Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.
Retrovirology. 2012 Dec 3;9:98. doi: 10.1186/1742-4690-9-98.
In contrast with human T-cell leukemia virus type 1 (HTLV-1) that causes ATL (adult T-cell leukemia), HTLV-2 has not been causally linked to malignant disease. The minus strand of the HTLV genomes encode the regulatory proteins HTLV-1 bZIP factor (HBZ) for HTLV-1 and antisense protein of HTLV-2 (APH-2) for HTLV-2. Unlike the viral proteins Tax1 and Tax2, both HBZ and APH-2 are constitutively expressed in infected cells suggesting that they may play important roles in the pathogenesis of these viruses. To date, very little is known about the function of APH-2 except that it inhibits Tax2-mediated transcription of HTLV-2 genes. In the present study, we investigated the role of APH-2 in basal and Tax2B-mediated activation of the AP-1 pathway.
We demonstrate that, unlike HBZ, APH-2 stimulates basal AP-1 transcription by interacting with c-Jun and JunB through its non-conventional bZIP domain. In addition, when Tax2 and APH-2 are co-expressed, they physically interact in vivo and in vitro and APH-2 acts as an inhibitor of Tax2-mediated activation of AP-1 transcription.
This report is the first to document that HTLV-2 can modulate the AP-1 pathway. Altogether our results reveal that, in contrast with HBZ, APH-2 regulates AP-1 activity in a Tax2-dependant manner. As the AP-1 pathway is involved in numerous cellular functions susceptible to affect the life cycle of the virus, these distinct biological properties between HBZ and APH-2 may contribute to the differential pathogenic potential of HTLV-1 and HTLV-2.
与导致 ATL（成人 T 细胞白血病）的人类 T 细胞白血病病毒 1（HTLV-1）不同，HTLV-2 与恶性疾病没有因果关系。HTLV 基因组的负链编码 HTLV-1 的调节蛋白 HTLV-1 bZIP 因子（HBZ）和 HTLV-2 的反义蛋白 APH-2。与病毒蛋白 Tax1 和 Tax2 不同，HBZ 和 APH-2 均在感染细胞中持续表达，这表明它们可能在这些病毒的发病机制中发挥重要作用。迄今为止，除了它抑制 Tax2 介导的 HTLV-2 基因转录外，对 APH-2 的功能知之甚少。在本研究中，我们研究了 APH-2 在基础和 Tax2B 介导的 AP-1 途径激活中的作用。
我们证明，与 HBZ 不同，APH-2 通过其非传统 bZIP 结构域与 c-Jun 和 JunB 相互作用，刺激基础 AP-1 转录。此外，当 Tax2 和 APH-2 共表达时，它们在体内和体外相互作用，并且 APH-2 作为 Tax2 介导的 AP-1 转录激活的抑制剂起作用。
本报告首次证明 HTLV-2 可以调节 AP-1 途径。总之，我们的结果表明，与 HBZ 相反，APH-2 以 Tax2 依赖性方式调节 AP-1 活性。由于 AP-1 途径参与许多细胞功能，容易影响病毒的生命周期，因此 HBZ 和 APH-2 之间这些不同的生物学特性可能有助于 HTLV-1 和 HTLV-2 的不同致病潜力。
