Centre for Research in Infectious Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland.
J Virol. 2013 Jul;87(13):7435-44. doi: 10.1128/JVI.00070-13. Epub 2013 Apr 24.
Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). The viral regulatory protein Tax1 plays a pivotal role in T-cell transformation and ATL development. Previous studies in our laboratory, using the yeast 2-hybrid approach to screen a T-cell library for Tax1-interacting partners, identified the cellular Four and a Half Lim domain protein 3 (FHL3) as a possible Tax1-interacting candidate. FHL3 is a member of the FHL family of proteins, which function as transcriptional coactivators and cytoskeleton regulators and have a role in cancer progression and development. The aim of this study was to investigate the physical and functional interaction between Tax1 and members of the FHL family of proteins. We show that Tax1 and FHL3 interact both in vitro and in vivo. Furthermore, both FHL1 and -2 also interact with Tax1. We have demonstrated that FHL3 enhances Tax1-mediated activation of the viral long terminal repeat (LTR) without affecting basal activity and that FHL1 to -3 regulate NF-κB activation by Tax1 in a cell-specific manner. In addition, we have found that the interaction between Tax1 and FHL1 to -3 affects the localization of these proteins, leading to their redistribution in cells. Tax1 also affected FHL3 cytoskeleton function by increasing FHL3-mediated cell spreading. Overall, our results suggest that the interaction between Tax1 and the FHL family alters both the transactivating activity and the subcellular localization of Tax1 and provide new insights into molecular mechanisms that underlie the oncogenic nature of this HTLV-1 protein.
人类 T 细胞白血病病毒 1 型（HTLV-1）是成人 T 细胞白血病（ATL）的病原体。病毒调节蛋白 Tax1 在 T 细胞转化和 ATL 发展中起着关键作用。我们实验室之前的研究使用酵母 2 杂交方法筛选 T 细胞文库中与 Tax1 相互作用的伙伴，鉴定细胞 Four and a Half Lim 结构域蛋白 3（FHL3）为可能的 Tax1 相互作用候选物。FHL3 是 FHL 蛋白家族的成员，作为转录共激活因子和细胞骨架调节剂发挥作用，在癌症进展和发展中发挥作用。本研究旨在研究 Tax1 与 FHL 蛋白家族成员之间的物理和功能相互作用。我们表明 Tax1 和 FHL3 在体内和体外均相互作用。此外，FHL1 和 -2 也与 Tax1 相互作用。我们已经证明 FHL3 增强 Tax1 介导的病毒长末端重复序列（LTR）的激活，而不影响基础活性，并且 FHL1 至 -3 以细胞特异性方式调节 Tax1 诱导的 NF-κB 激活。此外，我们发现 Tax1 和 FHL1 至 -3 之间的相互作用影响这些蛋白质的定位，导致它们在细胞中重新分布。Tax1 还通过增加 FHL3 介导的细胞铺展来影响 FHL3 细胞骨架功能。总体而言，我们的结果表明 Tax1 与 FHL 家族之间的相互作用改变了 Tax1 的转录激活活性和亚细胞定位，并为理解这种 HTLV-1 蛋白的致癌性质的分子机制提供了新的见解。
