Bakre Abhijeet, Wu Weining, Hiscox Julian, Spann Kirsten, Teng Michael N, Tripp Ralph A
Department of Infectious Diseases, University of Georgia, Athens, GA, USA.
Institute of Infection and Global Health, University of Liverpool, Liverpool, UK.
J Gen Virol. 2015 Nov;96(11):3179-3191. doi: 10.1099/jgv.0.000261.
Human respiratory syncytial virus (RSV) is a major health challenge in the young and elderly owing to the lack of a safe and effective vaccine and proven antiviral drugs. Understanding the mechanisms by which viral genes and proteins modulate the host response to infection is critical for identifying novel disease intervention strategies. In this study, the RSV non-structural protein NS1 was shown to suppress miR-24 expression during infection. Lack of NS1 was linked to increased expression of miR-24, whilst NS1 overexpression suppressed miR-24 expression. NS1 was found to induce Kruppel-like factor 6 (KLF6), a transcription factor that positively regulates the transforming growth factor (TGF)-b pathway to induce cell cycle arrest. Silencing of KLF6 led to increased miR-24 expression via downregulation of TGF-β. Treatment with exogenous TGF-β suppressed miR-24 expression and induced KLF6. Confocal microscopy showed co-localization of KLF6 and RSV NS1. These findings indicated that RSV NS1 interacts with KLF6 and modulates miR-24 expression and TGF-β, which facilitates RSV replication.
由于缺乏安全有效的疫苗和经证实的抗病毒药物，人类呼吸道合胞病毒（RSV）对年轻人和老年人构成了重大的健康挑战。了解病毒基因和蛋白质调节宿主对感染反应的机制对于确定新的疾病干预策略至关重要。在本研究中，RSV非结构蛋白NS1在感染期间被证明可抑制miR-24的表达。NS1的缺失与miR-24表达增加有关，而NS1的过表达则抑制miR-24的表达。发现NS1可诱导Kruppel样因子6（KLF6），这是一种转录因子，可正向调节转化生长因子（TGF）-β通路以诱导细胞周期停滞。KLF6的沉默通过下调TGF-β导致miR-24表达增加。用外源性TGF-β处理可抑制miR-24表达并诱导KLF6。共聚焦显微镜显示KLF6和RSV NS1共定位。这些发现表明RSV NS1与KLF6相互作用并调节miR-24表达和TGF-β，从而促进RSV复制。
