SRSF1 RNA Recognition Motifs Are Strong Inhibitors of HIV-1 Replication.
SRSF1 RNA Recognition Motifs Are Strong Inhibitors of HIV-1 Replication.
复制标题
SRSF1 RNA 识别基序是 HIV-1 复制的强抑制剂。
DOI：
10.1128/jvi.00693-15
复制
发表时间：
2015
影响因子：
5.4
通讯作者：
Caputi,Massimo
中科院分区：
文献类型：
--
作者：
Paz,Sean;Lu,MichaelL;Takata,Hiroshi;Trautmann,Lydie;Caputi,Massimo
整合的HIV-1基因组的复制受到一系列细胞因子的严格调控。在以前的工作中，我们表明，HIV-1启动子的反式激活是由细胞剪接因子SRSF 1调节的。在这里，我们报告说，SRSF 1可以下调复制的B，C和D亚型病毒在细胞培养系统中的200倍以上。我们发现，SRSF 1表达抑制病毒的转录和剪接。此外，含有蛋白质RNA结合结构域但不含有富含精氨酸丝氨酸的激活剂结构域的SRSF 1缺失突变体可以将病毒复制下调> 2，000倍，而对细胞活力和细胞凋亡的影响最小。这些数据表明SRSF 1及其RNA结合域的治疗潜力。重要信息大多数用于治疗HIV-1感染的药物是基于直接靶向病毒编码蛋白的化合物。然而，鉴于病毒突变率高，新的耐药病毒株的出现是常见的。因此，需要具有不同作用机制的新型治疗剂。在这项研究中，我们表明，细胞蛋白SRSF 1是一个强大的病毒复制抑制剂。此外，SRSF 1 RNA结合结构域的单独表达可以在多种病毒株中抑制病毒复制> 2，000倍，而不影响细胞活力。考虑到这种蛋白质的强抗病毒特性、RNA结合结构域以及观察到的对细胞代谢的最小影响，有必要进行进一步研究以评估源自这些序列的肽的治疗潜力。
Replication of the integrated HIV-1 genome is tightly regulated by a series of cellular factors. In previous work we showed that transactivation of the HIV-1 promoter is regulated by the cellular splicing factor SRSF1. Here we report that SRSF1 can downregulate the replication of B, C, and D subtype viruses by >200-fold in a cell culture system. We show that viral transcription and splicing are inhibited by SRSF1 expression. Furthermore, SRSF1 deletion mutants containing the protein RNA-binding domains but not the arginine serine-rich activator domain can downregulate viral replication by >2,000-fold with minimal impact on cell viability and apoptosis. These data suggest a therapeutic potential for SRSF1 and its RNA-binding domains.IMPORTANCEMost drugs utilized to treat the HIV-1 infection are based on compounds that directly target proteins encoded by the virus. However, given the high viral mutation rate, the appearance of novel drug-resistant viral strains is common. Thus, there is a need for novel therapeutics with diverse mechanisms of action. In this study, we show that the cellular protein SRSF1 is a strong inhibitor of viral replication. Furthermore, expression of the SRSF1 RNA-binding domains alone can inhibit viral replication by >2,000-fold in multiple viral strains without impacting cell viability. Given the strong antiviral properties of this protein, the RNA-binding domains, and the minimal effects observed on cell metabolism, further studies are warranted to assess the therapeutic potential of peptides derived from these sequences.