Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax/rex mRNA Are RxRE/Rex Dependent
Nuclear Export and Expression of Human T-Cell Leukemia Virus Type 1 tax/rex mRNA Are RxRE/Rex Dependent
复制标题
DOI：
10.1128/jvi.06361-11
复制
发表时间：
2012-04-01
影响因子：
5.4
通讯作者：
Nicot, C.
中科院分区：
文献类型：
--
作者：
Bai, X. T.;Sinha-Datta, U.;Nicot, C.
人t细胞白血病病毒1型（HTLV-1）是一种复杂的逆转录病毒，与淋巴细胞增生性疾病成人t细胞白血病/淋巴瘤（ATL）和神经退行性疾病热带痉挛性截瘫/HTLV-1相关脊髓病（TSP/HAM）相关。HTLV-1的复制受两种主要的反式作用蛋白Tax和Rex的控制。先前的研究表明，Tax通过募集细胞CREB和转录辅激活因子激活病毒长末端重复序列（LTR）的转录。其他研究报道，Rex在转录后起作用，并允许细胞质输出未剪接或不完全剪接的仅携带gag/pol和env的病毒mrna。与HIV的Rev-responsive element （RRE）相反，Rex-responsive element （RxRE）存在于HTLV-1的所有病毒mrna中。然而，基于间接观察，我们认为核输出和双剪接的tax/rex RNA的表达是与rex无关的。在这项研究中，我们证明了Rex确实通过细胞核胞质输出Tax / Rex RNA刺激了Tax的表达，尽管存在一个与Rex无关的基础输出机制。这种作用依赖于RxRE元件和Rex的rna结合活性。此外，rex介导的tax/rex RNA的输出依赖于CRM1，并被leptomycin B抑制。RNA免疫沉淀（RNA- ip）实验证实，在HTLV-1分子克隆转染细胞和HTLV-1感染的T细胞中，Rex与tax/ Rex RNA结合。由于Rex和p30都与tax/ Rex RNA相互作用，这可能提供了HTLV-1复制的时间和动态调控。我们的研究结果揭示了HTLV-1的复制，并揭示了一个比之前预期的更复杂的调控网络。
Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with the lymphoproliferative disease adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Replication of HTLV-1 is under the control of two major trans-acting proteins, Tax and Rex. Previous studies suggested that Tax activates transcription from the viral long terminal repeat (LTR) through recruitment of cellular CREB and transcriptional coactivators. Other studies reported that Rex acts posttranscriptionally and allows the cytoplasmic export of unspliced or incompletely spliced viral mRNAs carrying gag/pol and env only. As opposed to HIV's Rev-responsive element (RRE), the Rex-responsive element (RxRE) is present in all viral mRNAs in HTLV-1. However, based on indirect observations, it is believed that nuclear export and expression of the doubly spliced tax/rex RNA are Rex independent. In this study, we demonstrate that Rex does stimulate Tax expression, through nuclear-cytoplasmic export of the tax/rex RNA, even though a Rex-independent basal export mechanism exists. This effect was dependent upon the RxRE element and the RNA-binding activity of Rex. In addition, Rex-mediated export of tax/rex RNA was CRM1 dependent and inhibited by leptomycin B treatment. RNA immunoprecipitation (RNA-IP) experiments confirmed Rex binding to the tax/rex RNA in both transfected cells with HTLV-1 molecular clones and HTLV-1-infected T cells. Since both Rex and p30 interact with the tax/rex RNA and with one another, this may offer a temporal and dynamic regulation of HTLV-1 replication. Our results shed light on HTLV-1 replication and reveal a more complex regulatory network than previously anticipated.