Abstract
BackgroundHuman T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of neoplasia designated Adult T cell Leukaemia (ATL). It is widely accepted that the viral transactivator Tax-1 is the major viral product involved in the onset, but not in the maintenance, of neoplastic phenotype, as only 30–40% of ATL cells express Tax-1. It has been recently demonstrated that HBZ (HTLV-1 bZIP factor), a protein encoded by the minus strand of HTLV-1 genome, constantly expressed in infected cells and in ATL tumor cells, is also involved in the pathogenesis of leukaemia. The full role played by HBZ in oncogenesis is not clarified in detail also because of the limited availability of tools to assess quantitative expression, subcellular location and interaction of HBZ with host factors in ATL.ResultsBy the use of the first reported monoclonal antibody against HBZ, 4D4-F3, generated in our laboratory it has been possible to carefully assess for the first time the above parameters in HTLV-1 chronically infected cells and, most importantly, in fresh leukemic cells from patients. Endogenous HBZ is expressed in speckle-like structures localized in the nucleus. The calculated number of endogenous HBZ molecules varies between 17.461 and 39.615 molecules per cell, 20- to 50-fold less than the amount expressed in HBZ transfected cells used by most investigators to assess the expression, function and subcellular localization of the viral protein. HBZ interacts in vivo with p300 and JunD and co-localizes only partially, and depending on the amount of expressed HBZ, not only with p300 and JunD but also with CBP and CREB2.ConclusionsThe possibility to study endogenous HBZ in detail may significantly contribute to a better delineation of the role of HBZ during HTLV-1 infection and cellular transformation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0186-0) contains supplementary material, which is available to authorized users.
Highlights
Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of neoplasia designated Adult T cell Leukaemia (ATL)
Experiments using cells transfected with tagged HTLV-1 bZIP factor (HBZ) have shown that HBZ interacts with CREB-2 via its bZIP domain resulting in strong inhibition of the CREB-2/Tax-1 interaction instrumental for the activation of HTLV-1 LTR [7]
TGFβ may increase the expression of FoxP3, a marker of regulatory T cells (Tregs) which can be infected by HTLV-1 [23]; this may predispose to the onset of ATL since the CD4+Foxp3+ Treg cell phenotype has been found in ATL leukemic cells [24, 25] this aspect is still controversial [26]
Summary
Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of neoplasia designated Adult T cell Leukaemia (ATL). It has been recently demonstrated that HBZ (HTLV-1 bZIP factor), a protein encoded by the minus strand of HTLV-1 genome, constantly expressed in infected cells and in ATL tumor cells, is involved in the pathogenesis of leukaemia. Experiments using cells transfected with tagged HBZ have shown that HBZ interacts with CREB-2 via its bZIP domain resulting in strong inhibition of the CREB-2/Tax-1 interaction instrumental for the activation of HTLV-1 LTR [7]. The binding of HBZ to JunD does not inhibit the JunD-mediated transcriptional activation of target genes; HBZJunD complex upregulates even the expression of HBZ encoding gene [13, 14]. HBZ inhibits, while Tax-1 activates, the classical Nuclear Factor kappa B (NFkB) pathway by inducing PDLIM2 expression which brings about proteasomal degradation of RelA [17]. HBZ interacts with Smad and C/EBPα in a ternary complex which suppresses C/EBPα signaling pathway, again favoring proliferation of ATL cells [22]. TGFβ may increase the expression of FoxP3, a marker of regulatory T cells (Tregs) which can be infected by HTLV-1 [23]; this may predispose to the onset of ATL since the CD4+Foxp3+ Treg cell phenotype has been found in ATL leukemic cells [24, 25] this aspect is still controversial [26]
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