Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
J Gen Virol. 2012 Feb;93(Pt 2):330-340. doi: 10.1099/vir.0.036087-0. Epub 2011 Oct 19.
Herpesvirus saimiri (HVS), a T-lymphotropic monkey herpesvirus, induces fulminant T-cell lymphoma in non-natural primate hosts. In addition, it can immortalize human T-cells in vitro. HVS tyrosine kinase-interacting protein (Tip) is an essential viral gene required for T-cell transformation both in vitro and in vivo. In this study, we found that Tip interacts with the STAT6 transcription factor and induces phosphorylation of STAT6 in T-cells. The interaction with STAT6 requires the Tyr(127) residue and Lck-binding domain of Tip, which are indispensable for interleukin (IL)-2-independent T-cell transformation by HVS. It was also demonstrated that Tip induces nuclear translocation of STAT6, as well as activation of STAT6-dependent transcription in Jurkat T-cells. Interestingly, the phosphorylated STAT6 mainly colocalized with vesicles containing Tip within T-cells, but was barely detectable in the nucleus. However, nuclear translocation of phospho-STAT6 and transcriptional activation of STAT6 by IL-4 stimulation were not affected significantly in T-cells expressing Tip. Collectively, these findings suggest that the constitutive activation of STAT6 by Tip in T-cells may contribute to IL-2-independent T-cell transformation by HVS.
猿猴疱疹病毒 1 型（HVS）是一种 T 淋巴细胞嗜性猴疱疹病毒，可在非自然灵长类宿主中诱导暴发性 T 细胞淋巴瘤。此外，它还可以在体外使人类 T 细胞永生化。HVS 酪氨酸激酶相互作用蛋白（Tip）是一种必需的病毒基因，在体外和体内均需要 T 细胞转化。在本研究中，我们发现 Tip 与 STAT6 转录因子相互作用，并诱导 T 细胞中 STAT6 的磷酸化。与 STAT6 的相互作用需要 Tip 的 Tyr（127）残基和 Lck 结合域，这对于 HVS 引起的 IL-2 非依赖性 T 细胞转化是必不可少的。还证明了 Tip 诱导 STAT6 的核易位以及 Jurkat T 细胞中 STAT6 依赖性转录的激活。有趣的是，磷酸化的 STAT6 主要与 T 细胞中含有 Tip 的囊泡共定位，但在核内几乎检测不到。然而，在表达 Tip 的 T 细胞中，IL-4 刺激引起的磷酸化 STAT6 的核易位和 STAT6 的转录激活并没有受到显著影响。总之，这些发现表明 Tip 在 T 细胞中对 STAT6 的组成性激活可能有助于 HVS 的 IL-2 非依赖性 T 细胞转化。
