HTLV-1 Tax Mediated Downregulation of miRNAs Associated with Chromatin Remodeling Factors in T Cells with Stably Integrated Viral Promoter
HTLV-1 Tax Mediated Downregulation of miRNAs Associated with Chromatin Remodeling Factors in T Cells with Stably Integrated Viral Promoter
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DOI：
10.1371/journal.pone.0034490
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发表时间：
2012-04-04
期刊：
影响因子：
3.7
通讯作者：
Jain, Pooja
中科院分区：
文献类型：
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作者：
Rahman, Saifur;Quann, Kevin;Jain, Pooja
RNA干扰（RNAi）是一种使基因表达沉默的天然细胞机制，主要由靶向信使RNA的微小RNA（miRNA）介导。病毒可通过靶向宿主RNAi机制来操纵其复制所必需的细胞过程。本研究利用CD4(+) T细胞系Jurkat，在染色体整合的病毒长末端重复序列（LTR）背景下，探讨了人类T细胞白血病病毒1型（HTLV - 1）反式激活蛋白Tax对RNAi通路的影响。对转染Tax的稳定整合HTLV - 1 LTR的T细胞克隆进行转录因子分析表明，与染色质重塑复合物相关的底物和因子的激活增加。通过微小RNA微阵列和生物信息学实验方法，还发现Tax下调了与染色质重塑所需因子的翻译调控相关的微小RNA的表达。这些观察结果通过选定的微小RNA以及HTLV - 1感染的T细胞系MT - 2得到了验证。发现miR - 149和miR - 873能够直接靶向p300和p/CAF，这两种染色质重塑因子已知在HTLV - 1发病机制中起关键作用。总体而言，这些结果首次确立了HTLV - 1/Tax - miRNA - 染色质的概念，并为理解特定细胞类型中逆转录病毒的潜伏和/或复制开辟了新途径。
RNA interference (RNAi) is a natural cellular mechanism to silence gene expression and is predominantly mediated by microRNAs (miRNAs) that target messenger RNA. Viruses can manipulate the cellular processes necessary for their replication by targeting the host RNAi machinery. This study explores the effect of human T-cell leukemia virus type 1 (HTLV-1) transactivating protein Tax on the RNAi pathway in the context of a chromosomally integrated viral long terminal repeat (LTR) using a CD4(+) T-cell line, Jurkat. Transcription factor profiling of the HTLV-1 LTR stably integrated T-cell clone transfected with Tax demonstrates increased activation of substrates and factors associated with chromatin remodeling complexes. Using a miRNA microarray and bioinformatics experimental approach, Tax was also shown to downregulate the expression of miRNAs associated with the translational regulation of factors required for chromatin remodeling. These observations were validated with selected miRNAs and an HTLV-1 infected T cells line, MT-2. miR-149 and miR-873 were found to be capable of directly targeting p300 and p/CAF, chromatin remodeling factors known to play critical role in HTLV-1 pathogenesis. Overall, these results are first in line establishing HTLV-1/Tax-miRNA-chromatin concept and open new avenues toward understanding retroviral latency and/or replication in a given cell type.