Murphy Jane, Hall William W, Ratner Lee, Sheehy Noreen
Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Virology. 2016 Jul;494:129-42. doi: 10.1016/j.virol.2016.04.012. Epub 2016 Apr 22.
The human T-cell leukaemia virus type 1 and type 2 (HTLV-1/HTLV-2) antisense proteins HBZ and APH-2 play key roles in the HTLV lifecycles and persistence in the host. Nuclear Factors Associated with double-stranded RNA (NFAR) proteins NF90/110 function in the lifecycles of several viruses and participate in host innate immunity against infection and oncogenesis. Using GST pulldown and co-immunoprecipitation assays we demonstrate specific novel interactions between HBZ/APH-2 and NF90/110 and characterised the protein domains involved. Moreover we show that NF90/110 significantly enhance Tax mediated LTR activation, an effect that was abolished by HBZ but enhanced by APH-2. Additionally we found that HBZ and APH-2 modulate the promoter activity of survivin and are capable of antagonising NF110-mediated survivin activation. Thus interactions between HTLV antisense proteins and the NFAR protein family have an overall positive impact on HTLV infection. Hence NFARs may represent potential therapeutic targets in HTLV infected cells.
人类1型和2型T细胞白血病病毒（HTLV-1/HTLV-2）反义蛋白HBZ和APH-2在HTLV生命周期及在宿主体内的持续存在中发挥关键作用。双链RNA相关核因子（NFAR）蛋白NF90/110在多种病毒的生命周期中发挥作用，并参与宿主针对感染和肿瘤发生的固有免疫。通过谷胱甘肽S-转移酶（GST）沉降和免疫共沉淀试验，我们证明了HBZ/APH-2与NF90/110之间存在特定的新型相互作用，并对相关蛋白结构域进行了表征。此外，我们发现NF90/110显著增强Tax介导的长末端重复序列（LTR）激活，HBZ可消除这一效应，而APH-2则增强该效应。此外，我们发现HBZ和APH-2可调节生存素的启动子活性，并能够拮抗NF110介导的生存素激活。因此，HTLV反义蛋白与NFAR蛋白家族之间的相互作用对HTLV感染具有总体积极影响。因此，NFAR可能是HTLV感染细胞中的潜在治疗靶点。
