The Role Of HTLV-1 Tax In Regulation Of Apoptosis And Autophagy And Its Molecular Mechanism

Human T-cell leukemia virus type 1 (HTLV-1) is an etiologic agent of adult T-cell leukemia/lymphoma (ATL) and tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HTLV-1 transactivator protein Tax is essential for malignant transformation of CD4+T cells, ultimately leading to ATL. HTLV-1-infected lymphocytes can also transmigrate into the central nervous system (CNS) through the blood-brain barrier (BBB), then damage the glial cells and neural cells, and release lots of cytokines and chemokines. Meanwhile, HTLV-1 carried by lymphocytes may also infect glial and neural cells then affect their normal function, thus finally cause TSP/HAM.The viral Tax protein is considered to play a central role in the process leading to HTLV-1 related diseases. Tax could activate regulatory factors involved in T cell replication, and cause transformation of CD4+T cells. Tax also interferes with DNA repair and then increases the genetic instability. In addition, Tax protects HTLV-1 infected cells from cell cycle arrest and apoptosis, so facilitats HTLV-1 escape from immune surveillance. Tax-mediated activation of CREB/ATF and NF-κB is critical for its biological functions. Cells expressing Tax are resistant to FasL-and TRAIL-induced apoptosis by activation of NF-κB. It was reported that T cell transformation also depends on Tax-mediated NF-κB activation.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is also designated as Apo-2 ligand (Apo2L), is a typical member of the structurally related TNF family. TRAIL has been known to induce apoptosis in a variety of tumor cells and some virally infected cells, but not in most normal cells. Thus, TRAIL and TRAIL death receptor (DR4, DR5) specific agonistic antibodies have attracted considerable attention for their potential use in cancer therapy.In this study, we investigated the effect of HTLV-1 Tax on TRAIL-mediated apoptosis, autophagy and related molecular mechanism. We showed that Tax could inhibit TRAIL or a DR5 agonistic antibody (AD5-10) induced apoptosis. Tax could upregulate the expression of c-FLIP, and stimulate autophagy. Knockdown c-FLIP with shRNA or pharmacological inhibitor 3-MA of autophagy could both inhibit the anti-apoptosis activity of Tax and reverse the cell resistance to TRAIL. Tax mutant-M22 could not induce autophagy or c-FLIP expression, and we further demonstrated that the regulation of Tax to c-FLIP and autophagy was dependent on the Tax ability of activate IKKa/p/y. Knockdown IKKα/βreduced c-FLIP expression and inhibited autophagy induced by Tax, however, knockdown p65 or overexpression IκBα-DN suppressed only c-FLIP expression, but not autophagy, indicating that Tax mediated c-FLIP expression is through Tax-IKK-NF-KB signal pathway, but Tax induced autophagy is dependent on activation of IKK and independent on NF-κB. We also demonstrated that TRAIL induced the degradation of Tax, which could be enhanced by autophagy inhibition or c-FLIP knockdown.In summary, Tax inhibits the death receptor-mediated apoptosis not only by upreglation c-FLIP, but also by induction of autophagy. The regulation of apoptosis and autophagy by Tax may shed light on a novel therapeutic strategy for HTLV-1 induced diseases by inhibiting autophagy.