Edery I, Petryshyn R, Sonenberg N
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Cell. 1989 Jan 27;56(2):303-12. doi: 10.1016/0092-8674(89)90904-5.
All mRNAs of human immunodeficiency virus 1 (HIV-1) contain in their 5' untranslated region a sequence termed TAR that responds to trans-activation by the tat (trans-activating) protein. This RNA sequence assumes a stable secondary structure, and its cap structure is relatively inaccessible. Here we report that these structural properties of the TAR sequence underlie the ability of TAR to inhibit in trans the translation of other mRNAs. This mechanism of translation inhibition involves the activation of the double-stranded RNA-dependent kinase (dsl), which in turn phosphorylates the protein synthesis initiation factor 2 (eIF-2). Mutations in the TAR region that diminish the stability of the secondary structure cause a significant reduction in the trans-inhibition. A similar reduction in the dsl activation occurs when TAR is placed further downstream of the cap structure. This is a clear demonstration of a specific naturally occurring mRNA sequence that can activate dsl. We suggest a novel translational regulatory mechanism that interdigitates the activities of eIF-2 and eIF-4F.
人类免疫缺陷病毒1型（HIV-1）的所有信使核糖核酸（mRNA）在其5'非翻译区都含有一个称为反式激活应答元件（TAR）的序列，该序列可对反式激活蛋白（tat）的反式激活作出反应。这个RNA序列具有稳定的二级结构，其帽结构相对难以接近。我们在此报告，TAR序列的这些结构特性是TAR反式抑制其他mRNA翻译能力的基础。这种翻译抑制机制涉及双链RNA依赖性激酶（dsl）的激活，而dsl又会使蛋白质合成起始因子2（eIF-2）磷酸化。TAR区域中降低二级结构稳定性的突变会导致反式抑制作用显著降低。当TAR置于帽结构下游更远的位置时，dsl激活也会有类似程度的降低。这清楚地证明了一种能激活dsl的特定天然存在的mRNA序列。我们提出了一种新的翻译调控机制，该机制将eIF-2和eIF-4F的活性相互交织在一起。
