Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70
Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70
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DOI：
10.1016/s0960-9822(01)00540-1
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发表时间：
2001-11-13
期刊：
影响因子：
9.2
通讯作者：
Cheng-Mayer, C
中科院分区：
文献类型：
--
作者：
Cheng, H;Cenciarelli, C;Cheng-Mayer, C
Tax 是一种由人类 T 细胞白血病病毒 1 型 (HTLV-1) 编码的致癌病毒蛋白，通过调节多种细胞基因表达来诱导 T 淋巴细胞的细胞转化 [1]。识别与 Tax 相互作用的细胞伙伴是阐明 Tax 诱导转化的分子基础的第一步。在这里，我们报告了一种新型的 Tax 相互作用蛋白 hTid-1。 hTid-1 是果蝇肿瘤抑制蛋白 Tid56 的人类同源物，最初是根据其与 HPV-16 E7 癌蛋白的相互作用来表征的 [2]。 hTid-1 和 Tid56 是 DnaJ 家族的成员 [2, 3]，该家族包含高度保守的特征 J 结构域，可通过充当辅助伴侣来调节热休克蛋白 70 (Hsp70) 的活性 [4-6]。在这种情况下，分子伴侣复合物参与与细胞凋亡、蛋白质折叠和膜易位相关的细胞信号传导途径，以及肿瘤抑制蛋白（包括视网膜母细胞瘤、p53 和 WT1）活性的调节[7-12]。我们发现 hTid-1 的表达抑制两种人肺腺癌细胞系的转化表型。我们发现 Tax 通过 hTid-1 的中央富含半胱氨酸的结构域与 hTid-1 相互作用，而 hTid-1 的特征 J 结构域介导其与 HEK 细胞中的 Hsp70 的结合。重要的是，Tax 与包含 hTid-1 和 Hsp70 的分子伴侣复合物结合，并改变 hTid-1 和 Hsp70 的细胞定位。在没有 Tax 的情况下，hTid-1/Hsp70 分子复合物的表达靶向核周线粒体簇。在存在 Tax 的情况下，hTid-1 及其相关的 Hsp70 被隔离在细胞质“热点”结构中，这种亚细胞分布是 HEK 细胞中 Tax 的特征。
Tax, an oncogenic viral protein encoded by human T cell leukemia virus type 1 (HTLV-1), induces cellular transformation of T lymphocytes by modulating a variety of cellular gene expressions [1]. Identifying cellular partners that interact with Tax constitutes the first step toward elucidating the molecular basis of Tax-induced transformation. Here, we report a novel Tax-interacting protein, hTid-1. hTid-1, a human homolog of the Drosophila tumor suppressor protein Tid56, was initially characterized based on its interaction with the HPV-16 E7 oncoprotein [2]. hTid-1 and Tid56 are members of the DnaJ family [2, 3], which contains a highly conserved signature J domain that regulates the activities of heat shock protein 70 (Hsp70) by serving as cochaperone [4-6]. In this context, the molecular chaperone complex is involved in cellular signaling pathways linked to apoptosis, protein folding, and membrane translocation and in modulation of the activities of tumor suppressor proteins, including retinoblastoma, p53, and WT1 [7-12]. We find that expression of hTid-1 inhibits the transformation phenotype of two human lung adenocarcinoma cell lines. We show that Tax interacts with hTid-1 via a central cysteine-rich domain of hTid-1 while a signature J domain of hTid-1 mediates its binding to Hsp70 in HEK cells. Importantly, Tax associates with the molecular chaperone complex containing both hTid-1 and Hsp70 and alters the cellular localization of hTid-1 and Hsp70. In the absence of Tax, expression of the hTid-1/Hsp70 molecular complex is targeted to perinuclear mitochondrial clusters. In the presence of Tax, hTid-1 and its associated Hsp70 are sequestered within a cytoplasmic "hot spot" structure, a subcellular distribution that is characteristic of Tax in HEK cells.