Human T cell leukemia virus type 1 Tax associates with a molecular chaperone complex containing hTid-1 and Hsp70

Abstract

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.

TID1, a mammalian homologue of the drosophila tumor suppressor lethal(2) tumorous imaginal discs, regulates activation-induced cell death in Th2 cells

“…The major Tid protein pool is localized to the mitochondria before and after activation of Jurkat or D10 cells (data not shown) consistent with all other reports where Tid localization has been analysed (Syken et al, 1999;Cheng et al, 2001;Sarkar et al, 2001;Trentin et al, 2001). Like in the osteosarcoma cell line U2OS, TidS affected activation of caspase 3 but not caspase 8 in Th2 cells, which would be consistent with the model that Tid proteins can affect mitochondrial aspects of apoptosis, even though no mitochondrial targets of Tid proteins have been identified yet.…”

“…This is consistent with our finding that despite similar caspase-8 activity, caspase-3 activity in the H121Q-TidS-expressing D10 cells is higher than in D5 Th1 cells (Figure 4). Recent reports have provided evidence for the existence of nonmitochondrial pools of Tid proteins (Cheng et al, 2001;Sarkar et al, 2001;Trentin et al, 2001;K Edwards and K Mu¨nger, unpublished), and human Tid protein was originally cloned as a cellular target of the predominantly nuclear human papillomavirus E7 oncoprotein (Schilling et al, 1998). Tid proteins have also reported to interact with other nonmitochondrial viral proteins, including HTLV-1 tax that induces marked cytoplasmic relocalization of Tid (Cheng et al, 2001).…”

“…Recent reports have provided evidence for the existence of nonmitochondrial pools of Tid proteins (Cheng et al, 2001;Sarkar et al, 2001;Trentin et al, 2001;K Edwards and K Mu¨nger, unpublished), and human Tid protein was originally cloned as a cellular target of the predominantly nuclear human papillomavirus E7 oncoprotein (Schilling et al, 1998). Tid proteins have also reported to interact with other nonmitochondrial viral proteins, including HTLV-1 tax that induces marked cytoplasmic relocalization of Tid (Cheng et al, 2001). In addition to mitochondrial hsp70 (Syken et al, 1999) Tid proteins can also interact with cytoplasmic hsc70 (Sarkar et al, 2001;Trentin et al, 2001), and several nonmitochondrial cellular target proteins of the Tid/hsc70 complex have been identified.…”

“…The TID1-encoded protein was originally isolated in a yeast two-hybrid screen with the human papillomavirus E7 oncoprotein as a bait (Schilling et al, 1998). Additional viral proteins reported to interact with Tid proteins include the HTLV-1 oncoprotein tax (Cheng et al, 2001), and the herpes simplex virus type 1 UL9 protein (Eom and Lehman, 2002). Ectopic Tid expression interferes with the transformed phenotype of tumor cell lines consistent with a tumor suppressor function of the human Tid proteins (Cheng et al, 2001).…”

The Tumor Suppressor hTid1 Inhibits STAT5b Activity via Functional Interaction

“…This central cysteine-rich domain resembles a zinc finger structure and contains four repeats of the motif CXXCXGXG. Previous reports have shown that this region also interacts with the human T-cell lymphotrophic virus viral protein Tax and the transcription factor Smad7, a downstream signaling effector of BMP (bone morphogenetic protein) (58,59). Interestingly, interaction with Smad7 was shown to alter the development of chicken embryos by inhibiting the signaling induced by BMP.…”