result from the cooperative activities of activation-induced Egrs and Tat.
HIV反式激活因子（Tat）可增强激活诱导的Fas配体（FasL）上调，这可能导致人类免疫缺陷病毒（HIV）感染个体的T细胞凋亡。我们评估了Tat与早期生长反应（Egr）转录因子家族（Egr-1、-2和-3）之间的功能和物理相互作用，其中后两者是激活诱导的FasL上调的主要参与者。在此我们报告，虽然Tat本身对FasL启动子没有影响，但它与Egr-2和-3结合，并与它们协同作用以超诱导FasL启动子驱动的报告基因的表达。一个含有单个氨基酸取代的Tat分子，该取代导致HIV长末端重复序列的反式激活活性丧失，仍然能结合Egr-3，但不再增强Egr介导的FasL启动子的反式激活。此外，突变的Tat作为一种显性负性抑制剂，阻断了野生型Tat引起的FasL超诱导。由于Tat存在于病毒感染的细胞以及HIV感染个体的血清中，这些结果表明在这些情况下FasL表达增加可能是由激活诱导的Egr和Tat的协同作用所致。
