Faculty of Engineering, Tokushima Bunri University, Sanuki, Kagawa, Japan.
1] Faculty of Engineering, Tokushima Bunri University, Sanuki, Kagawa, Japan [2] Faculty of Pharmaceutical Science at Kagawa Campus, Tokushima Bunri University, Sanuki, Kagawa, Japan.
Oncogene. 2014 May 1;33(18):2317-28. doi: 10.1038/onc.2013.181. Epub 2013 May 27.
Human T-cell leukemia virus type-1 (HTLV-1) infection causes adult T-cell leukemia (ATL). Modulation of the transcriptional control of cellular genes by HTLV-1 is thought to be associated with the development of ATL. The viral protein HTLV-1 basic leucine-zipper factor (HBZ) has been shown to dysregulate the activity of cellular transcription factors. Here, we demonstrate that HBZ is exported from the nucleus to the cytoplasm, where it activates the mammalian target of rapamycin (mTOR) signaling pathway through an association with growth arrest and DNA damage gene 34 (GADD34). The N-terminal region of HBZ interacts with the C-terminal region of GADD34. HBZ contains a functional nuclear export signal (NES) sequence within its N-terminal region and it is exported from the nucleus via the CRM1-dependent pathway. Nuclear export of HBZ is essential for its interaction with GADD34 and increased phosphorylation of S6 kinase, which is an established downstream target of the mTOR pathway. Starvation-induced autophagy is significantly suppressed by the overexpression of HBZ. These findings indicate that HBZ is actively exported to the cytoplasm, where it dysregulates the function of cellular factors.
人类 T 细胞白血病病毒 1 型（HTLV-1）感染可引起成人 T 细胞白血病（ATL）。人们认为，HTLV-1 对细胞基因转录控制的调节与 ATL 的发生有关。HTLV-1 基本亮氨酸拉链因子（HBZ）病毒蛋白已被证明可扰乱细胞转录因子的活性。在这里，我们证明 HBZ 从细胞核输出到细胞质，在细胞质中通过与生长停滞和 DNA 损伤基因 34（GADD34）结合来激活哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。HBZ 的 N 端区域与 GADD34 的 C 端区域相互作用。HBZ 在其 N 端区域包含一个功能性核输出信号（NES）序列，并且通过 CRM1 依赖性途径从细胞核输出。HBZ 的核输出对于其与 GADD34 的相互作用以及 S6 激酶的磷酸化增加是必需的，S6 激酶是 mTOR 途径的一个已建立的下游靶标。HBZ 的过表达显著抑制饥饿诱导的自噬。这些发现表明 HBZ 被主动输出到细胞质，在细胞质中它会扰乱细胞因子的功能。
