Human
T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of
adult T cell leukemia (ATL) and
HTLV-1-associated myelopathy/
tropical spastic paraparesis (HAM/TSP). The HTLV-1 transcriptional
transactivator protein Tax plays an integral role in virus replication and
disease progression. Traditionally, Tax is described as a
nuclear protein where it performs its primary role as a transcriptional
transactivator. However, recent studies have clearly shown that Tax can also be localized to the cytoplasm where it has been shown to interact with a number of host
transcription factors most notably
NF-kappaB, constitutive expression of which is directly related to the T cell transforming properties of Tax in ATL patients. The presence of a functional
nuclear export signal (NES) within Tax and the secretion of full-length Tax have also been demonstrated previously. Additionally, release of Tax from HTLV-1-infected cells and the presence of cell-free Tax was demonstrated in the CSF of HAM/TSP patients suggesting that the progression to HAM/TSP might be mediated by the ability of Tax to function as an extracellular
cytokine. Therefore, in both ATL and HAM/TSP Tax nuclear export and nucleocytoplasmic shuttling may play a critical role, the mechanism of which remains unknown. In this study, we have demonstrated that the
calcium binding protein calreticulin interacts with Tax by co-immunoprecipitation. This interaction was found to localize to a region at or near the nuclear membrane. In addition, differential expression of
calreticulin was demonstrated in various cell types that correlated with their ability to retain cytoplasmic Tax, particularly in astrocytes. Finally, a comparison of a number of HTLV-1-infected T cell lines to non-infected T cells revealed higher expression of
calreticulin in infected cells implicating a direct role for this
protein in HTLV-1
infection.