Abstract
Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL), an aggressive CD4+/CD25+ T-cell malignancy and of a severe neurodegenerative disease, HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The chronic activation or deregulation of the canonical and non-canonical nuclear factor kappa B (NF-κB) pathways play a crucial role in tumorigenesis. The HTLV-1 Tax-1 oncoprotein is a potent activator of the NF-κB transcription factors and the NF-κB response is required for promoting the development of HTLV-1 transformed cell lines. The homologous retrovirus HTLV-2, which also expresses a Tax-2 transforming protein, is not associated with ATL. In this review, we provide an updated synopsis of the role of Tax-1 in the deregulation of the NF-κB pathway, highlighting the differences with the homologous Tax-2. Special emphasis is directed toward the understanding of the molecular mechanisms involved in NF-κB activation resulting from Tax interaction with host factors affecting several cellular processes, such as cell cycle, apoptosis, senescence, cell proliferation, autophagy, and post-translational modifications. We also discuss the current knowledge on the role of the antisense viral protein HBZ in down-regulating the NF-κB activation induced by Tax, and its implication in cellular senescence. In addition, we review the recent studies on the mechanism of HBZ-mediated inhibition of NF-κB activity as compared to that exerted by the HTLV-2 antisense protein, APH-2. Finally, we discuss recent advances aimed at understanding the role exerted in the development of ATL by the perturbation of NF-κB pathway by viral regulatory proteins.
Highlights
Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), a malignancy of CD4+/CD25+ T cells and of a chronic inflammatory disease called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Poiesz et al, 1980; Hinuma et al, 1981; Gessain et al, 1985; Gallo et al, 2017)
While HTLV-1 bZip protein (HBZ) is consistently expressed in all ATL cells, Tax is not expressed in approximately 60% of them, even though the HTLV1 proviral genome is integrated and NF-κB is constitutively activated (Zhao, 2016)
HTLV-1 appears to benefit from the antagonistic functions of Tax and HBZ in the deregulation of cellular signaling pathways, resulting in the loss of control of many biological processes such as proliferation and survival of HTLV-1-infected cells
Summary
Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), a malignancy of CD4+/CD25+ T cells and of a chronic inflammatory disease called HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Poiesz et al, 1980; Hinuma et al, 1981; Gessain et al, 1985; Gallo et al, 2017). Adaptor proteins (TRAFs) are recruited to the cytoplasmic domain of the cell membrane tumor necrosis factor receptor (TNF-R) and activate the IKK complex inducing the phosphorylation of IκB inhibitor and the seclusion of NF-κB precursors within the cytoplasm (Sun, 2017) This phenomenon leads to IκB degradation and nuclear translocation of the p50/RelA transcriptional effectors. A recent study has shown that despite HBZ and APH-2 interact with p65/RelA and repress its transactivation activity in transfected cells, they diverge in the induction of p65 degradation since this is not detected in the presence of APH-2 (Panfil et al, 2016) This different effect suggests that the two proteins may adopt different mechanisms to interfere with NF-κB activation.
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