HTLV-1 Tax nucleocytoplasmic shuttling, interaction with the secretory pathway, extracellular signaling, and implications for neurologic disease

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Abstract
The human T cell leukemia virus type 1 (HTLV-1) oncoprotein Tax interacts with numerous cellular pathways promoting both the survival and pathogenesis of the virus in the human population. Tax has been studied extensively with respect to its role in transcriptional transactivation and its involvement in the up-regulation of a number of cellular genes during the process of oncogenic transformation. These processes are dependent on Tax localization to the nucleus where it interacts with a number of cellular transcription factors during its course of nuclear action. However, there is mounting evidence suggesting that Tax may shuttle between the nucleus and cytoplasm, localize to several cytoplasmic organelles with subsequent secretion from both Tax-transfected cells as well as HTLV-1-infected cells. In addition, the presence of cell-free Tax in cerebral spinal fluid (CSF) was recently demonstrated to occur during all stages of HAM/TSP. This has brought about an increased interest in the cytoplasmic localization of Tax and the implications this localization may have with respect to the progression of HTLV-1-associated disease processes. This review addresses the functional implications relevant to the localization and accumulation of Tax in the cytoplasm including the Tax amino acid signals and cellular protein interactions that may regulate this process. Specifically, we have discussed three important processes associated with the cytoplasmic localization of Tax. First, the process of Tax shuttling between the nucleus and cytoplasm will be described and how this process may be involved in regulating different transcriptional activation pathways. Second, cytoplasmic localization of Tax will be discussed with relevance to Tax secretion and the interaction of Tax with proteins in the cellular secretory pathway. Finally, the secretion of Tax and the effects of extracellular Tax on HTLV-1 pathogenesis will be addressed.