Identification of a novel motif responsible for the distinctive transforming activity of human T-cell leukemia virus (HTLV) type 1 Tax1 protein from HTLV-2 Tax2

Abstract

Background: Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia (ATL), whereas its relative HTLV-2 is not associated with any malignancies including ATL. HTLV-1 Tax1 transformed a T-cell line from interleukin (IL)-2-dependent growth to IL-2-independent growth, with an activity that was much more potent in comparison to HTLV-2 Tax2. This distinction was mediated by at least two Tax1 specific functions, an interaction with host cellular factors through the PDZ domain binding motif (PBM) and the activation of NF-kappaB2 (NF-κB2)/p100.

Ubiquitin-Specific Peptidase 20 Targets TRAF6 and Human T Cell Leukemia Virus Type 1 Tax To Negatively Regulate NF-κB Signaling

“…Activation of NF-B contributes to cellular transformation by HTLV-1, and Tax is a potent activator of NF-B (15,29,42). Protein ubiquitination plays an important role in signal transduction; indeed, individual NF-B pathway constituents are frequently ubiquitinated when cells are stimulated (4,14,36).…”

“…Tax (29) can potently activate NF-B through both the canonical and noncanonical pathways (15,42,45). Tax was recently found to inhibit A20 function by disrupting its interaction with TAX1BP1 and Itch (39).…”

Human T Cell Leukemia Virus Type 2 Tax-Mediated NF-κB Activation Involves a Mechanism Independent of Tax Conjugation to Ubiquitin and SUMO

“…Depending on the nature of the inducing signal, NF-B may become activated either through the canonical or the noncanonical pathway. In contrast to Tax2, which activates only the canonical pathway, Tax1 constitutively activates both pathways (25,27,(36)(37)(38)(39)(40)(41). The molecular determinant of the ability to activate the noncanonical pathway has been mapped to Tax1 aa 225 to 232 (41).…”

Roles of HTLV-1 Tax in Leukemogenesis of Human T-Cells

“…These are consequences of interaction of Tax1 with IKK complex. In contrast, although Tax2 can activate the canonical pathway to a level comparable to Tax1, Tax2 rarely induces the p100 processing because of lacking the LZR and PBM regions (Higuchi et al, 2007, Shoji et al, 2009). Recent studies demonstrate that Tax2 induces expression of IL-2, but Tax1 fails to induce IL-2 production (Figure 3) (Niinuma et al, 2005).…”

“…Differences in functional domains between Tax1 and Tax2 has been demonstrated. Tax1 possesses a leucine zipper like region (LZR) within amino acids 225-232 and the PDZ binding motif (PBM) at C-terminus, which are responsible for Tax1-mediated p100 processing and p52 nuclear translocation (Higuchi et al, 2007, Shoji et al, 2009). The NF-B pathway is tightly controlled in normal T-cells, and transiently activated upon immune stimulation.…”