Physical and Functional Interaction between the Human T-Cell Lymphotropic Virus Type 1 Tax₁ Protein and the CCAAT Binding Protein NF-Y

Abstract

Human T-cell lymphotrophic virus type 1 (HTLV-1) is the causative agent of the aggressive, usually fatal adult T-cell leukemia (see references 22, 23, 48 and 86 and references therein). Recent reports have linked HTLV-1 with additional and clinically diverse human diseases (31,46,53,59,63,65). The best characterized of these is a progressive demyelinating syndrome termed HTLV-1-associated myelopathy (HAM) or tropical spastic paraparesis (TSP) (see references 22, 23, 48, and 86 and references therein). Because of the long incubation period between viral exposure and disease onset, the mechanism of HTLV-1 pathogenesis is still unclear. It is clear that host cell control of HTLV-1 replication is a primary determinant of virus expression and subsequent disease. Studies on the variation of viral sequences among different infected groups have not revealed any particular determinant which distinguishes onset of a particular HTLV-1 associated disease (18,44,60,74,87,88).In vitro, HTLV-1 has been shown to activate and immortalize human T lymphocytes, resulting in the polyclonal proliferation of infected cells and subsequent oligoclonal or monoclonal growth (26, 43). HTLV-1 contains no known cellular protooncogene, and because there is no preferential site of integration among infected individuals, it is unlikely that insertional mutagenesis is responsible for viral transformation. Several lines of evidence suggest that the viral transcriptional activator Tax contributes to the development of disease (23,28,29,82).Tax, which is essential for viral replication (22,23,48,86), has recently been shown to transform established rodent fibroblasts to anchorage-independent growth (77, 82, 85). Moreover, Tax can transform primary rat embryo fibroblasts in cooperation with activated ras (67) as well as immortalize normal human T lymphocytes when expressed from a herpes simplex virus-based vector (28,29). Finally, transgenic mice carrying the Tax gene frequently develop mesenchymal tumors and neurofibromas (34, 62). These findings suggest that Tax plays a critical role in HTLV-1-associated leukemogenesis.Tax is believed to exert its effect by stimulating viral gene expression and by deregulating expression of cellular genes (22,23,48,86). Tax has been shown to activate transcription of a number of cellular genes involved in cell proliferation, such as those for interleukin-3 (IL-3), IL-2, the IL-2 receptor, granulocyte-macrophage colony-stimulating factor, c-Fos, c-Jun, parathyroid-related protein, and the major histocompatibility complex (MHC) class I (see references 22, 23, 48, and 86 and references therein). The aberrant expression of these growthrelated genes has been implicated in contributing to the establishment of HTLV-1-associated pathogenesis. While Tax does not bind DNA directly, it appears to stimulate RNA synthesis through protein-protein interactions with host cell transcription factors. The most well studied of these interactions is with the ATF/CREB family of transcription factors, which bind to cyclic AMP-responsive...

Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-κB activation

“…The expression levels of immunoglobulin kappa light chain and MHCII DQ-b were up-regulated in the presence of Tax, consistent with two previous reports (Lindholm et al, 1992;Pise-Masison et al, 1997).…”

Major Histocompatibility Complex Class II Transactivator CIITA Is a Viral Restriction Factor That Targets Human T-Cell Lymphotropic Virus Type 1 Tax-1 Function and Inhibits Viral Replication

“…On the basis of these findings, we sought to determine whether NF-YB could exert a similar negative effect on Tax-1 activity. Because a physical interaction between Tax-1 and NF-YB was previously reported (39), and this interaction might interfere with Tax-1 transactivation, we first assessed whether the two factors interact in vivo. Expression vectors for Tax-1 and myc epitope-tagged NF-YB (mNF-YB) were cotransfected in 293T cells.…”

“…CIITA does not bind DNA per se, but it is recruited to the MHC-II promoter via multiple interactions with DNA-bound factors, including CREB, the regulatory factor X (RFX), and nuclear factor Y (NF-Y) complexes (10,24,35). Of note, the B subunit of the NF-Y complex has been shown to bind to Tax-1 (39). Similarly to Tax-1, CIITA forms dimers, and several posttranslational modifications modulate its function (18,31,45,48).…”

Sp Family Members and Nuclear Factor-Y Cooperatively Stimulate Transcription from the Rat Pyruvate Kinase M Gene Distal Promoter Region via Their Direct Interactions

“…Sp1 interacts with p300/CBP (59). NF-YB interacts with Tax1, a potent activator of human T-cell lymphotropic virus type 1 transcription or CBP (60). NF-YB and NF-YC both interact with the TATA-binding protein (61) and the complete NF-Y interacts with P/CAF and GCN5 (62).…”