Secretion and extracellular function of the human T cell leukemia virus trans-activator protein Tax.

摘要

HTLV-I is the etiologic agent of ATL and HAM/TSP. The viral oncoprotein Tax is critically involved in the pathogenesis of HTLV-I. While Tax has traditionally been described as a transcriptional trans-activator, cytoplasmic Tax likely plays an important role in HTLV-I pathogenesis. Studies have suggested that cytoplasmic Tax plays interfaces with the NF-κB signaling pathway and the cellular secretory pathway. In addition, Tax has been identified in a cell-free form in both the peripheral blood and CSF of HAM/TSP patients. Extracellular Tax has been shown to mediate a variety of effects, including inducing the production and release of several pro-inflammatory cytokines. The purpose of this Thesis is three-fold: to identify the cytoplasmic proteins and cellular structures that Tax interacts with to facilitate its movement through cells, to determine the identity of amino acid motifs within Tax that may facilitate its transport through the secretory pathway, and to examine the function of extracellular Tax.;The release of Tax may occur through either of three distinct mechanisms: apoptosis, necrosis, or secretion. Secretion of Tax likely serves as an important mechanism of Tax release. Studies have been initiated to identify cellular proteins within the secretory pathway that interact with Tax. Antibody array analysis identified a number of Tax-interacting proteins. In addition, it appears that Tax moves along microtubules using the motor protein kinesin. In addition, the carboxy-terminal domain of Tax contains several putative secretory signals. We have demonstrated that two signals in particular, 312YTNI315 and 330DHE332 are important for the proper subcellular localization of Tax.;Finally, it was important to extend observations concerning the function of extracellular Tax. HAM/TSP patients have a highly stimulated Tax-specific CTL compartment. In order for CD8+ T cells to become activated, antigen must be presented via MHC class I to CD8+ T cells. APCs are critical to this process, and DCs are potent APCs. We show that extracellular Tax aids in DC maturation and activation. We have demonstrated that extracellular Tax renders DCs less capable of presenting an MHC class I-restricted antigen. This has suggested that Tax may induce functional alterations in DCs with regard to their maturation.